# SPMM # 01 - 11_Basic_Psychology # 01 - 1. Learning Theory # 1. Learning Theory © SPMM Course 1. Learning Theory The psychological construct of learning refers to the development of a relatively lasting change in behaviour as the result of a single or repeated experience. Non associative learning: These are simple forms of learning demonstrated in lower animals where only single events are used in learning paradigm - no pairing or ‘operation’ on the environment is required. - Habituation is a non-associative learning in which repeated stimulation leads to a reduction in response over time as the organism ‘learns’ the stimulus. - Sensitization is an increase in response to a stimulus as a function of repeated presentations of that stimulus. Similar to habituation, repetition of exposure is required to elicit the learning effect, but the response rates go up, not down (i.e. opposite to the effect seen in habituation). - Pseudoconditioning (cross-sensitization): The emergence of a response to a previously neutral stimulus simply as a result of exposures to a different but powerful stimulus. Associative learning: Here learning occurs through the association of two events. - Classic conditioning: learning takes place through repeated temporal association of two events. The learning organism is passive, respondent (i.e. shows an innate, reflexive response such as salivation) but not instrumental (i.e. does not actively operate on its environment). - Operant conditioning: learning results from consequences of one’s actions – operations. The learning organism actively operates (instrumental) on the environment. - Social learning theory: combines both classic and operant models of learning, and includes cognitive processes and social interaction to be relevant in human learning. Classical conditioning is produced by repeatedly pairing a neutral conditioned stimulus (CS e.g. bell) with an unconditioned stimulus (UCS e.g. food) that naturally evokes an unconditioned response (UCR e.g. salivation). Eventually the neutral stimulus alone eventually evokes the desired response (salivation – now called conditioned response, CR). It is a relatively rapid process and depends upon the nature of the unconditioned stimulus. Pavlov first demonstrated this paradigm in dogs. The development of the association between the CS and the UCR resulting in a CR is called acquisition. For animals this takes around 3 and 15 pairings; if sufficient emotional involvement is present acquisition can occur with even one pairing. Type of conditioning Pairing procedure Delayed or forward conditioning. CS (bell) presented before UCS (food); the CS+ UCS pairing continued till UCR (saliva) appears Backward conditioning. UCS (food) presented before CS (bell) – not useful in animals; used in advertising Simultaneous conditioning. UCS + CS presented together – often the case of learning in © SPMM Course real life situations. Trace conditioning. CS presented and removed before UCS presented – conditioning depends on memory trace. A delay of less than 0.5ms is proposed to be the optimum for trace conditioning. Temporal contiguity (time between stimulus and response) is important for conditioning according to Pavlov. But Rescorla showed that predictability is more important than temporal contiguity in humans i.e. if one can predict painful tooth extraction on hearing the dentist’s drill, then the noise gets conditioned to elicit fear response better than two unconnected, unpredictable events having temporal contiguity. Note that for classical conditioning it is not necessary that the organism understands an association in cognitive terms but such awareness facilitates the learning. Higher-order conditioning refers to the use of an already conditioned stimulus CS1 as UCS for the next level of conditioning and eliciting a CR for another stimulus CS2. In this way second order and subsequently higher order conditioning are possible. Animals do not respond higher than 4th order usually. Pavlovs’ experiments were conducted using human subjects by Watson & Rayner. Watson produced ‘phobia’ in an infant called Little Albert. By exposing him to loud frightening noise whenever he was shown a white rat, eventually Albert became fearful of the white rat, even when he heard no loud noise. A similar fear response was seen when any furry white object was shown to Albert. This ‘spread’ of associative learning from one stimulus to other is called stimulus generalisation. Discrimination is a process diametrically opposite to generalization; in many situations associative learning can be very selective. In such cases, learned responses are made only to specific stimuli and not to other similar stimuli e.g. a child may be afraid of dogs but not all four-legged animals. Extinction: reduction/disappearance of a learned response when the UCS – CS pairing (or the reinforcer in operant conditioning; see below) is not available anymore. Faster extinction may mean weaker learning. Extinction does not mean loss of learning, but only a suppression of behavioural response. Spontaneous recovery refers to regaining a previously extinguished learned response after a period of time. Counter conditioning is a form of classical conditioning where a previously conditioned response is replaced by a new response that may be more desirable. Utilised in behavioural therapy - systematic desensitisation, aversion therapy. Latent inhibition: A delay in learning the association between UCS and CS is seen if previous exposure to an isolated presentation of CS is present. An organism learns an appropriate behaviour after many trials because the right behaviour is followed by appropriate (desirable) consequence. This forms the basis of the concept of operant conditioning; this © SPMM Course phenomenon is termed the law of effect and is often demonstrated using trial-and-error learning experiments originally described by Thorndike. A conditioning that leads to increase in the frequency of behaviour following learning is called reinforcement. A conditioning that leads to decrease in the frequency of behaviour following learning is called punishment. Both reinforcement and punishment can be positive (i.e. something is given) or negative (something is taken away). Positive Reinforcer Food for pressing a lever (given) Negative Reinforcer Ceasing of electric shock on pressing a lever (taken away) Positive Punishment Points on your driving license for speeding (given) Negative Punishment A monetary fine from a parking ticket (taken away) Primary Reinforcer Stimulus affecting biological needs (such as food) Secondary Reinforcer Stimulus reinforcing behaviour associated with primary reinforcers (money, praise) Both positive and negative reinforcement increase the desired response. The use of a “star chart,” with a variable interval schedule so that about 2 or 3 stars are administered per day depending on the good behaviour, and none for bad behaviour. This part would be positive reinforcement by giving something additional to increased the desired response In a patient with OCD, compulsions provide short-term relief of obsessional anxiety via negative reinforcement. When carrying out compulsive rituals, anxiety is reduced acutely. This provides a reinforcement to engage in the compulsions repeatedly - the termination of the aversive anxiety cued by obsessions, increases the compulsive behaviour that removed the anxiety, without addressing the core of obsessions. Reinforcement Schedules A reinforcement schedule refers to how and when behaviour is reinforced on the basis of the number of responses. Reinforcement Schedule Explanation/Example Continuous (aka contingency reinforcement) Reinforcement every time the positive response occurs - e.g. food pellet every time a rat presses a lever in an experiment Partial Only some of the positive responses result in positive reinforcement – the reinforcement is determined by number of responses (ratio) or time (interval) Fixed Interval Reward occurs after a specific period of time regardless of number of responses e.g. a monthly salary irrespective of your level of performance! Variable Interval Reward occurs after a variable (unpredictable) period of time, regardless © SPMM Course of the number of responses e.g. an angler catching a fish - the first may be after 10 minutes, the next after 45, then 5 minutes etc. Fixed Ratio Reward occurs after a specific number of responses e.g. after completing 20 MCQs, you give yourself a coffee (or chocolate) break. Variable Ratio Reward occurs after a random number of responses e.g. gambling slot machines. Your first win of £20 on a gamble may occur after 3 tries; then the next win may not occur even if you play 30 times, while the third win may follow in quick succession after the second. Important points to note:  In fixed schedules, a pause in response is seen after reinforcement as the organism knows the reinforcement will not be happening for some reasonable time or attempts hereafter. The pause for fixed interval schedule is greater than the pause for fixed ratio schedule. When we interpret an operation to be under control (as in fixed schedules) we learn more quickly.  Variable schedules generate a constant rate of response as the chance of obtaining a reward stays the same at any time and for any instance of behaviour. In general, partial schedules are more resistant to extinction than continuous schedule though they take longer to learn. Variable ratios are the most resistant to extinction. This may explain why gambling is such a difficult habit to eradicate.  Another important determinant of operant conditioning is contingency - learning the probability of an event. Premack’s principle (a.k.a. Grandma’s rule): high-frequency behaviour can be used to reinforce lowfrequency behaviour e.g. “eat your greens and you can have dessert”. An existing high-frequency behaviour (eating dessert) is used to reward low-frequency behaviour (eating greens). Avoidance learning: an operant conditioning where an organism learns to avoid certain responses or situations. Avoidance is a powerful reinforcer and often difficult to extinguish. A special form of avoidance is escape conditioning seen in agoraphobia where places in which panic occurs are avoided / escaped from leading to a housebound state eventually. Aversive conditioning: This is an operant conditioning where punishment is used to reduce the frequency of target behaviour e.g. the use of disulfiram (noxious stimuli) to reduce the frequency of drinking alcohol. Covert reinforcement: In covert reinforcement schedules, the reinforcer is an imagined pleasant event rather than any material pleasure e.g. imagining MRCPsych graduation event to reinforce the behaviour of practicing MCQs. Covert sensitization: The reinforcer is the imagination of unpleasant consequences to reduce the frequency of an undesired behaviour e.g. an alcoholic may be deterred from continuing to spend on alcohol by imagining his wife leaving him, being unable to support himself and ending up broke and homeless. © SPMM Course Flooding: An operant conditioning technique where exposure to feared stimulus takes place for a substantial amount of time so the accompanying anxiety response fades away while the stimulus is continuously present e.g. a man with a phobia of heights standing on top of the Burj Khalifa or the Shard. This will lead to the extinction of fear. When a similar technique is attempted with imagined not actual exposure then this is called implosion. Shaping (a.k.a. successive approximation): This is a form of operant conditioning where a desirable behaviour pattern is learnt by the successive reinforcement of behaviours closer to the desired one. Note that shaping is used when the target behaviour is yet to appear (i.e. it is novel and does not exist already). Dog runs towards a wheel but doesn’t jump Runs and makes a jump close to the wheel Runs, jumps through the wheel Runs, jumps through the wheel on fire Circus on show Gets a bone Gets a bone Gets a bone Gets a bone Behaviour is shaped Chaining: This refers to reinforcing a series of related behaviours, each of which provides the cue for the next to obtain a reinforcer. Chaining is used when the target behaviour is already notable in some form but not in the fully formed sequence. An example is teaching a child to write his name. The shape of individual alphabets is first taught using reinforcers and forward chaining can be used to link each alphabet in the correct order, finally reinforcing the completed name. Backward chaining starts at the end e.g. when making cupcakes, the child is first taught how to sprinkle over a fnished cupcake, the next time icing the cake and sprinkleing, the next time placing the prepared cake mixture into cupcake wrappers then icing then sprinkling etc. Incubation: An emotional response increases in strength if brief but repeated exposure of the stimulus is present. Rumination of anxiety-provoking stimuli can serve to increase the anxiety via incubation. This is a powerful mechanism that maintains phobic anxiety and PTSD. Stimulus preparedness (Seligman) explains why snake and spider phobia are commoner than ‘shoe phobia’ or ‘watch phobia’. In evolutionary terms, the stimuli that were threatening to hunter-gatherer men has been hard wired into our system, reflexively eliciting responses immediately – and phobia develops more readily for such ‘prepared stimuli’. Learned helplessness (Seligman): initially put forward as a behavioural model for depression. When confronted with aversive stimuli from which escape is impossible, an animal stops making attempts to escape. This was shown experimentally with a dog on an electrified floor unable to escape. After a while, the dog stopped trying, as if accepting its fate. This paradigm is frequently invoked to explain the dependence seen in victims of domestic abuse. Reciprocal inhibition (Wolpe): If stimulus with desired response and stimulus with the undesired response are presented together repeatedly, then the incompatibility leads to a reduction in frequency of the undesired response. This is evident when your dog barks at your friend; try hugging her in front of © SPMM Course your dog every time the dog barks and slowly the dog will stop barking at your friend. This is used in relaxation therapy for anxiety and in systematic desensitisation. Cueing (a.k.a. prompting): specific cues can be used to elicit specific behaviours – e.g. in a classroom a teacher puts her finger on her lips to reduce chatter and elicit the response of silence. The process of unlearning such cue associations is called fading. Bandura’s social learning theory: Bandura believed that not all learning occurred due to direct reinforcement, and proposed that people could learn simply by observing the behaviour of others and the outcomes. According to behaviourists, learning is defined as a relatively permanent change in behaviour but social learning theorists differentiate actual performance from learning a potential behaviour. Social learning theorists emphasize the role of cognition in learning; awareness and expectations rather than the actual experience of reinforcements or punishments are sufficient to have a major effect on the behaviours that people exhibit. Cognitive processing during social learning: 1. Attention to observed behaviour is the basic element in learning. 2. Visual image and semantic encoding of observed behaviour memory 3. Memory permanence via retention and rehearsal 4. Motor copying of the behaviour and imitative reproduction 5. Motivation to act. Reciprocal causation: Bandura proposed that behaviour can influence both the environment and the individual and each of these three variables, the person, the behaviour, and the environment can have an influence on each other. The most commonly discussed experiment illustrating Bandura’s theory is the Bobo Doll experiment. Children watching a model showing aggression against a bobo doll learnt to display the aggression without any reinforcement schedules. Cognitive learning (Tolman): reinforcement may be necessary for a performance of learned response but not necessary for the learning itself to occur (latent learning). He inferred that rats can make cognitive maps of mazes – called place learning - which consists of cognitive expectations as to what comes next. Insight learning (Kohler) is diametrically opposite to associative learning and views learning as purely cognitive and not based on S-R mechanism - a sudden idea occurs and the solution is learnt. Hierarchy of learning: Gagne’s hierarchy of learning (see the attached table) describes that simple or basic learning steps are prerequisites for later complex learning. This pattern of learning can also be seen during human development and in the hierarchy of evolution. Stages Gagne’s learning hierarchy Classical conditioning (signal learning) Operant conditioning Chaining Verbal association Discrimination learning Concept learning Rule learning Problem solving # 02 - 2. Basic principles of visual and auditory pe # 2. Basic principles of visual and auditory perception © SPMM Course 2. Basic principles of visual and auditory perception When perceiving an object it needs to be differentiated from its background. Determinants of figure vs. ground differentiation include 1. Contour – surroundedness 2. Size 3. Orientation 4. Symmetry This is also influenced by perceptual set (see below). Reversal of figure-ground perception frequently occurs so that sometimes, the ground is perceived as figure and vice versa e.g. try googling for images of Rubin’s vase illusion. This indicates that same stimuli can produce more than one perception. Figure-ground differentiation is also crucial for perceiving auditory stimuli e.g. when we are at a crowded party we are still able to filter our friend’s voice and have a conversation amidst all noisy background (cocktail party phenomenon). Shadowing is an experimental extension of this effect where two different messages are given to the right and the left ear and the subject is asked to follow one and suppress the other. These experiments are called dichotic listening tests (see below for further information in ‘attention’ section). The principle of Gestalt: Gestalt means shape or form; it also refers to the global whole of an object. Gestalt law of perceptual organisation includes According to Gestalt laws, global processing occurs before local processing of components. The whole is different from the sum of its parts. This is true at least for 2 dimensional objects though ecological validity is lower for 3D objects. •Objects close to each other are perceived as one figure Proximity Proximity •Incompletely closed figures are perceived as fully closed Closure Closure •Continuous items are perceived as one object. Continuity Continuity •Similar items are grouped together based on colour or shape etc. Similarity Similarity •Things moving together are perceived as one object. Common fate Common fate © SPMM Course Depth perception depends on pictorial and non-pictorial primary cues. The non-pictorial cues are generally binocular cues and include a. Retinal image disparity b. Stereopsis c. Accommodation (monocular) d. Convergence Pictorial cues (secondary) include largely monocular elements such as a. Size b. Brightness c. Superimposition d. Texture e. Linear perspective (rails converge at distance, wide apart when closer) f. Aerial perspective (colour – blue mountains means a distant sight) g. Motion parallax (closer it is faster it seems) Visual cliff is an apparatus used to test an infant’s perception of depth. A pane of thick glass covers a shallow drop and a deep drop. The underlying surfaces of both deep and shallow sides are covered with the same chequered pattern. Children of six months and older will not venture to the ‘deep side’ and this is taken as an indication that the child can perceive depth. Perceptual constancy is defined as the ability to perceive objects to be the same and unchanging in character despite varied inputs. It consists of 1. Size constancy 2. Shape constancy e.g. a door is always a door no matter which angle it is showing to the viewer 3. Location constancy – movement of the head gets nullified somehow so we do not perceive objects around us getting relocated as we move our head! 4. Brightness, hue and colour constancy Autokinesis refers to the phenomenon that if light is shown from a small, dim, and fixed light source for an extended period of time in a dark room, it will appear as if the light source is moving. This visual illusion can explain UFO sightings and can also affect pilots. The phi phenomenon is a perceptual illusion described by Wertheimer. This refers to the phenomenon in which a false perception of motion is produced by a succession of still images shown with fixed time interval rapidly. Theories of perception: Bottom-up theory: Gestalt is an example of a bottom-up theory. According to bottom up theories, perception is purely data driven and directly starts with the optic array. Piecing together of basic elements of the data gives rise to more complex systems. This makes the original elements sub-systems of the ‘emergent system’. But perception is not just seeing, it is ‘seeing as’. © SPMM Course Top-down theory: Gregory’s constructivist theory is an example of a top-down theory. According to this theory, retinal images are sketchy and cannot explain the complex and fully formed perceptions that we experience. Perception is best defined as a process of using information known already to formulate and test a hypothesis. It is driven from the ‘top down’ – i.e. from higher cortical areas. Illusions such as Muller Lyer (i.e. when you compare >----< and , despite the horizontal line being of same length in both instances, the first one may appear to be longer) support top-down processing. A perceptual set is defined as the readiness to perceive selected features as an object. This is related to the level of motivation e.g. hunger, emotional state, values, beliefs, context and expectations (e.g. UFOs are sighted only by those who believes in them and ‘expects’ them). Illusions and hallucinations Illusion is defined as any perceptual situation in which a physical object is perceived but appears different from what it really is e.g. a white wall appears yellow if a yellow light is shone on it. A hallucination is an experience in which an object (e.g. sound or light) is perceived in the absence of any corresponding object in the real world. A hallucination is often indistinguishable from genuine perception. Human visual perception The development of human visual perception is an illustration of a constitutional-environmental interaction. Most of the time during development, complex visual stimuli such has human faces are preferred. Innate visual processes such as visual scanning, tracking, fixating, figure-ground discrimination are present from birth. Learnt visual processes include size constancy, shape constancy, depth perception, shape discrimination. From birth we have the ability to discriminate brightness and carry out eye tracking, visual acuity is significantly impaired and focusing is fixed at 20cm. At 2-4 months – depth perception is apparent (as evidenced by visual cliff experiments). By 4 months – accommodation and colour vision seems to be present in most children. By 6 months – 6:6 acuity is achieved. # 03 - 3. Information processing and attention # 3. Information processing and attention © SPMM Course 3. Information processing and attention Focused or selective attention refers to the mechanism by which certain information is registered while others are rejected. Capacity or divided attention refers to the upper limit of the amount of processing that can be performed on incoming information at any one time. Many studies of attention have used auditory tasks.  Dichotic listening refers to feeding one message into the left ear and a different message simultaneously into the right ear. Participants have to repeat one of the messages aloud. This process is called Shadowing (first used by Cherry). This is a method to study selective attention. Divided attention can be tested using a dual-task technique whereby the individual is asked to attend and respond to both or all incoming messages.  Cocktail party effect: It is a concept related to selective attention. It is a term used in early attention research ‘to describe the ability of people to be able to switch their attention rapidly to a nonprocessed message’. The cocktail party effect shows that certain types of stimuli can elicit switching between messages e.g. the physical location of the speaker, the pitch of the voice or the use of familiar stimuli such as the listener’s name. (Lunch-queue effect)  Broadbent’s early selection filter theory: o Our ability to process information is capacity limited. o A temporary buffer system receives all information and passes it to a selective filter. o The selection is based on physical characteristics of the information – one source is selected and others are rejected. o Processing two different pieces of information will take longer and will be less efficient as switching takes a substantial period of time.  Triesman’s attenuation theory: o Treisman (1964) proposed that physical characteristics and semantic relevance (meaning) are used to select one message for full processing while other messages are given partial processing.  Deutsch-Norman late selection filter model: o This model rejects Broadbent and suggests that filtering occurs only later, after all inputs are analysed at a higher level. This is also called the pertinence model.  Pigeon-holing: o Later Broadbent revised the early selection filter theory and stated that apart from filtering, pigeon-holing can also take place. STM Selective Filter short term memory sight sound smell Selected stimulus Selected stimulus Senses © SPMM Course o Pigeonholing is similar to filtering but selection is not based on physical characters; it is based on categorization. o E.g. if one is asked to attend to the names of animal (a category) from many stimuli, this will take place irrespective of physical characters such as volume, pitch etc.  Automaticity o Automatic processing:  Does not require conscious attention  Unaffected by capacity limits  Difficult to modify  E.g. driving a car or listening to the radio o Controlled processing:  Requires attention  Heavy demands  Slow and capacity limited  E.g. reading this notes!  Closed loop control: when we first learn a task it is under conscious attention system. When we become skilled at it, open loop control takes over. Open loop is controlled by automatic motor processes. It is fast and allows conscious attention to be diverted to other activities.  Stroop test and letter cancellation tasks can test selective attention. A hierarchical model of attention: Sohlberg and Mateer proposed a clinically useful model of evaluating attention in a hierarchical fashion based on the sequential recovery of attentional ability in patients with brain damage. Five different kinds of activities of growing difficulty are described in the model connecting with the activities that patients could do as they recover gradually. This model has been clinically useful in terms of rehabilitation of brain-damaged patients. Studies of attention in schizophrenia suggest that there is an underlying attentional abnormality for those with a genetic predisposition for psychosis. The overall reaction time is much slower in patients with schizophrenia and their relatives; sustained attention, distraction, verbal memory and controlled processing are also affected. Focused attention The ability to perceive individual items of information (respond discretely to the specific modality of stimuli). Sustained attention The ability to maintain a consistent behavioral response during continuous and repetitive activity. Also called as vigilance or concentration Selective attention The ability to avoid distractions from internal or external cues and maintain a behavioural or cognitive set in the face of competing stimuli. Alternating attention The ability of mental flexibility that allows individuals to shift their focus of attention and move between tasks having different cognitive requirements. Divided attention This is the highest level of attention and it refers to the ability to respond simultaneously to multiple tasks or multiple task demands. It is much more difficult to achieve within same modality (e.g. visual) as it is between different modalities (visual and auditory) # 04 - 4. Memory # 4. Memory © SPMM Course 4. Memory In all cognitive operations involving memory 3 different processes are thought to occur.  Encoding - It leads to the formation of initial memory traces and receives information from the outside.  Storage - Retention of information and maintenance  Retrieval - Accessing and recovering information from memory stores William James divided memory to primary (short term) and secondary memory (long term). In fact 3 forms of memory are now recognised. 1. Sensory memory: This is modality specific, has a large capacity but gets disrupted by the inflow of new information in the same modality. Each sense has its own sensory memory e.g. iconic (visual) lasting 0.5 seconds, echoic (auditory) lasting 2 seconds etc. No processing is involved in sensory memory. If attention is paid to the sensory memories during perception, sensory memory gets consolidated or ‘moves’ into the short-term memory system. 2. Short term memory: The capacity of STM according to Miller is 7+/- 2 items. This is evident while testing digit span (but see below for chunking). Unaided, STM lasts 15 to 30 seconds. By maintenance rehearsal, this duration can be increased further up to indefinite periods. If maintenance rehearsals are prevented, then by 15 seconds the original material is completely forgotten. Brown Paterson task involves introducing distraction (such as counting a three digit number backwards) immediately after the digit span test in order to prevent rehearsal. STM uses acoustic coding (mostly) or visual coding. Recall of information is effortless and usually error-free. Information is held in STM by the process of rehearsal. Loss of information from STM occurs mainly through displacement (newly acquired items entering STM displaces existing material) and decay (older materials have a weaker trace strength than the recently acquired items). In order for memory to move from temporary to long-term storage, elaborative encoding (Daniel Schacter) must take place. NOTE: The term working memory is increasingly used to describe a large part of what was called as STM in the past. Working memory allows cognitive processes to be performed on data that is briefly stored in short-term memory. 3. Long term memory: This has unlimited capacity and lasts for an indefinite duration. The coding is largely semantic, though visual and acoustic coding can occur to some extent. According to Atkinson & Shiffrin, STM and LTM are regarded as structural components. Rehearsal is supposed to be the transient control process that can aid maintenance of STM and transfer to LTM. Other control processes include encoding, retrieval strategies and decision to STM LTM Encoding Acoustic Semantic Retrieval Error-free Error-prone Capacity 7+/-2 chunks Unlimited © SPMM Course remember. Rehearsal may be maintenance/rote rehearsal or elaborative rehearsal where encoding is semantically elaborated or changed. It is proposed that rehearsal can take place at 3 levels of processing. Shallow processing where surface features are only rehearsed, phonemic processing where sound features are rehearsed or semantic processing where deeper encoding and meaning related associations are made. Higher level of processing depends on time available and nature of the material processed. [The terms often used in psychology are short term memory (corresponds to immediate memory in clinical psychiatry) and long term memory (recent memory and remote memory in psychiatry). STM (immediate memory) is tested by the recall of digits immediately after their presentation (Digit span).] Other classifications: Recent memory is the ability to remember what has been experienced within the past few minutes (recall of items after five minutes), hours (recall of last meal), days (recall of recent news items). Remote memory is the ability to remember events in the distant past (weeks to years). This can be tested by inquiring about important dates in their lives such as date of birth, date of marriage, how many siblings they have etc. Tulving elaborated multistore model (LTM) to have two forms - declarative (explicit – includes semantic and episodic memory) and non-declarative (implicit) memory. Procedural or Implicit memory: This cannot be consciously inspected. This is not affected by an organic amnesia of hippocampal origin. It is made of procedural memory for skills and habits, priming, classical conditioning and nonassociative learning. Episodic memory is autobiographical, self-focused, spatio-temporal memory. Semantic memory includes factual knowledge of the world. It is proposed to be made of multiple episodic memory components. Priming is a form of learning that occurs without conscious recall of the episode of learning; performance demonstrates that the information is learnt but conscious episodic recall is absent. Baddley & Hitch proposed a working memory model. Working memory is proposed to have central executive and 2 arms – phonological loop and visuospatial sketchpad. The central executive is capacity limited but modality free, similar to attention system. The phonological loop consists of auditory rehearsal loops while visuospatial scratch pad consists of pattern recognition and movement perception components. It is proposed that dyslexia may be related to erratic phonological loop. The 4th component of WM is sometimes called episodic buffer. This is a multimodal store that integrates info from the slave systems onto LTM. This buffer is important for chunking. Working memory is important for various processes including executive functions, decision-making, error detection and correction, new learning (anterograde memory formation) and judgement. Serial position effect: While memorising and recollecting a list of words both primacy and recency effects are seen. Regardless of the length of a list, the initial words (primacy) and last few words © SPMM Course (recency) are remembered better than those at the middle of the list. Primacy is supposed to be due to LTM as consolidation has occurred in the sufficient time between learning the first word and testing recall. Recency effect is due to STM wherein last heard words are freshly retained. In those with organic anterograde amnesia, recency is better preserved than primacy. Here the problem is in transferring to LTM from STM and/or retrieval from LTM. In retrograde amnesia, the physical establishment of LTM memory (called consolidation) fails. Retrieval: Modes of retrieval (i.e. moving from LTMSTM) are through  Recognition (solving MCQs)  Recall (actively searching and reproducing),  Reintegration/reconstruction (recollection of past experiences based on certain cues). An eyewitness testimony is a reconstructive memory, which is a mode of retrieval from long-term memory. However, reconstructive memory of events as in eyewitness testimony is affected by the type of questioning asked to elicit the memory. Forgetting: Hermann Ebbinghaus plotted the forgetting curve by plotting the proportion of words retained in memory against time. The curve shows a sharp drop over the first nine hours and particularly during the first hour. After nine hours, the rate of forgetting slows and declines little thereafter, even after the lapse of 31 days. The main findings from his and other studies are;  Forgetting is maximum in the first few hours, and the rate of forgetting gets less with time.  Forgetting is never complete, and some information is retained over longer periods of time, even for life.  Recalling the material during the test period increases the probability of remembering items or events.  Continuous motor skills, such as cycling and swimming, show no forgetting at all. But discrete motors skills such as typing are lost more quickly. Problems with encoding (registration), retention or retrieval, can all result in forgetting. Decay theory states that neural engrams breakdown with time. This means that disuse with time is the cause of forgetting, but no evidence exists that neurological decay occurs. Also what happens before and after learning is more important than the mere passage of time in forgetting. FLASHBULB MEMORIES Distinctly vivid long-lasting memories of a personal circumstance surrounding a person’s discovery of shocking events. These are not as accurate or permanent as photographic memories but forgetting curve for the flashbulb memories is far less affected by time than other types of memories. These memories are often associated with important historical or autobiographical events. Such events could include, for example, the 9/11 or 7/7 etc. © SPMM Course Displacement theory states that due to capacity limitation new info replaces old information. Retrieval failure theory states that due to lack of proper cues to recall we forget things. According to encoding specificity principle, anything we encode during learning can be a cue/tag for later retrieval. Recall improves if same cues are available when recalling, but this holds true only for recall, not recognition. Hence, some times recall is better than recognition! Such cues can be the context (place, external state) specific or emotion/ inner state specific. According to interference theory forgetting occurs due to interference. When newly learnt material interferes with recall of old material, this is called retroactive interference. Proactive interference refers to the interference of new learning from older learnt material. There is a low ecological validity for interference model as most experiments were conducted with memorizing word lists, a skill that is rarely required in daily life. Strategies to improve encoding include – order and sorting info, chunking, mnemonics, using imageries, adding importance and salience to the info and using primacyrecency effects. Retrieval can be helped by cueing and reinstatement of learning context. Chunking is a method of increasing the capacity of short-term memory by combining units or information (usually numbers) into chunks. By doing so, impressive feats of memory can result. For example the numbers 1,5,2,3,5.2,5,8,5,3,7,8 would normally overload our short-term memory but if they are arranged into chunks 152, 352, 585, 378, they become a lot more manageable. The more similar the retrieval situation is to the encoding situation, the better retrieval. This is called encoding specificity principle. Amnesia refers to a marked impairment in episodic memory, although other types of memory such as working memory, semantic memory and procedural memory may remain relatively intact. Anterograde Amnesia: The loss of the ability to form or retain new episodic memories after an injury/lesion/event Lack memory for events taking place in immediate future after an event Classic cases often involve hippocampal damage The subject cannot learn anything new. Nothing can be moved from STM to LTM. RIBOT’S GRADIENT Theodule Ribot first suggested that recent memories might be more vulnerable to brain damage than remote memories in 1881. After damage to the hippocampal memory system, patients tend to lose more of their recent than of their remote memories. This pattern, unique to organic amnesia, is called the Ribot gradient. This may be related to the dependence of retrieval on hippocampal systems, while consolidation gradually ‘pushes’ stored memories to the neocortex, making them independent of the hippocampal system. © SPMM Course Retrograde Amnesia: The loss of episodic memories that were stored before brain damage had occurred.  Lack memory for immediately preceding events.  Follows head injury  The subject never consolidates the information that is already in STM (retrieval failure i.e. fails to move from LTM to STM). Transient global amnesia is caused by transient cerebral ischemia causing a temporary lack of blood supply to the regions of the brain concerned with memory functions. The main features include sudden onset of severe anterograde amnesia with a retrograde amnesia for the preceding days or weeks. Sometimes amnesic episodes may occur in patients who have had no brain injury but suffered a traumatic or emotionally disturbing life event (hysterical or psychogenic amnesia). There are two types-Global and situation specific. Fugue state is a type of psychogenic global amnesia in which there is a sudden loss of all autobiographical memories, knowledge of self and personal identity. Usually, there is a period of wandering, and there is an amnesic gap upon recovery. It usually last a matter of hours or days. Memory recovery is complete after few hours or days. In most cases, the fugue states will clear over a few days and the amnesia is mainly transient. If not, the patient usually adopts a new name and identity and begins a new life. As in organic amnesia, fugue patients will normally retain their procedural and semantic memories. The patient may have episodic memory loss that is usually only retrograde memory loss and no anterograde impairment. Situation specific amnesia: Offenders, as well as victims of crimes commonly, claim amnesia regarding the offence. In 25-45% of homicides, 8% of other violent crimes and a small percentage of non-violent crimes, offenders claim amnesia (Kopelman 2002a). Amnesia for an offence is associated with alcohol or substance misuse and acute psychosis, but purely psychological amnesia is often limited to crimes of passion. In people with PTSD anterograde memory dysfunction has been demonstrated with some reduction in hippocampal volume on MRI (Bremmer 1999) attributed to effects of glucocorticoids (Markowitsch 1996) Amnesic syndromes: Various disorders can give rise to amnesic syndromes (e.g. hypoxia, herpes encephalitis) and the features would include 1. Immediate memory is unimpaired. 2. Anterograde amnesia- inability to acquire new information (impaired delayed recall) 3. Retrograde amnesia of variable extent and severity-The degree depends on the extent of brain damage 4. Preserved global intellectual abilities 5. Preserved implicit memory © SPMM Course Korsakoff’s syndrome: It is a form of an amnesic syndrome caused by thiamine deficiency. The patient may have severe anterograde amnesia and extensive retrograde memory loss. This retrograde memory loss includes autobiographical memory loss with relative sparing of the most distant memories. Working memory and procedural memory are unimpaired. Bedside tests: Three words learning task (e.g. apple, table, penny) is a test of anterograde memory and learning, useful to investigate Korsakoff’s syndrome. Post-traumatic amnesia: The time between the injury and recovery of normal continuous memory, seen in head injury patients. The longer the PTA, the more severe the brain damage and poorer the prognosis for the recovery. PTA Retrograde amnesia is also possible after head injury – tested with recent autobiographical questions (what did you eat for dinner yesterday?). In most cases, the amnesic gap is short and (< 1 min). It is not a good indicator of prognosis. Memory loss following ECT: The impairment is usually temporary. There may be both anterograde and retrograde amnesia, both of which reduce rapidly in most patients. A third of patients report persistent memory loss following ECT (Rose et al. 2003). Memory impairment is less pronounced with unilateral ECT. Tests of memory: Digit span is the commonest test of auditory, verbal working memory. Both forward and backward digit span are tested in routine clinical practice. The average range of digit forwards is 6+/-1 and for reverse digit span is 5+/-1 Three words learning task (e.g. apple, table, penny) is a test of anterograde memory and learning. Name and address recall task (7 items) is the commonest test of recent (verbal) memory. Here the subject is asked to recall as many items, without prompts, in five or ten minutes Rey-Osterrieth complex figure test is one of non-verbal memory test. Here the subject is first asked to copy a complex geometric figure and then to draw from memory after an interval of 30 minutes. The recall is impaired in patients with dementia and amnesic syndrome. Wechsler memory tests: Here the subject is asked to read a short story from the Wechsler memory scale containing 25 elements and both immediate and delayed recall after an interval of 30 minutes is tested. Infantile amnesia: The average age of the earliest retrieved memory is 3.5 years. There is a total lack of memories for events occurring during the first few years of life, and there is a variable degree of amnesia for events that occurred in the first 2 to 5 years. This is termed infantile amnesia. Emotion and retrieval: Retrieval is reconstructing past experiences and is influenced by a number of variables including emotion. Current mood affects what is attended, encoded and retrieved. The mood-congruent effect refers to the ability to more easily recall information if it is congruent with the current mood e.g. in a depressed mood, negative thoughts and circumstances are more readily retrieved. Mood-state dependent retrieval refers to the phenomenon wherein retrieval of information is easier if the emotional state at the time is the same as the emotional state at the time of encoding. © SPMM Course Elaboration: Material that is fully elaborated produces stronger memory trace as it is believed that consolidation is linked to the depth with which the data is processed. Schemas are mechanisms for elaborating and for reconstructing memory at test. They are organized sets of facts. During recall, distortion can occur in order to ensure the information fit the schemas or to fit cultural stereotypes. This then impacts the recall of the information. Inference is a method where known, easily accessible information is used to piece together the retrieved information, resulting in a biased recall. Brain imaging and neuropsychological studies provide strong evidence that a. The brain areas mediating performances in STM are principally the pre-frontal lobes b. The phonological STM system is mediated by the left hemisphere regions of Broca's’ area and prefrontal cortex. c. The visuospatial STM system is mediated by the parietal and prefrontal areas of the right hemisphere. d. The brain areas responsible for LTM includes the regions of the limbic system especially the hippocampus and the entorhinal cortex of the medial temporal lobe # 05 - 5. Thought & language # 5. Thought & language © SPMM Course 5. Thought & language There are several different theories that consider how language can affect thoughts and behaviour. Sapir-Whorf Hypothesis Grammatical structure of mother tongue influences how we perceive the world e.g. a language that does not have a word for a specific colour makes that colour less likely to be remembered - this has largely been disputed as very little experimental data has been produced in support. Behavioural economics People are more likely to believe events that are verbally described more vividly (e.g. availability heuristics) Prospect theory People make different economic choices based on how something is framed Cognitive distortions Challenging our 'internal dialogue' can change our cognitive distortions (as in CBT) Counting Some cultures do not have numbers above 10, or even 2 - instead using the word 'many' to describe any number above the highest. This indicates a conceptual difference in how some people would interpret 100 vs. 1000 vs. 1 million. Neuro-linguistic programming A theory that language patterns can affect behaviour, such as influences a consumer in a sale setting. Concepts, prototypes and cores Constituents of thoughts are defined as concepts and are important to psychological processes such as learning, memory and decision-making. There are several theories of concepts – one of which is the prototype theory. Let us consider a lexical concept termed X. This concept may not yet have a defined structure but many constituent features of X are well defined. In this case we can conceptualize that something will fall under the concept X, if sufficient number of constituent features are satisfied. In other word, we obtain a prototype of a concept using the linguistic components, thus acquire further knowledge of the world around us. Consider the concept of FRUITS – most fruits are rounded. Now consider the properties of apple and banana. Apple Banana Edible Edible Red Yellow Sweet Sweet Crunchy Soft Rounded Elongated © SPMM Course Using this model, apples would be judged to be more typical of fruits than bananas as the idea of an APPLE shares more of its constituents with the idea of a FRUIT. Deductive and Inductive reasoning: Reasoning is broadly divided into deductive and inductive reasoning. Deductive reasoning starts with a theory with which we form a hypothesis and collect observations to confirm or dispute our hypothesis. This is often known as top-down reasoning. THEORY  HYPOTHESIS  OBSERVATION  CONFIRMATION Inductive reasoning starts with observations and formulate tentative hypotheses that are then explored and a theory is formed. This is known as bottom-up reasoning. OBSERVATIONS  PATTERN  HYPOTHESIS  THEORY Inductive reasoning is open-ended and exploratory in comparison to the narrow nature of deductive reasoning. Problem-solving: Two methods of information processing have been described in problem-solving.  Algorithmic method involves step-by-step search which guarantees solution but it is timeconsuming and more useful in simpler and smaller magnitude problems.  Heuristic method uses rules of thumb; more likely solutions are tried before others – hence solution is not guaranteed but it is more quick and ‘dirty’! Means-end analysis is a type of heuristics in which the solution is sought from working backwards and may include reduction and breaking down of a complex problem into easily solvable steps. Heuristics in decision-making: 1. Availability heuristics: the decision is based on readily available information without systematic search. 2. Representativeness bias: fitting a problem into one of the well-known categories and solve it in a similar fashion. 3. Gambler’s fallacy: an outcome is due as it has not happened for some time. A gambler thinks that more he loses, the more chances that he wins later. 4. Base rate fallacy: tend to ignore the relative frequency of occurrence of events but stick to stereotypes. Consider that a very good student fails an exam, the probability of which is not negligible. Someone has earlier said that this student could fail only if the examiner gets annoyed by his handwriting and does not read his answer fully. One believes this has happened even though the probability of such an event is ridiculously small, as the primary event of that student failing has now occurred. 5. Sunk cost bias or entrapment: no choice than to continue to a decision, as one believes withdrawal would not justify the cost incurred. # 06 - 6. Personality # 6. Personality © SPMM Course 6. Personality Theories of personality consider the following different dimensions: 1. Personality as an enduring and consistent feature (dispositional) vs. differing with and influenced by situations (situationalism) 2. Personality traits are shared and comparable (nomothetic) vs. traits are unique to individuals and not comparable (idiographic) Various theories of personality differ in the degree to which they embrace situationalism (vs. dispositionalism) and the notion of idiography (uniqueness). (Adapted from Gross Psychology 9e Page 731) Allport’s theory: Allport analysed 18000 adjectives used as ‘trait labels’. A trait refers to an enduring disposition viewed as a continuous dimension. He described three types of traits: 1. Cardinal traits: influential, core traits 2. Central traits: 5 – 10 traits, less general 3. Secondary traits: least important, least consistent traits that only close friends can notice. Cattell’s approach: Cattell selected 4500 traits from Allport’s work, and further reduced them to 171 elements before factor analyzing them to identify 16 dimensions. Surface traits are correlated to one another but not important for understanding one’s personality and Source traits that are basic building blocks of the 16 PF questionnaire devised by Cattell. Cattell undertook oblique factor analysis to identify these source traits. Cattell’s factors are a larger number of less powerful somewhat correlated (not fully independent) factors arising out of first order analysis – called traits. Cattell maintained that a •Unique features •Variable and situational •Unique features (idiographic) •Consistent and enduring •Variable and situational •Shared features •Shared features (nomothetic) •Consistent/enduring (dispositional) Eysenck's factors Cattell's traits Eysenck's factors Cattell's traits Psychoanalytic theories Psychoanalytic theories Situationlism Humanistic school Situationlism Humanistic school Kelly's personal construct theory Kelly's personal construct theory © SPMM Course fundamental discontinuity exists between normal and abnormal personalities (categorical). During his work Catell identified 3 types of data that reveal qualities of one’s personality: 1. Q-data: obtained from questionnaires 2. L-data: Obtained from lifetime records (e.g. report cards, friend’s accounts etc.) and 3. Tdata: test based data (e.g. Thematic Apperception Test etc.). Eysenck’s approach: Eysenck used second order analysis (orthogonal factor analysis) that identified small number of powerful independent factors. This method yielded 3 dimensional traits. These are neuroticism (vs. stability), psychoticism and extraversion (vs. introversion). Eysenck’s personality questionnaire contains a lie scale. Biologically, extraversion is related to arousal and ascending reticular activating system; neuroticism may be related to sympathetic system reactivity. Introverts are said to be easily aroused. Hence they are also more easily conditionable than extraverts; this may explain why introverts stay indoors more often. Extraverts have low arousal state; hence they are not easily conditionable. Eysenck maintained that no fundamental discontinuity exists between normal and abnormal personalities (dimensional view). Cloninger’s psychobiological model of personality includes four dimensions of temperament (each 50 to 60 % heritable), which manifest early in life and 3 components of character, which are shaped by environment. The temperamental dimensions include  Novelty-seeking (includes frustration avoidance, impulsive decision-making)  Harm-avoidance (pessimistic worry about the future, passive avoidant behaviour, fear of uncertainty);  Reward-dependence (sentimentality, social attachment, and dependence on praise and approval)  Persistence (high perseverance and tolerance of frustration) The character dimensions are self-directedness, cooperativeness, and self-transcendence. DSM identifies 3 clusters of personality disorders. In general Cluster A personalities are associated with low reward-dependence. Cluster B personality with high novelty-seeking and Cluster C personalities with high harm-avoidance traits. Rotter’s locus of control theory is a single trait theory – where external and internal loci are used to measure personality attributes. Note that both Cattell’s and Eysenck’s are multitrait theories. Big Five Traits– McCrae & Costa 1992: 1. Openness 2. Conscientiousness 3. Extraversion 4. Agreeableness 5. Neuroticism (OCEAN) The Big-Five concept has provided a unified framework for trait research. NEO decreases with age; AC increases with age. © SPMM Course Kelly’s personal construct theory: Kelly proposed an idiographic theory of personality influenced by the humanistic school. According to him one’s personality can be deciphered only when observations regarding interpersonal relationships are made and hypotheses are formulated and tested. For this purpose, Kelly used a repertory grid. Initially a list of important people is generated (called elements). 2 elements are chosen and contrasted with the third one to see what themes emerge – called constructs. Such constructs are applied to elements down the list till all are exhausted and sufficiently descriptive. Such constructs and elements can also be used for measuring formal thought disturbances (Bannister grid). Humanistic or phenomenological school of personality focuses on the individuals’ view of the world rather than their unconscious impulses. In contrast to trait-based approaches that view personality as relatively enduring and shared, the humanistic school emphasises on the uniqueness of an individual’s personality and the capacity for growth in an optimistic manner. Therapeutic models such as Roger’s Client Centred Therapy originated from humanistic school. Interactionism: A major issue with trait theories (nomothetic approaches) is the poor correlation between one’s traits and observed behaviour. This led to a raise in the prominence of the so-called situationalism that contends that all are apparently enduring behavioural patterns are in fact a result of environmental demands on an individual. A middle path is the concept of interactionism (Magnusson and Endler, 1977), which proposes that personality and the environment interact with each other to produce the observed behaviour. Typology: Early personality theorists such as Sheldon and Kretschmer used body shape based physical types to describe associated personality traits. Kretschmer related body types to personality variations and dispositions to major psychoses (1921).  Asthenic – thin body; aloof individuals; correlated with schizophrenia  Pyknic – plump individuals; childish with swings in mood; correlated with manic-depression  Athletic – well-built individuals with a steady temperament. Based on the study of thousands of nude photographs of first year college students, Sheldon proposed three body types (1954).  Endomorphic - plump and round people who are relaxed and outgoing.  Mesomorphic - strong and muscular people who are energetic and assertive.  Ectomorphic - tall and thin people who are fearful and restrained; associated with schizophrenia Friedman & Rosenman introduced Type A / Type B personality classification. Type A persons show impatience, excessive time consciousness, insecurity, high competitiveness, hostility and aggression and are incapable of relaxation. They may be high achievers and workaholics. Type B persons are relaxed, and easy-going; creative, often self-analyze and evade stress but cope poorly when under stress. Type A was first described as a risk factor for coronary disease but MRFIT study later concluded that there is no difference between Type A and Type B in regard to coronary proneness. This classification has poor # 07 - Measuring personality traits # Measuring personality traits: © SPMM Course psychometric construct and content validity. The hostility component of Type A is the only significant risk factor for CHD association. Measuring personality traits: Projective tests are individually administered tests to obtain information about emotional functioning. They are based on the principle that ambiguous unstructured open-ended situations stimulate projection of an individual’s internal emotional world onto the stimulus (environment). Murray was a major proponent of projective tests. But the first projective test introduced was Rorschach’s inkblots. Thematic Apperception Test (Murray), Draw-a-person test, sentence completion tests are other examples. Projective tests do not have much place in contemporary practice.  Classification of projective tests: 1. Association inducing: verbalizing response pertaining to a stimuli e.g. Rorschach. 2. Completion tests: completing unfinished stimulus e.g. sentence completion test 3. Choice or ordering: rank order or categorise stimuli. 4. Construction: develop or construct story or narration e.g. TAT. 5. Self-expression: create something without stimulus e.g. Draw a man (Goodenough), House Tree Person (Buck).  Rorschach is the most commonly used, consists of 10 inkblots, sequentially presented and asked to describe. Has two phases – free association and inquiry phase – both are analyzed later. Can be scored using Exner’s system. Needs extensive training to be used.  Thematic Apperception Test (Murray) TAT has 20-30 pictures and one blank card and the subject has to make a story from each depicted picture; not all cards are used. Stimuli somewhat more structured.  Jung introduced Word Association Test (WAT). In WAT and sentence completion tests, time pressure is usually applied. Minnesota multiphasic personality inventory (MMPI) is a popular inventory for measuring personality. It has 10 scales with clinical labels. It is NOT a projective test.  Self-report inventory  Most researched personality inventory  Developed by Hathaway & McKinley  567 statements included  Empirically derived 10 clinical scales are used to score responses 1. Hypochondriasis 2. Depression 3. Hysteria 4. Psychopathic deviance 5. Masculinity-femininity. 6. Paranoia. 7. Psychasthenia. © SPMM Course 8. Schizophrenia. 9. Hypomania. 10. Social introversion  Also contains lie scale (validity component) The Q-sort technique developed from client-centered therapy involves a person sorting cards with selfdescriptive statements(e.g. ‘I don’t trust my own emotions’, ‘I like to be around friends’) on them into ordered piles under the headings ‘self’ and ‘ideal’. A numerical discrepancy score between ideal and real self can be thus computed. The International Personality Disorder Examination (IPDE):  Psychometric trait instrument for the clinical assessment of personality disorders (for those > 5 years age).  IPDE comprises both a pencil-and-paper self-report screening questionnaire (77 true/false), and semi-structured diagnostic interview rated by trained clinician.  Compatible with both ICD 10 and DSM IV.  Allows for a definite, probable, or negative diagnosis with respect to each personality disorder  Translated into several foreign languages  Ratings can be based either on the patient's answers or informant responses.  Allows a "past personality disorder" diagnosis prior to the past 12 months  Allows a "late onset" diagnosis when the diagnostic criteria have only been met after age 25 years. # 08 - 7. Motivation needs and drives # 7. Motivation: needs and drives © SPMM Course 7. Motivation: needs and drives Motivation refers to the process involved in initiation, direction and energisation of behaviour. It can have various dimensions including internal vs. external, innate vs. learned, conscious vs. unconscious and mechanistic vs. cognitive. Maslow identified deficiency needs called D motives and growth needs (or ‘being’) needs called B motives. He proposed a hierarchy of human needs with phylogenic and ontogenic evolution through the hierarchy. The needs become less biological as one ascends through the hierarchy. The higher needs come into focus only when the lower needs are satisfied at least to some extent. Once an individual has moved upwards to the next level, needs in the lower level will no longer be prioritized. If a lower set of needs is no longer being met, the individual will temporarily re-prioritize those needs by focusing attention on the unfulfilled needs, but will not permanently regress to the lower level. Some authors place aesthetic needs and cognitive needs (need to know & understand) in between esteem needs and actualisation. Transcendence can be placed above self-actualisation. The need for self-actualisations is "the desire to become more and more what one is, to become everything that one is capable of becoming." According to Maslow, the following characters are seen in self-actualizing people:  Spontaneous in their ideas and actions.  Creative.  Interested in solving problems.  Appreciate life.  Have a system of internalized independent morality.  Able to view all things in an objective manner. Law of Effect related to learning theories can also be considered as a theory of motivation. A satisfying effect strengthens behaviour; a dissatisfying effect weakens behaviour. So behaviour is contingent on the consequences ( the basis of behaviourism) (Thorndike, 1911). © SPMM Course Drive-Reduction Theory (Hull): According to this, the physiological aim of drive reduction is homeostasis- the tendency for organisms to keep physiological systems (e.g. temperature) at equilibrium. Any imbalance in homeostasis creates a need – a biological requirement for well-being. The brain responds to such needs by creating a psychological state called drive – a feeling of arousal that prompts action to reduce drive. According to Hull, primary drives stem from biological needs; secondary drives are psychological and learned from primary drives (e.g. self-esteem, power etc.) Similarly Murray (1938) divided needs into primary or vasculogenic needs that are physiological (e.g. air, water, food, sex) and secondary needs that are acquired or learned through experiences e.g. money etc. Yerkes-Dodson Law: An inverted U-shaped curve relates the level of arousal with the performance of an act. Optimum arousal (moderate) is required for best performance; too low or too high arousal proves to be a hindrance e.g. sexual performance. But it is demonstrated that the relationship is not as simple as proposed as task difficulty varies highly. So, difficult or intellectually demanding tasks may require a lower level of arousal (to facilitate concentration). But tasks demanding stamina or persistence may be performed better with higher levels of arousal (to increase motivation). Because of task differences, the shape of the curve can be highly variable. Curiosity is an intrinsic motivator – it is stimulated when something in our environment attracts our attention. There are two types of curiosity that can stimulate intrinsic motivation – sensory curiosity (change in tone of voice or level of contrast e.g. typing bold letters) or cognitive curiosity (learner believes it may be useful to modify existing cognitive structures e.g. improving knowledge in statistical models in order to improve understanding of baseball batting averages). The optimal discrepancy is the strongest curiosity when information appears different from what we know but is not so dissimilar as to be considered strange or irrelevant. Cognitive consistency theory focuses on the cognitive balance that is created when inconsistencies result in tension, which motivates our brains/body to respond. The theory suggests people see imbalances and correct them through the motivation to make things consistent. 1. People expect consistency. 2. Inconsistencies create a state of dissonance 3. Dissonance drives us to restore consistency. Need for achievement (nAch) refers to the individual’s desire for significant accomplishment and mastering skills to a high standard. First used by Henry Murray, it is associated with a range of actions. Need for achievement motivates an individual to succeed in competition. People high in nAch are characterised by a tendency to seek challenges and a high degree of independence. nAch is a personality trait measured in the Thematic Apperception Test (TAT). Sources of high nAch include: 1. Parents who encouraged independence in childhood 2. Praise and rewards for success © SPMM Course 3. Association of achievement with positive feelings 4. Association of achievement with one's own competence and effort, not luck 5. A desire to be effective or challenged 6. Intrapersonal strength 7. Desirability 8. Feasibility 9. Goal Setting abilities # 09 - 8. Emotions # 8. Emotions © SPMM Course 8. Emotions Ekman identified 6 primary human emotions – surprise, fear, sadness, anger, happiness and disgust. These are universal, innate and ready-wired responses, also seen in primates to some extent. An emotion has 3 components – 1. Subjective ‘cortical’ experience 2. Physiological ‘visceral’ changes 3. Associated behavioural (‘skeletal’) changes. James-Lange theory of emotions:  Perception of a stimulus leads to bodily (skeletal and visceral) changes. The peripheral responses send feedback to the cortex via thalamus leading to the perception of the emotion.  A modification is a facial feedback hypothesis, according to which different facial movements elicit different emotional perceptions.  But wide repertoires of bodily changes are not available to explain the widely variant emotions perceived. Also, emotional perception occurs faster than that could be explained by a feedback theory.  Studies on peripheral features of emotions have shown that anger is associated with the maximum rise in temperature, while fear and disgust are associated with a drop in temperature. The increase in heart rate produced by sadness is usually greater than that produced by happiness. Cannon-Bard theory: On the perception of a stimulus, thalamus coordinates signals to cortex leading to a conscious experience and simultaneously sends signals to hypothalamus leading to physiological changes. The thalamus is considered to be cardinal in the emotional appraisal. Schachter-Singer labelling theory: On the perception of a stimulus, both physiological changes and a conscious experience of general arousal take place simultaneously. This generic arousal is then interpreted to either positive or negative and labelled appropriately according to the situational cues. This is also called jukebox theory or two-factor theory. If an appropriate label is not found, by default, negative appreciation of arousal occurs (e.g. ‘dysphoria’ when experiencing boredom). Lazarus cognitive appraisal theory states that appraisal precedes affective reaction – hence affective primacy cannot be supported. Cognitive appraisal refers to the immediate, intuitive, personal evaluations of a situation that gives an idea of how the individual subjectively experiences their environment. Roseman and Scherer propose eight cognitive appraisal dimensions to distinguish emotional understanding, rather than the traditional two (pleasantness and arousal). A third group of theorists suggest that each emotion is categorised by a unique pattern of cognitive appraisals. # 10 - 9. Stress physiological and psychological asp # 9. Stress: physiological and psychological aspects © SPMM Course 9. Stress: physiological and psychological aspects Stress is an organism’s response to a challenge in the environment or stimulus. The response, deemed fight-or-flight, is via the activation of the sympathetic nervous system. Though the sympathetic nervous system activation is short-lived (as the parasympathetic system calms down the physiological response), prolonged stress can have systemic effects (e.g. cardiac dysfunction). The neuroendocrine system plays an important role in regulating response to stress. (see the chapter on Neuroscience for further details.) In psychological terms, stress is the feeling of pressure – positive stress or ‘eustress’ is a small amount of stress that improves motivation and ability but large amounts of negative stress (‘distress’) can be detrimental to mental health. As well as the external environment, stress can also be caused by internal cognitions, which can be addressed in CBT for anxiety. Stress can be classified into four categories: Crises/catastrophes Completely out of the control of the individual e.g. natural disasters, war – can lead to post-traumatic stress disorder Major life events Going to university, marriage, birth of a child, the death of a loved one (NB not all life events produce detrimental stress; the context of occurrence is important). Daily hassles or microstressors Meeting deadlines, making decisions, irritating colleagues. Ambient stressors Low-grade environmental e.g. pollution, traffic, noise Stressors can result in various levels of conflicts.  Approach-approach conflict: choosing between two equally attractive options e.g. which restaurant to have dinner  Avoidance-avoidance: choose between two unattractive options  Approach-avoidance conflict – attractive and unattractive traits e.g. going to university but incurring significant debt Stress Vulnerability model (Zubin and Spring, 1977) proposes individuals have strengths and vulnerabilities for dealing with stress. On the diagram shown here, person a has low vulnerability and thus can deal with a high deal of stress without much negative consequences, whereas person c has high vulnerability and therefore even moderately low stress can cause them to become mentally unwell. This model applies to a wide variety of psychiatric disorders including psychosis. Causes of increasing vulnerability include genetic factors, childhood loss and trauma. This is a simplistic model and more # 11 - The Stress Vulnerability Model # The Stress Vulnerability Model © SPMM Course sophisticated models exist. Medications, psychological interventions and training to improve coping skills can build resilience and reduce vulnerability. The Stress Vulnerability Model Coping process: Lazarus (1999) developed the most popular model of coping – the cognitive-mediation model which explains why different individuals respond differently to the same types of stressors, and why the same individual may respond differently to a similar stressor at different times. This model proposes three stages in the coping process. Three stages: Primary appraisal Evaluation of stressor Secondary appraisal Evaluation of resources and options to manage the stressful situation Coping stage Choose and use strategy to cope with stressor Coping strategies may be divided into either problem-focused coping, where an individual attempts to change the stressful situation or the relationship between oneself and the stressful context, or emotionfocused coping, in which the individual alters his or her appraisal or emotional reaction to the stressful situation. Locus of control refers to the extent to which individuals believe that they control events affecting them. It is one of the four core dimensions affecting self-evaluation, the others being neuroticism, self-efficacy and self-esteem. Locus of control concept is aligned with the framework of the social-learning theory of personality (Rotter 1954). According to the locus of control, outcomes of an individual’s actions can be attributable to the 4 features shown in the box. SEROTOIN TRANSPORTER & LIFE EVENTS In an interesting study of environmentgene interaction, Caspi et al (2003) noted that individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. © SPMM Course Learned resourcefulness is a concept that is related to Seligman’s concept of learned helplessness. It refers to the conscious appreciation of the acquired repertoire of behaviour and skills that aids a person to selfregulate internal events (emotions, cognitions), which would otherwise interfere with ability to execute target behaviour. Psychological resilience: individual’s ability to appropriately adapt to stress and adversity. Factors developing and sustaining resilience: communication and problem-solving skills, ability to manage strong feelings/impulses, ability to make and execute plans, confidence in own ability. Both learned resourcefulness and helplessness can explain how stressors are appraised in their context. ABILITY (Internal & stable) EFFORT (Internal unstable) TASK DIFFICULTY (External stable) LUCK (External unstable) # 12 - 10. States and levels of awareness # 10. States and levels of awareness © SPMM Course 10. States and levels of awareness Consciousness is defined loosely as human awareness of stimuli. There are many theories of consciousness, e.g. Sigmund Freud’s Topographical model of the mind. The topographical model was elaborated in The Interpretation of Dreams in 1900. Here, the mind is divided into three systems: the conscious system, the preconscious system, and the unconscious system. The conscious system  Receives and process information from the outside world.  Its contents are communicated via speech and behaviour.  Attention cathexis refers to the investment of psychic energy on a particular idea or feeling to process it consciously. Cathexis is ‘stable’ in the conscious mind.  Operates secondary process thinking mainly. The unconscious system:  Contains the contents of censored or repressed wishes.  Characterized by primary-process thinking, and is governed by the pleasure principle.  Shift of cathexis happens very often and quickly  Evident via parapraxes (Freudian slips) and dreams. The preconscious system:  As and when needed service  Interfaces with both unconscious and conscious - contents of unconscious become conscious by ‘squeezing’ through the preconscious  Maintains the ‘repressive barrier’ to censor unacceptable wishes and desires (not the repressed contents). Problems with a topographic theory: When someone employs defense mechanisms such as displacement, repression etc., he or she is not aware of the process of this defense. Hence, these cannot be represented by preconscious as Freud originally proposed – as preconscious is available to the conscious ‘as and when’ needed. Further, an ‘unconscious need for punishment’ was frequently noted among Freud’s patients – topographical theory fails to explain this. The role of the unconscious mind in decision-making is still greatly debated. Unconscious cognition is processing of memory, thought, learning and perception without awareness. Freud believed the unconscious stored memories and desires that influenced an individual's thought process. Freud believed the unconscious could be accessed through dream analysis and random association. Carl Jung categorised the unconscious into personal unconscious (holding individual memories/experiences) and collective unconscious (holding memories/experiences of a species passed down through generations). Arousal: physiological and psychological state of being awake/reactive to stimuli. Activation of the reticular activating system in the brain stem, along with the autonomic nervous system leads to an ‘alert © SPMM Course state’ – raised blood pressure and heart rate, alertness and readiness to respond. Arousal regulates consciousness and attention, important for fight-or-flight response and sexual activity. Arousal is also crucial for the appraisal of emotion (see notes for emotion theory) and motivation (see notes for motivation). Alertness is a state of heightened awareness of environmental stimuli resulting in ability to act promptly to danger. Biorhythms: Chronobiology refers to the study of biological rhythms. Various biological processes of the human body repeat themselves in a cyclical fashion indicating the presence of a biorhythm. Processes repeating approximately every 24 h are considered to have a daily rhythm (circadian e.g. sleep-wake cycle); those with cycles lasting less than a day are called ultradian (e.g. daily arousal levels, phased brain activity patterns during sleep) while those lasting more than a day are called infradian (e.g. menstrual cycles last 28-30 days). Infradian rhythms may also occur as a result of seasonal changes in animals e.g. migration cycles in birds and hibernation in some mammals - these are called circannual rhythms. Biorhythms are driven mostly by endogenous factors but are entrained by external time cues (called ‘zeitgebers’ or time givers). For example, light is an important zeitgeber without which the sleep-wake circadian cycle may indeed be a 25h cycle instead of the entrained 24h cycle that we have. Social zeitgebers are external social cues that function to entrain biological rhythms, e.g. the need to go to work by 8AM, etc. Life events that disrupt social zeitgebers can increase one’s vulnerability to depression/manic episodes. The suprachiasmatic nucleus is an internal pacemaker located in the anterior hypothalamus that regulates many biorhythms. More details on this neuroendocrine system are given in the Neuroscience section along with details regarding sleep structure and parasomnias. Sleep deprivation: Most cognitive processes cope surprisingly well despite sleep deprivation. In early stages, sleep deprived individuals show reduced arousal and perform poorly on monotonous tasks, but optimally on interesting tasks, indicating that the motivation to perform is more affected than one’s performance capacity. With further deprivation, 2-3 second periods of micro-sleep (wherein the individual is unresponsive) are noted. The individual also complains of ‘hat phenomenon’ a feeling that “something is gripping one’s forehead and temples”. Further deprivation results in delusional ideations, paranoia, loss of sense of identity and difficulty in social interaction including disorganized speech; this syndrome is termed sleep-deprivation psychosis. Upon deprivation, sleep debt accumulates over time, some of which is ‘paid back’ when an individual resumes sleep after the period of deprivation. REM sleep deprivation has profound effects on concentration and other psychological functions. REM phases of sleep recover better than NREM sleep, a phenomenon known as REM rebound. Hypnosis: the state of consciousness involving focused attention and reduced peripheral awareness. There are two theories about what occurs – altered state: hypnosis is an altered state of mind with a level of awareness different from normal; non-state: hypnosis is a form of imaginative role-enactment. © SPMM Course Normally preceded by ‘hypnotic induction’, non-state theory suggests the client becomes more focused, heightens expectation. The term suggestion (instruction or suggestion of subject into the hypnotic state) was not used in the initial description of hypnotism, but suggestion now forms part of the language associated with hypnosis. Some state that ‘suggestion’ is communication directed at the conscious mind whereas others believe it is communication with the unconscious. Braid defined hypnotism as focused (conscious) attention upon a dominant idea (or suggestion). Other hypnotists (e.g. Erickson) who believed that responses are mediated through an ‘unconscious mind’, employed indirect suggestions such as metaphors. Meditation is defined the practice of training one’s mind or inducing a mode of consciousness for the benefit or as an end itself. It often involves self-regulation and clearing the mind. It can help reduce blood pressure, help with anxiety and depression. Mindfulness-based therapy is about increasing awareness of emotions/cognitions in order to address them. Trance is a state of consciousness other than normal waking consciousness. It can be associated with hypnosis meditation, prayer and illicit substances. It denotes any state of awareness or consciousness other than normal waking consciousness. # 13 - 11. Intelligence # 11. Intelligence © SPMM Course 11. Intelligence The two-factor theory of intelligence was postulated by Spearman. Spearman carried out a factor analysis of the result of children’s performance on a number of tests and concluded that all tests measured both a common factor of general intelligence (g) and a specific factor (s). He believed that individual differences were due to differences in g. Triarchic theory of intelligence: Sternberg's Triarchic Theory of (Successful) Intelligence contends that intelligent behaviour arises from a balance between analytical, creative and practical abilities, and that these abilities function collectively to allow individuals to achieve success in particular sociocultural contexts (Sternberg, 1999). Analytical abilities enable the individual to evaluate, analyze, compare and contrast information. Creative abilities generate invention, discovery, and other creative endeavours. Practical abilities tie everything together by allowing individuals to apply what they have learned in the appropriate setting. To be successful in life, the individual must make the best use of his or her analytical, creative and practical strengths while at the same time compensating for weaknesses in any of these areas. Three sets of components are essential for this process: 1. Knowledge-acquisition components: used in obtaining new information. 2. Meta-components: executive processes used in problem-solving and decision-making. 3. Performance components: processes that actually carry out the actions that the meta-components dictate. Flynn effect: An interesting feature of IQ measurements is the observation that IQ scores increased from one generation to the next for all of the countries in which generational cohorts have been studied to date (Flynn, 1994). This is called Flynn phenomenon. In general, countries have seen generational increases between 5 and 25 points. The largest gains appear to occur on tests that measure fluid intelligence (problem solving: These tests on average have shown an increase of about 15 points or one standard deviation per generation e.g. Raven’s progressive matrices) rather than crystallized intelligence (verbal and math skills: These tests on average have shown an increase of about 9 points per generation e.g. Weschler’s tests). Salient features of Flynn effect: 1. Non-verbal IQ has risen more rapidly than has verbal IQ. 2. Performance gains are smallest on the most culturally specific tests, and largest on the most abstract tests. 3. Performance gains, as they occur over time, are roughly constant for all age groups. 4. Problem-solving abilities have seen the biggest performance gains. © SPMM Course What causes Flynn phenomenon?  Artifacts (i.e. IQ tests do not actually measure the construct of intelligence but measure something that has a link to intelligence that can change with generations)  Test sophistication (e.g. improvement in test taking strategies across time)  Actual intelligence increases (e.g., due to improved nutrition, improvement in early childhood education).  Regression towards the mean (repeated resampling tends to reveal the true mean value) Paradoxes of the Flynn Effect: There are several observations that highlight the baffling nature of the Flynn Effect.  The factor paradox: Prior factor analysis research suggests that a single factor, ‘general intelligence’ or ‘g,’ underlies IQ. The Flynn Effect does not affect all sections of the intelligence tests to the same degree. Hence if we’re getting smarter every generation, some parts not all of our intelligence is getting smarter, and this is difficult to explain.  The interaction paradox: As Flynn Effect suggests, a difference of some 18 points in the average IQ over two generations exist. In that case, it ought to be highly visible when the elderly interact with the young! This is not the case though.  The mental retardation paradox: If Flynn effect was true then in 1900, average IQ was 75, just above mental retardation range; this assumption predicts a very high frequency of persons with mental retardation. But no such phenomenon has been noted.  The identical twins paradox: Twins raised apart tend to have very similar IQ scores, but the Flynn Effect suggests that intelligence as measured by IQ is more subjected to environmental effects than genes. Commonly used tests for measuring IQ  Stanford-Binet Scale is the first formal IQ test introduced before 1st World War in 1905 (used for ages 2 to 18).  Wechsler Adult Intelligence Scale (WAIS-Revised version) is for individuals aged older than 16.  Wechsler Intelligence Scale for Children (WISC-Revised) is for those aged 6 to 16.  Wechsler Preschool and Primary Scale of Intelligence (WPPSI) is for children aged 4 to 6. © SPMM Course Notes prepared using excerpts from:  Carskadon MA, Dement WC. Normal human sleep: An overview. Philadelphia: Elsevier Saunders; 2005. pp. 13–23.  Eysenck MW (2004). Psychology: An International Perspective. Taylor & Francis.  Fox, J. (1996) Projective testing. In Jacobson & Jacobson (ed.) Psychiatric secrets, Hanley & Belfus. Page 22.  Gross, R (2012). Psychology: The Science of Mind and Behaviour 6th Edition. Hatchette UK.  Hiscock, M (2007) 'The Flynn effect and its relevance to neuropsychology', Journal of Clinical and Experimental Neuropsychology, 29:5, 514 – 529  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007  Mates, M (1992). "Altered Levels of Consciousness in Schizophrenia". Journal of Orthomolecular Medicine 7 (4): 216–220.  Mischel, W. (1999). Introduction to Personality. 6th edn. Orlando: Harcourt Brace Jovanovich. An interesting introduction to personality research.  Salvatore etal.Biological rhythms and mood disorders. Dialogues Clin Neurosci. Dec 2012; 14(4): 369–379.  Williams, R. B. (2001). Hostility: Effects on health and the potential for successful behavioral approaches to prevention and treatment. In A. Baum, T. A. Revenson & J. E. Singer (Eds.) Handbook of Health Psychology. Mahwah, NJ: Erlbaum.  McKay, GC & Kopelman MD. Advances in Psychiatric Treatment Mar 2009, 15 (2) 152-158; http://apt.rcpsych.org/content/15/2/152 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgments have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information # 02 - 12_Social_Psychology # 01 - 1. Attitudes # 1. Attitudes # 02 - Functions of attitudes (Katz) # Functions of attitudes: (Katz) # 03 - Why do attitudes change # Why do attitudes change? © SPMM Course 1. Attitudes Attitudes are “learned predispositions to respond in a consistently favourable or unfavourable way towards a given object, person or event” (Fishbein & Ajzen,1975). An attitude is a combination of beliefs and values.  Beliefs are based on our knowledge of the world and link an object to an attribute. They are non-evaluative and objective e.g. ‘USA is a nation built on capitalism’.  Values relate to the importance or desirability of the object. It is largely subjective and has preferential patterns attached e.g. ‘I do not like capitalism’. Values can turn beliefs to attitudes – ‘I dislike American people’. Three-component model of attitudes: 1. Affective component: what the person feels about the object (favourable/ unfavourable evaluations) – e.g. I love chocolate 2. Cognitive component: thoughts, beliefs, knowledge about the object – e.g. Chocolate keeps me active 3. Behavioural component: actual or intended responses to the object e.g. I eat chocolate every day Functions of attitudes: (Katz)  Knowledge function: attitudes are frames of reference that simplify the world, help make quick appraisals of situations  Value expressive function: reflect fundamental self-concepts – self-expressive and maintains personal integrity e.g. vegetarianism  Social adjustment function: help to function in a group setting, social acceptance  Ego-defensive function protects from character or personal deficiencies – this function makes attitudes very resistant to change Why do attitudes change? 1. Cognitive dissonance theory: (Festinger) People strive for consistency between thoughts, feelings and actions. If there is a discrepancy between different attitudes (cognitive dissonance) or between attitudes and behaviours (attitude-behaviour discrepancy), then this initiates and drives either a change in attitudes (more common) or a change in behaviours. # 04 - Measuring Attitudes # Measuring Attitudes © SPMM Course For example, in smokers, discrepancy between cognitions (‘smoking is injurious’) and behaviour (repeated smoking) may influence behaviour leading to a cut down, or alternatively, may alter the cognitions (‘there is too little evidence available to link smoking to poor health’). 1-Dollar 20-Dollar experiment: All subjects in an experiment were asked to do a very boring repetitive task for 30 minutes. The first group was a control group; the second group (called 1dollar group) was paid $1 to say that the task was fun and interesting, the third group (called 20dollar group) was paid $20 to say that the task was fun and interesting. All participants were asked to rate how enjoyable they had found the task. Contrary to popular belief, the group, which was paid more, did not appreciate the boring task. As they obtained a good incentive, they did not develop a dissonance. They lied about its usefulness but in fact they did not change their belief about the boring nature of this task. In contrast, the lowly paid group did experience a cognitive dissonance between the two facts - ‘This task is boring’ and ‘I am doing this task without much incentive’, hence they changed their initial attitude towards the task and, in fact, started liking the task. This highlights the processes relating to counter-attitudinal behaviours. How to reduce dissonance? Apart from modifying attitudes or behaviours, one can have selective exposure to information to avoid or prevent dissonance; to reduce a dissonance one can make a commitment after which primary attitudes get stronger e.g. after betting on a horse, the belief that the horse will win strengthens! Other methods are 1. Removal or denial of the dissonant cognition 2. Trivialising the dissonant cognition 3.Adding a new consonant cognition to counterbalance the dissonance Self-perception theory: According to Bem, self-report of attitude after a behaviour is usually an inference of one’s own behaviour and context. Dissonance cannot explain this adequately. In the 1 dollar/20 dollar experiment, the 20 dollar group made situational attribution (‘I did it for money, it was boring) while 1 dollar group made dispositional attribution (‘There is not much incentive, but I really liked it’). Hence, while cognitive dissonance explains both counter-attitudinal behaviour and attitude-attitude discrepancy; self-perception applies better when attitude congruent behaviour occurs, but it cannot explain attitude-attitude discrepancy. Measuring Attitudes Attitudes are largely subjective and so cannot be measured directly. Attitude measures usually rely on self-report, assume that the same statement has the same meaning for all respondents and # 05 - Attitude behaviour correlation # Attitude behaviour correlation © SPMM Course assume that subjective attitudes can be quantified meaningfully. An alternative method of measurement is to observe behaviours, but behaviours do not always reflect attitude.  Thurstone scale: While constructing a Thurstone scale, hundreds of statements are initially produced pertaining to a particular topic. These statements are presented to a sample (similar to a panel of judges) who is asked to score the statements on an 11 point scale. A set number of statements e.g. 10 each on both extremes (positive and negative attitude) are chosen based on the consistency of scores given by the judges. Each of these statements will carry a value, which is the average of 100 judgments on the 11 points scale. These 20 statements are clubbed together in producing an attitude scale, which is administered to the subject. The subject will then indicate what statements he agrees to. It is not often used because the method is too tedious. The 11 points (used to rate each statement) are assumed to be intervals and averages are used to obtain the value scores. This is not entirely accurate as the 11 points scale is, in fact, ordinal.  Likert scale includes graded ‘agree’ to ‘disagree’ measures. This is one of the most popular and statistically more reliable measures. It is easy to construct, and no assumptions are made about the equality of intervals.  Sociometry is used to measure interpersonal attitudes in a repertory grid-like fashion i.e. who like whom tables. These are called sociograms.  Guttman introduced scalograms that include cumulative statements where accepting a statement usually means accepting all that comes below a statement, in a step-wise fashion.  Osgood’s semantic differential scale is used to measure verbally expressed attitudes. It allows different attitudes about a particular topic to be measured on the same scale. It includes various factors constituting an attitude; e.g. while expressing one’s attitudes regarding a politician, one can rate him using an evaluative component (good ---- bad), activity component (active ----- inactive) and potency component (powerful ---- weak) etc. With these bipolar adjectives being the two extremes, a 7 points scale is designed, and the subject is asked to indicate a score for each factor. Osgood’s semantic differential assumes that every concept can be represented in a hypothetical semantic space with two extremes. Attitude behaviour correlation Attitudes and behaviours are not correlated in simple linear fashion. Attitudes are only predispositions; actual behaviours depend on: 1. Perceived consequences. 2. Social desirability. © SPMM Course 3. Habitual behaviours. 4. Situational factors If attitudes are measured with specified assessment of target, action, context and time element, however, then measured attitudes will be closer to actual behaviour e.g. if one wants to measure public attitude on the issue of abortion, simply eliciting attitudes on abortion may not be appropriate. Instead if we measure attitudes on legal abortion in a married woman after 3 months of marriage, it may provide a more accurate measure of the actual behavior of the respondents when the issue arises in their personal or family life. Single instances of behaviours are unreliable indicators of attitudes. Various attitudes aggregate to result in behaviour; also the strength of an attitude is proportional to its influence on behaviour. # 06 - 2. Self psychology # 2. Self psychology © SPMM Course 2. Self psychology In self-psychology, various concepts are often used to describe the nature of self.  Self-consciousness: Awareness of distinct self, compared to other objects in the environment. Only humans are thought to possess full self-consciousness.  Self-image: This refers to an answer one might give for the question ‘who are you?’ It includes one’s description of social roles (social self), personality traits and physical characters (bodily self).  Self-esteem: This refers to a personal judgment of worthiness expressed in the attitudes one holds towards oneself. Self-image is descriptive, but self-esteem is evaluative.  Ideal self: This represents ‘what we would like ourselves to be’. One’s self-esteem depends on the discrepancy between one’s ideal self and self-image. We develop self-concept depending upon: 1. Reaction of others (Theory of looking glass self by Cooley suggests that like a mirror, others around us reflect our self-image) 2. Comparison with others 3. Social roles we play 4. Identification with role models Self-recognition could be demonstrated in a growing infant by using a mirror. Gallup conducted the famous ‘touching the dot’ experiments to demonstrate self-recognition. It is noted that only higher primates and humans older than 20 months successfully demonstrate ‘touching the dot’. When a red dot is unknowingly placed on the face of a child, the child starts touching its face to explore the dot when a mirror is shown. This ‘touching the dot’ phenomenon does not occur less than 15 months of age. 5 to 25% infants touch the dot by 18 months while nearly 75% touch the dot by age 20 months. It is thus concluded that self-recognition rapidly develops between 18 to 20 months. Object permanence is necessary for self-recognition. Mirror recognition by primates may be a reflection of behavioural recognition i.e. ‘the one in the mirror is same as me’ rather than self-recognition i.e. ‘the one in the mirror is me’. Autobiographical memory in humans develops around age 3 ½ to 4 ½ yrs. # 07 - 3. Interpersonal issues # 3. Interpersonal issues # 08 - Attribution # Attribution © SPMM Course 3. Interpersonal issues Attribution This is the process by which we make judgments about causes of behaviour. Heider (1958) was the first to propose a psychological theory of attribution - he called this “naïve” or “commonsense” psychology. In his view, people act like amateur scientists, trying to understand other people’s behaviours by piecing together information until they arrive at a reasonable explanation or cause. During this process, we make a distinction between intentional vs. unintentional behaviours in others and make internal vs. external attribution of the cause of the observed behaviour. We tend to attribute behaviours to events that co-vary with those behaviours over time. e.g. if A is an event that occurs when the behaviour B is observed, then we often assume A causes B (Kelly’s co-variation model). When making such covariant related observations, three elements are important to ensure validity of the inference. Consider a student X, who arrives late for a physiology lecture. Another student wants to infer the cause behind this. To make an appropriate attribution, he/she needs to consider 1. Consensus: Does everyone come late or is it only student X? 2. Distinctiveness: Does student X come late to other classes too? 3. Consistency: Does student X come late to physiology lecture every time? Consistency is most used in attribution; consensus is least used. Generally speaking if consensus is low, dispositional attribution is made (student X has a problem). If consistency is low, situational attribution is made (something must have happened to him today, perhaps, he missed his train). If distinctiveness is high, stimulus or target is considered to be at fault (the physiology class is so boring that X always comes late). Weiner developed a systematic attributional theory. Accordingly there are 3 dimensions identified in the process of attributions 1. Locus: external/internal 2. Stability: transient/permanent 3. Controllability: controllable/uncontrollable External stable and uncontrollable cause attributed to a negative event generates a sense of failure with anger. © SPMM Course Some consistent errors (attribution bias) are noted in making attributions.  First impression effect: (primacy effect). Generally first impressions on people count more unless specific instruction is given to attend or repeatedly observe. A positive first impression is more likely to change than a negative first impression. Primacy is more important in strangers; recency effect plays more in evaluating friends and others who will come into repeated contacts.  Halo effect is the tendency to perceive other persons as wholly good or bad based on few observed traits (e.g. physical attractiveness); i.e.making inferences about people using limited, superficial information. Thus a person's positive or negative traits "spill over" from one area to influence the total perception of their personality. Investigators evaluating crime suspects are susceptible to halo effect (to be accurate – reversed halo effect or devil effect or association fallacy). For example, a policeman may conclude someone is guilty by association with attributes he has previously seen in other criminals. Mere similarity of a person to a suspect often causes the police to associate the innocent wrongly with a guilty act. Actor-observer effect: When one is involved as an agent in a specific behaviour then he/she attributes external causality to the behaviour. For the same behaviour, others who are merely observers without direct participation may invoke internal causality (intentional and dispositional). Just world hypothesis refers to the idea that ‘I am a just person living in a just world; everyone here gets what they really deserve’. ‘Bad things happen to bad people’, leading to blaming-the-victim culture. Fundamental attribution error or correspondence bias: This refers to overestimating dispositional factors and not situational factors while attributing causes for other’s behaviours. This allows a sense of predictability to be developed about the other person. It is more pronounced if the attributed behaviour is negative and undesirable. Self-serving bias (SSB): the actor observer effect is most pronounced when judging negative behaviours This may be absent or reversed for positive behaviours. Hence such self-serving bias offers selfenhancement and defense. In depression, an exception to SSB is seen - The patient takes excessive selfblame for personal failures. False consensus effect and illusion of in group homogeneity: This refers to the tendency to view other person’s behaviour to be representative of a group’s behaviour (culture or racial stereotypes are thus formed). # 09 - Theory of Mind # Theory of Mind © SPMM Course  The term Barnum effect or Forer effect refers to the widespread predisposition to believe that general and vague personality descriptions or predictions (often given by astrologers, horoscopes, and palmistry) have specific relevance to certain individuals. This effect has frequently contaminated research on personality assessment.  Hawthorne effect refers to a short-term improvement caused by observing worker performance.  Pygmalion effect or Rosenthal effect is a form of self-fulfilling prophecy wherein students with poor expectations from their teachers internalize their negative label and perform poorly, and those with positive expectations internalise their positive labels and succeed academically. Theory of Mind Theory of Mind (ToM) develops around age 3 ½ to 4 years. ToM refers to the understanding that other persons do have mental processes similar to self; in this context it forms an essential part of the social attribution process. Lack of development of the theory of mind (trait related) could explain the apparent lack of empathy seen in autism. In acute psychosis, state related deficits in ToM are noted i.e. the deficit is not pervasive but seen only when relapsing into positive symptoms. Poor ToM in association with reduced empathic ability is also demonstrated in conduct disorder and in antisocial personality disorder. First-order false belief tasks These tasks relate to the understanding that other people can have their own thoughts about a given situation. First-order tests involve inferring one person’s mental state e.g. What Jim thinks. Wimmer and Perner (1983) noted that three-year-olds tend to fail whereas four-year-olds tend to succeed a false-belief task called Sally-Anne Test. Children are first shown the picture of Sally, leaving a chocolate on the counter before departing the scene. Anne later comes in and moves the object from the counter to a box. The children are then asked to predict where Sally will look for the chocolate when she returns to the room. Children aged 4 and above generally grasp the notion that Sally will hold a false belief and look at the place where she left the chocolate initially. 3-year-olds fail to ascribe this false belief to Sally. In the deceptive container task, a child is shown a closed candy container and is asked, “What’s in here?” When the child answers ‘candy’, the container is opened, revealing a pencil. Later when the child is asked what she originally thought was in the container when she was first asked, Three-year-olds incorrectly answer “a pencil,” demonstrating a lack of false belief whereas 4year-olds correctly say “candy.” # 10 - Interpersonal relationships # Interpersonal relationships © SPMM Course Flavell et al. (1986) noted that children older than 4 years old distinguish appearance from reality and show an ability to discuss objects that have misleading appearances (‘it looks like an apple but it is really a ball’). Note that when task demands are reduced, even 15-month old show some signs of ToM. Furthermore, many children with autism and Asperger’s syndrome, can pass first order tests albeit at a developmentally later age (average 5.5 years according to Happe et al., 1995) Second-order false belief tasks These tasks relate to the understanding that other people (a second person) can have their own thoughts about another (third) person’s state of mind. Second-order tests involve inferring one person’s thoughts about another person’s mental state e.g. What Jim thinks that Varun thinks. These tests are usually passed by the age of 6 years in typically developing children. Children with autistic spectrum disorders may never pass second-order false belief tasks or pass only by teenagers. Key neural regions for normal ToM are considered to be the amygdala, orbitofrontal cortex, inferior parietal and medial frontal cortex. Interpersonal relationships Following factors influence relationships: 1. Proximity: minimal requirement for most relationships. 2. Exposure refers to reciprocal disclosure – this may enhance the relationship. Females do more self-disclosure than males. 3. Similarity – may increase self-esteem in a relationship as one gets validation for similar interests. 4. Complementarity – not so important initially but increases in importance as a longterm relationship develops. 5. Compatibility is proportional to both similarity and complementarity. Types of love:  Companionate love: True or conjugal love where intimacy and commitment seen; passion is not high.  Passionate love: intimate and passionate but not much commitment – obsessive, romantic and infatuated.  Consummate love: intimacy, passion and commitment all well mixed. # 11 - Linguistics of interpersonal communication # Linguistics of interpersonal communication # 12 - Persuasive communication # Persuasive communication © SPMM Course  Fatuous love: passion and commitment but no intimacy seen. According to SVR theory, – relationships proceed from Stimulus (external attributes) to Values to Role stage. Linguistics of interpersonal communication Some linguists view language as a “system of signs that have been developed to serve the communicative needs of people living in a social context”. Thus language is a product of sociocultural evolution. In this context, language serves 3 functions: 1. Ideational Function: enable people thinking with language to interpret experience. 2. Interpersonal Function: enable people acting with language to communicate experience and thoughts 3. Textual Function: enable people organise of a message with language. Fields of enquiry in linguistics • Phonology: The study of sound structure • Morphology: The study of sound structure • Syntax: The study of sentence structure • Phonetics: The study of physical act of speaking • Semantics: The study of the connection of language to meanings. Semanticists consider that meanings are inherent in sentences; while communication-intentionists consider that meaning is not inherent but comes from something that people do when using language • Pragmatics: The study of the connection of context to meanings. • Sociolinguistics: The study of the connection of language to social situations • Semiotics: The study of signs and symbols in relation to their form and content Whorfian hypothesis or Sapir-Whorf linguistic relativity hypothesis states that the semantics of a language can affect the way in which its speakers perceive and conceptualize the world. Language determines the basic categories of thought and that, as a consequence, speakers of different languages think differently. This extreme position is also called linguistic determinism. Noam Chomsky argues against this stance (see Language Development section in the notes on Human Development). Persuasive communication Techniques of persuasive communication (e.g. used by sales representatives) include 1. Ingratiation: eliciting likeableness © SPMM Course 2. Reciprocity: doing a favour first, making one indebted. 3. Arousal of guilt 4. Scarcity: ‘offers valid only till stocks last; so hurry!’ 5. Social validation: ‘everyone is going to Argos? What about you?’ 6. Multiple requests 1. Foot in the door technique: if one agrees to small request this increases the likelihood of saying yes again. 2. Door in the face technique (concession effect): when a larger request is turned down initially this increases the likelihood of agreeing to a smaller subsequent request. 3. Low-ball tactic: hiding the costs and disadvantages initially but revealing after an agreement is reached. When attempting to persuade others, one-sided arguments may strengthen existing beliefs but two-sided arguments more effective in changing beliefs/attitudes. Similarly, highly fear-inducing messages may increase anxiety but may not result in behaviour change (Jansis & Feshback 1953); while moderately fear-inducing messages can produce greater behaviour change in some instances. Thus, an inverted U-shaped curve relates fear and attitude/behaviour change. Feeling vulnerable also increases behaviour change. The credibility of a perceived message has been found to be a key factor affecting persuasive communication (Hovland & Weiss, 1951); if we read a report about health in a professional medical journal, we are more easily persuaded than if we read it from a tabloid. Propaganda refers to mass suggestion or influence via emotional manipulation of an individual. While educating an individual about an issue gives independence for making a judgment, propaganda over an issue provides ready-made judgments to be adopted by the individual. This may be done using 1. Induction of stereotypes 2. Substitution of names to facilitate scapegoating and scaremongering 3. Selected facts presentation 4. Repeating same messages in various forms 5. Presenting assertions instead of rational arguments 6. Pinpointing an enemy # 13 - 4. Leadership, social influence, power and ob # 4. Leadership, social influence, power and obedience # 14 - Conformity & obedience # Conformity & obedience © SPMM Course 4. Leadership, social influence, power and obedience Conformity & obedience Conformity is a process where no explicit requirement is made to do a certain task, but peer influence, and the need for acceptance pushes one to carry out the task. Obedience refers to conditions where the individual is explicitly asked to do a task, and this instruction comes from an authority. Conformity can be either true internalisation of values or compliance externally without changing one’s private beliefs. Men conform less than women; people with lower intelligence, poorer ego strength, poor leadership abilities and having inferiority feelings conform more often. Sherif used an autokinetic effect (the apparent, false perception of movement of a pinpoint of light in a dark room, aka Phi Phenomenon) to study conformity. Individuals initially provided idiosyncratic responses (individual norms) when asked about the distance moved by the light source. But when subjects were grouped together, individuals compromised on their assessments and gave modified answers, so as to conform to the rest (group norms emerged). Asch used an unambiguous paradigm (length assessment test) to study conformity. It was noted that the size of group majority up to 3 to 5 people influenced conformity; a much larger majority did not influence individual decisions. Further, the more unanimous/consistent the majority was, the more the conformity of the rest. Giving opinions privately reduced conformity. Collectivist cultures showed more conformity than nuclear cultures. Can minorities effectively influence the majority? This is possible if the minority is consistent, perceived to be autonomous and having real interest in the issue at hand, appear to have CONFORMITY OBEDIENCE No explicit instruction given Instructed explicitly Peer influence is the source Authorities are the source of pressure Mutually a subject can influence Mutuality absent as it is one Need for acceptance Need for compliance Done by ‘example’ Done by ‘directions.' Factors increasing obedience Factors reducing obedience Authority figure providing instructions Administering by proxy Relieving the subject from responsibility for actions Achieving ‘agentic state.' Authoritarian personality of subjects (they obey more!) Proximity to shocked victim Remoteness of authority Peer rebellion against instructions Increased sense of responsibility for plight of the victim # 15 - Group processes # Group processes # 16 - Social power # Social power © SPMM Course balanced flexibility, and if the minority appeared to have some similarity to the rest of the group. Milgram’s experiments on obedience: Subjects were recruited by an authoritative university faculty and were asked to administer electric shock to victims kept in a different room by pressing buttons. The sham victim would make crying sounds in pain on increasing the dose of electricity. Group processes There are various processes that influence individuals when making decisions as a part of a group. The group can make more risky decisions than what an individual him/herself can. This is called risky shift. A group discussion process can strengthen average individual inclinations and polarise the group in the direction where most individuals were heading already. This is called group polarisation. While making extreme decisions, the desire to agree with other members of a group can override rational judgment applicable in individual decision-making. This is called groupthink. Group processes, especially polarization, are considered to be due to three underlying phenomena:  Normative influence: People have a need not to appear odd or ‘stick out’ like a sore thumb. So they say yes to what others in the group say.  Informational influence: Having more information after group discussion can facilitate decision-making  Social identity: A group norm is established soon after a group is formed. This creates a social identity and pressure to conform to maintain the belongingness. Robert Bales made observations around small group communication in early 1950s. In small groups, discussion initially tended to shift back and forth quickly between a task and its relevance to the group members. This helped to balance task completion and group cohesion. Later a linear phase emerged – the discussion moved from a mere exchange of opinions to evaluating values underlying a decision and then to making a decision. He also noted that no matter how large the group, the most talkative member spoke for 40-50% of the time, and second most talkative 23-30% of the time – dominating the conversation to the detriment of the others. Social power French and Raven identified 6 sources of social (or organizational) power. They used the term Bases of Social Power to describe these factors. # 17 - Leadership # Leadership # 18 - Social Influence # Social Influence © SPMM Course 1. Reward Power - based on the perceived ability to give positive consequences or remove negative ones 2. Coercive Power - the perceived ability to punish those who not conform with your ideas or demands 3. Legitimate Power - based on the perception that someone has the right to prescribe behaviour due to election or appointment to a position of responsibility 4. Referent Power - through association with others who possess power 5. Expert Power - based on having distinctive knowledge, expertness, ability or skills 6. Information Power (Similar to 5) - based on controlling the information Leadership Lewin (1939) identified the following leadership styles.  Autocratic – leader’s decision-making occurs without consultation from the others and causes the most discontent. It works if no need for input on decision i.e. that motivation would not be affected by not being consulted.  Democratic – leader’s decision-making involves others though the decision may ultimately made by the leader having facilitated group discussion and discussed opinions. It is a well-regarded process but can be time-consuming.  Laissez-Faire – leader’s involvement in decision-making is minimal, so others make their own decision. It works well if those involved are capable and motivated, and no need for central coordination. Social Influence Kelman described three psychological factors that underlie the process of influence of one person on the other in social settings.  Compliance – responding favourably to a request (implicit or explicit) from another. It is a change of behavior rather than a change in attitude (i.e. one can hold private objections but still comply). Satisfaction from compliance is due to the positive social effect (i.e. reward or avoid punishment).  Identification – change in attitude/behavior due to the influence of someone that is liked e.g. celebrity endorsement. A resultant desired relationship the identifier relates is the reward.  Internalisation – process of acceptance of a set of norms established by a person/group influential to the individual. The content of the influence is intrinsically rewarding. # 19 - 5. Intergroup behaviour # 5. Intergroup behaviour # 20 - Prejudice # Prejudice © SPMM Course 5. Intergroup behaviour Prejudice Prejudice is essentially an attitude. It has 1. Cognitive component – stereotypes 2. Affective component – hostility 3. Behavioural component – which according to Allport can be a. anti-locution b. avoidance c. discrimination d. physical attack or e. extermination in terms of increasing severity. Prejudice can be positive or neutral as well as negative though the term is mostly used to describe negative prejudice. Theories of prejudice  Adorno’s authoritarian personality theory: Authoritarians are prejudiced in a generalised manner; difficult upbringing and disciplinarian rules in childhood may lead to a projection of difficulties on minorities. But this theory does not explain the sudden surges of prejudice that occur in history. It has no experimental proof either.An allied theory says that ideological dogmatism in rigid, authoritarian people can explain prejudice.  Scapegoating theory: It is related to the frustration-aggression model of Dollard. In situations of extreme frustration when the source of such frustration is too powerful, we may tend to displace aggression towards a soft target – the scapegoat. The choice of scapegoat depends on the prevailing social mood. Hence, the society provides the content of one’s prejudice though one’s personality may predispose to such prejudice according to Adorno.  Relative deprivation theory: This supplements scapegoating theory. The discrepancy between actual attainments and expectations of a society is called relative deprivation. Any acute changes can cause a sudden substantial relative deprivation, leading to unrest and scapegoating follows. Note that the relative deprivation is subjective to individuals in a group, and the competition may be within individuals (egoistic) or between groups (fraternalistic).  Realistic conflict theory: This asserts that the mere suggestion of competition is enough to trigger prejudices. Famous Robber’s Cove experiments by Sherif supported this theory. The mere perception of another group’s existence can spark discrimination. At a summer camp at Robber’s Cove, two groups were created from unrelated individuals. Even when © SPMM Course these groups were allowed to interact freely, they developed strong in-group preferences and anti out-group ideas. When a competition was introduced, the groups exhibited a high degree of aggression and hatred against each other. Sherif concluded that mere competition is sufficient to create conflicts, and no real lack of resources or acute deprivation is necessary.  Social identity theory: An individual’s positive self-image depends on both personal and social identities. So each individual strives to improve his group’s success to foster his own image. This leads to prejudice against other groups. How to reduce prejudice?  Blue eyes and brown eyes experiment (Elliott): Prejudice exhibited by a person could be lesser when he/she himself experienced such prejudice in the past. In a class room, blueeyed children were initially treated badly by instructing brown eyed pupils that blue eye stood for inferiority and weakness. When the roles were reversed later, and opposite information was now provided, supporting the supremacy of blue-eyed children, the amount of aggression shown was lesser. This suggested that when one experiences prejudice first hand, his own discriminatory behaviour reduces later.  Contact hypothesis (Allport): When contact occurs between opposite group members under equal status and in pursuit of common goals, this can reduce prejudice. Personal friendship is not needed though. Due to lack of knowledge about what happens in the other group a degree of autistic hostility exists. This reinforces negative stereotypes as mirror image phenomenon i.e. ‘we are right, so they are wrong’, etc. Also, one group starts believing that the members of the opposite groups all are alike – illusion of out-group homogeneity. # 21 - 6. Aggression # 6. Aggression © SPMM Course 6. Aggression There are several types of aggression as outlined below.  Hostile aggression: aimed solely at hurting someone.  Instrumental aggression: used as a means to an end – may be self-defense or to attain something. Instrumental aggression is carried out for the purpose of achieving a particular goal e.g. kidnapping for ransom. Hence, it is often planned and not impulsive. Hostile (also called angry or affective) aggression is motivated by the need to express negative feelings, such as anger.  Positive aggression: combating prejudice, self-defense.  Pathological aggression: violence for the sake of being violent- may be associated with pathological personality.  Overt aggression: This is readily observable, either reactive & impulsive or proactive, planned aggression.  Covert aggression is much more subtle, e.g. telling lies, spreading rumours, excluding a child from a group of friends, etc. It is seen more in girls than boys. Hydraulic or build up models  Psychoanalysis Theory: Human aggression is due the death instinct Thanatos - an instinctive biological destructive death related urge that gradually builds up in everyone and must at some point be released.  Evolutionary Theory: Through the process of natural selection, aggression ensures survival of the aggressor’s genes passing from one generation to the other. It helps in the fight for the survival of the fittest.  Lorenz studied animal aggression and proposed that features such as territorial imperative are linked to the survival benefits of aggression. According to him aggression is a fixed action pattern elicited by specific sign stimuli. But he found non-human aggression to be mostly constructive. Ritualisation refers to a series of stereotyped fight scenes, carried out by animals without actual physical harm to both the victor and the vanquished. Appeasement rituals or gestures form a part of such ritualisations in which certain behaviours (e.g., lying down, dropping and tucking one’s tail) can reduce aggression expression. Non-hydraulic models These models refute the notion of ‘building up’ and ‘release’. © SPMM Course  Genetic theory: It is controversial whether aggression is inherited; it is often the case in animal species. But in humans however, people may not necessarily inherit the tendency to be aggressive; instead they may inherit certain temperaments, such as impulsiveness, that in turn make aggression more likely (Baron and Richardson, 1994).  Social learning theory: Bandura’s ‘Bobo Doll’ experiments provide impressive demonstrations of the power of observational learning. When children observe an aggressive model, they often reproduce many of the model’s acts precisely, especially if the model’s aggression was rewarded. Vicarious conditioning refers to a kind of observational learning where learning is influenced by seeing or hearing about the consequences of others’ behaviour. Observational learning can occur even when there are no vicarious effects of reinforcement, but the performance of an aggressive behaviour is more likely if vicarious reinforcement was observed instead of just seeing behaviour in isolation without knowing its consequences.  The frustration-aggression hypothesis was originally proposed by Dollard et al. (1939). It holds that frustration always results in aggression and conversely aggression will not occur unless a person is frustrated. But this is not true as sometimes frustration produces depression or withdrawal instead of aggression. The modified frustration-aggression hypothesis considers aggression to be one of the many possible products of frustration. In a meta-analysis including 49 studies, Marcus-Newhall et al. (2000) found consistent evidence that frustrated individuals show displacement of aggression from the source of the frustration onto a less powerful or more accessible target.  Berkowitz (1993) later modified Dollard’s proposal. This is called aggressive cue theory or weapons effect: Frustration produces not aggression but a readiness to respond aggressively; once this readiness exists, cues in the environment (e.g. knives, guns, etc.) will often lead a frustrated person to behave aggressively; neither frustration nor cues alone can trigger the aggressive behaviour.  Generalised arousal theory maintains that arousal (e.g. physiological) from one source may energise some other response. This is called transferred excitation (Zillman).  Festinger’s deindividuation theory: According to this, people in-group context act uncharacteristically more aggressive as a sense of identity and belongingness and diffusion of responsibility occurs in groups. Similarly, uniforms can reduce individuality, promoting expression of aggression (hence its use in Police and military forces). But deindividuation does not always cause aggression. Media influences on aggressive behaviour: TV can influence through modelling effects. In a natural experiment at St Helena Island when TV was first introduced, some increase in prosocial behaviour was recorded, surprisingly. Media influence is mediated via # 22 - Stress and aggression among primates # Stress and aggression among primates © SPMM Course 1. High arousal 2. Disinhibition – ‘this is happening everywhere; it is not uncommon.' 3. Imitation: e.g. copycat crimes and suicides – Shannon Matthews incident in UK (2008) is speculated to be akin to a channel 4 drama episode (Shameless). 4. Desensitisation: due to repeated showing 5. Priming- enhancing automatic associations of certain stimuli with a crime. Family background and aggression: Aggressive children tend to commit violent and non-violent offences in adulthood. Antisocial behavior is much more common in men. Harsh and inconsistent discipline and an absence of positive parenting may be an aetiological factor in aggression. Note that cultural differences exist in expression of aggression; it is said to be much more common in individualist than in collectivist cultures (Oatley, 1993) Stress and aggression among primates  In most species, dominance ranks influence the extent of sustaining stressors. It is too simplistic to say higher / lower ranking individuals have the highest stress or aggression levels. The actual amount of stress and aggression depends very much on group’s social structure and dynamics.  Ability to avoid confronting dominant individuals will reduce stress levels. When this is lost in captivity (artificial environments) the subordinates show high-stress hormones. For example dominant wolves have more cortisol in the wild; subordinates have higher levels in captivity.  The most frequent context in which aggression is seen is in defense of status. But the best fighter does not become the highest-ranking individual in a group all the time (ability to form coalition and source social support are important).  In some species, aggression is a primary cause of mortality.  The most important modulating influence on aggression is social dominance; once it is established the rate of aggression drops substantially.  Aggressive encounters are highest among adolescent males during group migrations. Aggression is also higher under conditions of crowding.  Males are generally more aggressive than females, but once dominance is stabilized, males have a substantial drop leading to females showing higher aggression than or as high as males.  Mating competition can increase male-to-male aggression. The presence of children can act as agonistic buffers to reduce aggression among both males and females in some species. © SPMM Course  Socially living primates learn social cues of aggression and restraint from the early period of development by observing their parents and older individuals; they later practice these skills with their peers. In fact, parental control is essential for the development of cortical areas involved in impulse control.  Coping outlets for stress include social support (grooming, coalition formation and physical contact). Reconcilative behaviour immediately after a competition may help the loser to cope. Poor availability of this support with low presence of kin will increase stress among subordinates. # 23 - 7. Altruism # 7. Altruism © SPMM Course 7. Altruism Any action that is intended to help others is called Prosocial Behaviour in psychology. Altruism is often considered to be a motivation behind people’s prosocial acts. Altruism refers to the wish to help others with no expectation of reward. Bystander apathy: When alone, individuals will typically intervene if another person is in need of help: this is called bystander intervention. But intervention becomes less likely to an extent that no single person will intervene from a crowd or group of observers when someone is in need of help. This is called bystander apathy or Genovese effect. Pluralistic ignorance: This refers to members of a crowd looking at each other for signs of distress but remaining calm themselves, leading to misappraisal of the situation being safe leading to lack of intervention. Bystander competence is usually not required for intervention except in ambiguous situations where technical help is required e.g. blood at the scene. According to arousal/cost-reward model, emotional arousal on seeing a victim increases motivation to act. But a cognitive appraisal of costs and rewards occurs before an intervention is carried out. If the cost of helping is high, the bystander undertakes a cognitive reinterpretation - calling the situation as non-urgent, blaming the victim or diffusing or dissolving responsibility. Diffusion of responsibility: Similar to social loafing – ‘I have some responsibility, but so do others; let someone else help.' Dissolution of responsibility: Not knowing what others are doing, rationalizes that someone would have helped the victim. Males show higher agentic help and intervention while females show higher communal help and empathy. Social loafing: This is also called Ringelmann’s effect. It is seen in games such as tug-of-war and in clapping hands after a performance. The larger a group is, the less the individual performance - as one thinks the others will do the job © SPMM Course Notes prepared using excerpts from  Sapolsky, R. (2005) The Influence of Social Hierarchy on Primate Health Science, 648-652  Thambirajah, MS. Psychological Basis of Psychiatry, Elsevier 2005  Gross, R. Psychology: The Science of Mind and Behaviour, Hodder Education; 6th Revised edition  Wolff, P., & Holmes, K. J. (2011). Linguistic relativity. Wiley Interdisciplinary Reviews: Cognitive Science, 2(3), 253-265.  Baron-Cohen, S., Leslie, A. M., & Frith, U. (1985). Does the autistic child have a “theory of mind”?. Cognition, 21(1), 37-46.  J. French and B. Raven, The bases of social power in D. Cartwright and A. Zander (eds.), Group dynamics (pp. 607-623). New York: Harper and Row, 1960 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgments have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information # 03 - 13_Sociocultural_Psychiatry # 01 - 1. Social Classification # 1. Social Classification © SPMM Course 1. Social Classification In Britain occupational classification forms the principal mode of social classification: The social class of a household is determined on the basis of the head of a family. Dominance and dependence are two essential underlying themes behind the categorical divisions of social classes. Most psychiatric disorders are more common in lower social classes; with controversial exceptions noted for anorexia, alcohol use and bipolar disorders. Anorexia: It is debatable whether social class affects the true prevalence of anorexia or whether the differential rates noted in various studies reflect variations in helpseeking/referral pattern. At present the growing consensus is that the social classes 1 and 2 are more prevalent in clinical (as opposed to community-based) samples but there are no differences in distribution of various clinical features across the social groups. The quality of family relationships and types of family constellations are also broadly consistent across the social classes in affected families. A prodrome of excessive diet consciousness and the actual onset of the disease itself are noted at somewhat younger ages in social classes 1/2. Community studies have shown that the degree of urbanization has a significant impact on the prevalence of anorexia, bulimia and binge eating disorder (Favaro et al., 2003). Social class, professional status, and education are not associated with an increased risk of reporting an eating disorder in such community samples. Bipolar disorder: An overrepresentation is found in the higher occupational class in bipolar probands' brothers and children. It is consistently noted that the family of origin in bipolar probands belong to a higher social class though the patients themselves might be at a lower social class. Tsuchiya et al., (2004) showed that higher social class of parents together with longer paternal education history and larger possession of wealth increased the risk of bipolar disorder in the offspring. It is speculated that ‘bipolar genes’ may offer some survival benefits such as superior creativity or productivity, which uplifts the families to higher social status. Suicide: The relationship between suicide and social class has not been conclusively established as of yet. While some authors have reported that higher social class is related to higher rates of suicide, most other studies indicate that lower social class is associated with Classes Categories Class 1: Professional, managerial and Class 2: Intermediate Class 3: Skilled, manual, clerical Class 4: semi-skilled Class 5: unskilled Class 6: unemployed © SPMM Course higher rates of suicide. It is shown that among mentally ill, the higher the social class, the more the risk of suicide (Silverton et al. 2008). Alcoholism seems to defy social class boundaries. A Swedish conscript study (Hemmingson et al., 1999) reported that intergenerational social mobility that is associated with healthrelated factors, but not alcoholism itself, makes a significant contribution to explaining variation in the rates of alcoholism among the different social classes. The class-related differences in alcoholism among young adults seem to be influenced heavily by factors that are established by adolescent years. But such adverse conditions did not seem to be well reflected by social class of origin. By far, a significant influence on the prevalence of alcoholrelated harm seems to be the public health policy regarding pricing and the sales of alcohol. In all aspects of health including life expectancy, infant and maternal mortality, there is a discrepancy between social classes, despite the existence of the NHS, which was developed to combat this. There is a question of whether the low social class has lead to poor health or if poor health leads to deterioration in social status (as suggested in the Danish bipolar study above). There is a consideration for cultural differences among social classes in terms of diet, exercise, alcohol intake and awareness of mental health problems and the treatments available. JARMAN INDEX A scoring system developed by the British general practitioner Brian Jarman for the level of social deprivation in a community, using census data on percentages of old people living alone, single-parent families, children younger than 5 years of age, unskilled and unemployed persons, ethnic minorities, overcrowded dwellings, changes of address in previous year, etc. Although a valid indicator, it is not generally accepted outside the United Kingdom. # 02 - 2. Sick role and illness behaviour # 2. Sick role and illness behaviour © SPMM Course 2. Sick role and illness behaviour The sick role is a concept described by the American sociologist Talcott Parsons with 4 characteristics: The sick person is freed or exempted from carrying out normal social roles. The more severe the illness, the more is the freedom from normal social roles. This is granted to everyone in society irrespective of social status. People who are ‘sick’ are not directly responsible for their disease. They are not blamed or expected to take the blame, and if one takes self-blame, this is viewed as odd behaviour. It is necessary that a sick person tries to get well. The sick role is regarded as a temporary stage that should not be prolonged if at all possible. A sick person must seek competent help and cooperate with medical care to get well. This implies that a doctor is an agent of social control – one that restores people’s social roles. The concept of disease: Disease: refers to actual pathology (e.g. a process that results in illness) Illness refers to personal experience (a set of symptoms suffered by a patient) Sickness refers to social consequences (e.g. absence from work) Health behaviours are seen in healthy people who try to maintain their health – these are related to primary prevention of disease and are intended to reduce susceptibility to disease in the first place. Mechanic and Volkart, 1961, proposed the concept of illness behaviour which refers to any behaviour undertaken by an individual who feels ill to relieve that experience or to better define the meaning of the illness experience. Illness behaviour is an active process “that involves interpreting symptoms, evaluating possible responses and, finally, deciding whether to try to alleviate those symptoms or simply to ignore them”. Abnormal illness behaviour (Issy Pilowsky, 1969) is an extension of the concept of illness behaviour; it is defined as the persistence of a maladaptive mode of experiencing, perceiving, evaluating, and responding to one’s own health status, despite the fact that a doctor has provided a lucid and accurate diagnosis and management plan (if any), with opportunities for discussion, negotiation, and clarification, based on adequate assessment of all relevant bio-psycho-socio-cultural factors. These can be excessive illness affirming (e.g. somatoform or malingering) or denying behaviours (e.g. loss of insight in psychosis). Factors influencing individual response to illness  Symptom visibility & their perceived importance  Assessment of symptom’s significance  Potential for symptoms to disrupt community  Symptom denial for fear of confirmation of serious illness  Deferring response to symptoms because of competing social demands  Assessment of social & economic costs of responding to symptoms versus potential health-related benefits © SPMM Course  Available information knowledge & cultural assumptions & understandings  Symptom frequency & persistence  Competing interpretations of symptoms International Classification of Impairments, Disabilities and Handicaps (ICIDH) provided a descriptive conceptual framework of consequences of illnesses. Impairment: interference with structural or psychological functions (that is, parts of the whole person e.g. loss of an arm’s function due to fracture). Disability is interference with activities of the whole person in relation to the immediate environment (simply ‘activities of daily living' e.g. not able to cook for oneself due to the fracture) Handicap is the social disadvantage resulting from disability (e.g. loss of work and inability to meet friends due to restricted driving secondary to fracture) Health Beliefs Model: The health beliefs model was developed with the observation that patients have their own beliefs about disease risks and treatment benefits. According to HBM patients’ beliefs about their disease states may be more influential than medically determined disease information. The health beliefs model identifies several factors for which patients’ beliefs may affect their treatment participation: (1) Patient’s beliefs about the severity of their condition, (2) Patient’s beliefs about their susceptibility of acquiring the disease or complications of the disease, (3) Patient’s beliefs about cost of treatment adherence (including costs in inconvenience, effort, time, and money), (4) Patient’s beliefs about benefits of treatment adherence, and (5) Patient’s beliefs regarding the environmental and social cues to action that may assist in their treatment adherence. The Transtheoretical Model (TTM) was developed by Prochaska and DiClemente (1982). This was developed largely in response to increasing divergence in the practice of psychotherapy, and the authors attempted a (transtheoretical) synthesis among the various therapeutic systems. They identified five common processes of change that are applicable to how individuals can be motivated to change their illness-related behaviours. These processes are (1) Consciousness raising – helping the patient gather information about self and the problem (2) Choosing – increasing awareness of healthy alternatives, (3) Catharsis – emotional expression of the problem behaviour and the process of change, © SPMM Course (4) Conditional stimuli – includes stimulus control and counterconditioning, a. Stimulus control: Avoidance of stimuli associated with the problem behaviour and the operant extinction cueing effect of the stimulus on behaviour. b. Counterconditioning: Training an alternative, healthier response to the cue stimuli. (5) Contingency control: Positive reinforcement from others and self-appraisal and improving self-efficacy by self-reinforcement. From these five processes of change, Prochaska and DiClemente identified six stages of change. These are (1) precontemplation, (2) contemplation, (3) Preparation, (4) action, (5) maintenance, and (6) relapse. In the precontemplation stage, a person is not even considering changing his or her behaviour, does not see the behaviour as a problem, minimizes and denies associated risks, and avoids information to the contrary. In the contemplation stage, the person has become aware of why the behaviour is a problem but is ambivalent about changing, and likely sees equal or more benefits than costs from the behaviour. During preparation, the person has made a decision to change, and is planning a strategy for change, but has not yet taken action. In action, the person has implemented a plan and is changing the behaviour. In maintenance, the person has been able to sustain the change and avoid reverting to problem behaviour for a significant period of time. In relapse, the person does revert to problem behaviour, ‘back to square one’.  These stages are not linear in sequence but rather cyclical, in that a person can relapse and reenter at a later stage such as preparation.  The stages do not operate in an invariant sequence (unlike Piaget’s models).  Each stage can be moved into back and forth (reversibility).  The stages are not qualitatively different. Motivational Interviewing (Miller & Rollnick, 1991) is often used together with TTM and stages of change. # 03 - 3. Social role of doctors # 3. Social role of doctors © SPMM Course 3. Social role of doctors General Medical Council (UK) and other professional organisations have expounded the concept of multitude roles expected from a doctor. The RCPsych has adapted this to suit the psychiatric practice. The Consensus Statement on the Role of the Doctor (from medschools.ac.uk) highlights the social role of the doctor:  To support patients in understanding their condition and what they might expect, including in those circumstances when patients present with symptoms that could have several causes  To identify and advise on appropriate treatment options or preventive measures  To explain and discuss the risks, benefits and uncertainties of various tests and treatments and where possible support patients to make decisions about their own care. •Accessing, interpreting and assimilating new knowledge critically Doctors as scientists Doctors as scientists •Listening and communicating appropriately, the ability to work as part of a team, non-judgmental behaviour, compassion and integrity Doctors as health professionals Doctors as health professionals •Making day-to-day clinical decisions based on medical knowledge to assess the impact, risk and likely outcome of decisions; apply skills in the development of policy, strategy, service design, and clinical processes. Doctors as leaders Doctors as leaders •Acting as critical decision makers with responsibility for allocation of significant health resources; influence to advocate for increased resources to improve health outcomes for their patients and populations Doctors as health advocates Doctors as health advocates •Accepting duty to contribute to the education of other professionals and patients in addition to carrying a responsibility for continued personal education. Doctors as teachers Doctors as teachers •Sharing a responsibility to positively influence the culture and the environment in which they work Doctors as health sector representatives Doctors as health sector representatives © SPMM Course  All doctors have a role in the maintenance and promotion of population health, through evidence-based practice.  The doctor must appreciate the needs of the patient in the context of the wider health needs of the population. For all doctors, the patient must come first but they will achieve this in different ways and in different settings. The social role of a psychiatrist includes being an appropriate role model providing effective support and guidance for those seeking treatment for psychiatric disorders and various societal dilemmas related to them. Some leaders extend this role as being a public figure in one’s community whose opinions are valued by laymen as well as other professionals and to serve as an ambassador for the profession by educating the public via various media outlets to erase misperceptions about mental illness or psychiatry (Henry Nasrallah in The model psychiatrist: 7 domains of excellence, 2011). Professionalism: There has been a great deal of interest in defining and adopting the concept of professionalism in psychiatry. American Board of Internal Medicine Foundation sets out three core principles specific to medical professionalism that is widely adopted by doctors in the US, the EU and the UK. The 3 principles are the primacy of patient welfare (based on dedication and altruism), patient autonomy and social justice. These principles are further set out in the 10 commitments recommended for developments to promote professionalism in medical practice (from Bhugra & Gupta, 2010): 1. Professional competence 2. Honesty with patients 3. Patient confidentiality 4. Maintaining appropriate relations with patients 5. Improving quality of care 6. Improving access to care 7. Just distribution of finite resources 8. Scientific knowledge 9. Maintaining trust by managing conflicts of interest 10. Professional responsibilities (including maximising patient care, self-regulation, remediation, disciplining) Health advocacy is the process of supporting and empowering patients and carers to express their opinions, ideas and concerns and enabling them to access appropriate information and services and promote their rights. Dual loyalty: World Medical Association’s Medical Ethics Manual highlights this issue when discussing professionalism. “When physicians have responsibilities and are accountable both to their patients and to a third party, and when these responsibilities and accountabilities are © SPMM Course incompatible, they find themselves in a situation of ‘dual loyalty’. Third parties that demand physician loyalty include governments, employers (e.g., hospitals and managed healthcare organizations), insurers, military officials, police, prison officials and family members. Although the WMA International Code of Medical Ethics states “A physician shall owe his/her patients complete loyalty,” it is generally accepted that physicians may in exceptional situations have to place the interests of others above those of the patient. The ethical challenge is to decide when and how to protect the patient in the face of pressures from third parties.” One such situation pertains to the issue of resource allocation. Resource allocation: In most countries governments decide the overall healthcare budget; institutions and local bodies decide the allocation to each service provided locally; doctors and healthcare professionals decide on the tests to be ordered, services to be offered and treatments to be provided. From the overall allocated budgets, the distribution of around 80% of healthcare expenditures is controlled by end-providers. Where resources are limited, all patients are entitled to a fair selection procedure for that resource. WMA recommends that this choice must be based on medical criteria and made without discrimination. In practice, physicians balance the principles of compassion and justice and are called to employ several approaches for resource allocation depending on where and when the need arises. LIBERTARIAN Resources distributed according to market principles (patient is a consumer; if he/thy have the willingness to pay, the resources will be made available to them). UTILITARIAN Resources distributed according to the principle of maximum benefit for all. EGALITARIAN Resources distributed according to the need (estimated by the provider). RESTORATIVE Resources should be distributed with a positive discrimination towards the disadvantaged (e.g. poor gets priority over the rich who can pay for private care). WMA notes “physicians have been gradually moving away from the traditional individualism of medical ethics, which would favour the libertarian approach, towards a more social conception of their role”. # 04 - 4. Family life in relation to major mental il # 4. Family life in relation to major mental illnesses © SPMM Course 4. Family life in relation to major mental illnesses Family is essentially the most basic social unit and microcosm of an individual. The General Systems Model of families holds that families are systems where every action in a family produces a reaction in one or more of its members. Such a system has external boundaries and internal rules, and every member is supposed to play a relatively stable but interchangeable role. Family cycle:  Stage 1: formation of the new family: 2 individuals unite - the  first child is born. Tasks include formation of working dyad and restructuring relationships with families of origin.  Stage 2: child rearing stage: birth of child  adolescence  Maintaining satisfactory marital relationship amidst the demands of childrearing is a major task.  Stage 3: child launching: Children leave home. Tasks include re-establishing individual interests and reexamining the marital relationship.  Stage 4: return of independence – growth and extension of family leads to the task of maintaining ties across generations  Stage 5: dissolution of the family: occurs due to decline or demise of partners. Family instability can affect children to a various extent depending on sex (boys affected > girls), age (younger affected > older children), and temperament hyperactive affected > placid). This has a demonstrable effect on a child’s cognitive achievements; the most common psychopathology noted is a behavioural difficulty. Family systems have been studied in detail with respect to schizophrenia especially. Lidz studied family systems in relation to schizophrenia and described two ‘schizophrenogenic’ family patterns:  Marital schism: family is in a state of disequilibrium due to repeated threats of parental separation. Parents downgrade roles of each other and may even attempt to collude with children and exclude partners.  Marital skew: family is at an equilibrium that is skewed and achieved at an expense of the distorted parental relationship. One parent may be dominant and other submissive, making the marriage ‘a stable fit’. Wynne and colleagues described certain communication patterns that may relate to the later development of perceptual and thought disorders in schizophrenia. Pseudo-hostility and pseudo-mutuality refer to the disjointed or fragmented communication where the child is © SPMM Course forced to accept and develop a pattern of communication that will negate and deny the existence of meaningless relationships in the family. Bateson described the double-bind relationship where superficial verbal communications contradict the behavioural and deeper communications among the members of a family. These mixed messages keep a growing child in a double bind (cannot be correct either way) that can later increase the risk of psychosis. Freida Fromm-Reichmann coined the concept of schizophrenogenic-mother. These mothers were described as 'rejecting, impervious to the feelings of others, rigid in moralism concerning sex and had a significant fear of intimacy'. Causal links between the above four family functions and schizophrenia are disputed, and these models have fallen out of favour in recent times. There is no experimental evidence to support these claims and any small data regarding the above theories are poorly reproducible. Expressed emotions concept was developed by Brown & Rutter in 1966 as a part of the Camberwell Family Interview [CFI] and later modified by Vaughn & Leff in 1976. The ratings were based on content and prosodic aspects and emphasis of speech. Five measures are considered; 1. Critical comments 2. Positive remarks 3. Emotional over involvement 4. Hostility 5. Emotional warmth The final scores of emotional over-involvement, critical comments and hostility were the most predictive measures for relapse of schizophrenia. CFI is a long interview process where individual members of a family are interviewed (including the patient). If one relative is classified as high EE person, then the whole family could be classified as a high EE family. CFI ratings based on interviewing parents singly have the most predictive value. A Five Minute Speech sample (FMSS) measure was introduced as a substitute for CFI, but it tends to underestimate EE. FMSS is more useful for measuring professional or staff carers’ level of EE. Studies have indicated:  Worldwide the proportion of high EE in carers of patients with schizophrenia is 52%. Lowest rates are found in India and other developing nations.  The strength of association between relapse and EE is identical for both genders. © SPMM Course  A meta-analysis of EE data reveals that for patients living in situations rated as showing high expressed emotion, the relapse rate is 50%, whereas in the ‘low expressed emotion group’ the rate is 21%.  In a majority of the studies, high expressed emotion was predictive of relapse in symptoms of schizophrenia 9 months later for both genders. A significant amount of face-to-face contact (more than 35 hours per week) with a relative with a high expressed emotion score increased the risk of relapse, but in households with a low expressed emotion score, high levels of contact appeared to be protective.  Pakistani families in the UK were more likely to be rated as high expressed emotion than White families, indicating that components such as emotional over-involvement may be cultural rather than pathogenic traits (Hashemi & Cochrane, 1999). # 05 - 5. Life events # 5. Life events © SPMM Course 5. Life events (This section is best read in conjunction with the section on Stress in Basic Psychology chapter) The impact of social and family life events on mental health can be measured in two ways. a. Ranking various events according to the degree of association with mental difficulties in a sample and use this list to study other populations. This is the method followed by Holmes & Rahe (1967) Social Readjustment Rating Scale where 43 life events in the last 2 years are rated using arbitrary ‘stress’ units. The death of spouse generates 100 units of stress while divorce tops the rest of the list of stressors list with 73 units. b. Brown and Harris popularized a different method whereby life events are graded according to the inherent meaning of the events to the individual concerned – i.e. contextual rating of the social adversity. Accordingly the effect and impact of a life event is understood in light of one’s current social context and self-perspective. LEDS – Life events and Difficulties schedule was devised by Brown and Harris. Types of life events 1. Loss includes events such as death, respondent initiated separation (long-term separation) and other key losses which are rated as ‘high’ by the subject. If the lower loss is felt by the subject, these are placed at lower dimensions. 2. Humiliation includes other-initiated separation from a spouse or partner or a falling out, quarrelling, or rift in a relationship involving a close tie with a reasonable inference that the separation would be permanent or long duration event. Here the separation or estrangement is either initiated by the other person or “forced” by circumstances such as the infidelity of the subject or marked violence. The delinquent behaviour of a child or a criminal act committed by a close tie could be a humiliation. ‘Put down’ events are events such as rejection or verbal or physical attack by a close tie, or any other person if the event is highly public. This may be humiliating or threaten a core role. It includes all rapes; if the subject feels responsible in some way this might increase the humiliation felt. 3. Entrapment includes long-term sustained entrapment includes serious difficulties that can only get worse or persist according to the subject; or a failed positive event where a potential fresh start went disastrously wrong within 1-2 wk, leaving the person stuck in ‘square one’. It is recognised that the unidimensional measure of severity of life events (either loss or threat, etc.) is not sufficient to explain the effects on mental illness. Combined loss and humiliation events are more depressogenic than a threat or other individual types of events. Humiliation events induce defeat and submission responses which may be directly related to depression. In a study by Kendler et al. (2003), humiliation predicted onsets of pure major depression but not pure generalised anxiety episodes, and danger © SPMM Course predicted pure generalised anxiety but not pure major depression episodes. But the results had only moderate strength in prediction. Depressed patients may recall more stressful life events due to cognitive bias. It is shown that the frequency of desirable or entrance life events in the depressed population is comparable to controls – so the absence of positive events cannot be the simple explanation for depression. It is demonstrated that those with a recurrent episode of depression have less preceding life events than those with the first episode of depression. This may be related to kindling phenomenon. Genes and life events: Kendler (1997) examined the relationship between genetic vulnerability to depression and the risk of experiencing stressful life events. A reverse causality effect (i.e. vulnerability to depression itself could explain the occurrence of more frequent stressful life events) was demonstrated. In a sample of over 2000 female twins, genetic liability to depression was associated with a significantly increased risk of experiencing an assault, serious marital problems, divorce/break-up, job loss, serious illness, major financial problems, and trouble getting along with relatives/friends. Similarly, the genetic liability to alcoholism impacted on the risk of being robbed and having trouble with the law. Hence, genes can probably impact on the risk for psychiatric illness by causing individuals to select themselves into high-risk environments. Therefore, life events are ‘heritable’ to some extent. Life events measures Semi-structured interviews  Life events & Difficulties Scale (Brown & Harris)  Interview for Recent Life Events (Paykel) Life events scales  Social Readjustment Rating Scale (Holmes & Rahe)  Adverse Childhood Events Scale  Hassles & Uplifts Scale (Lazarus & Folkman) . # 06 - 6. Social factors and mental health issues # 6. Social factors and mental health issues # 07 - Society as a risk factor # Society as a risk factor © SPMM Course 6. Social factors and mental health issues Society as a risk factor Engel’s model of biopsychosocial approach is widely used in aetiological formulations in psychiatric practice, highlighting the prominence of social factors in the practice of psychiatry. Social Causation Theory: According to this concept, mental illnesses are caused by social deprivation. Most psychiatric disorders are seen in lower socio-economic class as a mental disorder is seen as directly due to the poverty and social conditions. This theory may hold for some conditions such as depression or alcohol misuse, but not for others such as bipolar disorder or schizophrenia. In a survey sampling males aged 25-34 on first admission of schizophrenia, an expected excess of social class V was noted but social class distribution of fathers of the patients was the same as the general population suggesting that schizophrenia results in a downward drift of economic status rather than poverty being a cause for schizophrenia. This Social Drift or Social Selection Theory was first suggested by Faris & Dunham on the basis of their ‘Chicago study 1922 – 1934’ that explored the relation between the spatial distribution of psychosis and social organization by applying the concentric zone model of urban organization (see the figure from university of Manitoba, Centre of Health Policy website). In this model, the social organization increased with distance from the epicenter. (Inner urban zones = most disorganized and unstable communities; outer zones = most organized and stable communities). Faris and Dunham found that the least socially organized inner urban zones had the highest rates of schizophrenia; they argued that this effect was due to the downward drift in economic status after developing the illness. Factors mediating the effect of social class: Several factors such as lower educational levels, poverty, immigration, overcrowding, poorer physical health and nutrition influence the higher prevalence of mental illness in some social classes. For example, high parental education levels are associated with a lower risk of ADHD, especially in boys. There is no proven link with food additives but lead exposure is associated with risk. Similarly, # 08 - Sociology of mental illness # Sociology of mental illness © SPMM Course pregnancy complications such as toxaemia or eclampsia, poor maternal health, maternal age, foetal post-maturity, long duration of labour, foetal distress, antepartum haemorrhage, low birth weight and prematurity are associated with ADHD, increasing the likelihood of its prevalence among lower social classes. In fact, Rutter’s landmark studies revealed six inter-related risk factors in the family environment that correlated significantly with childhood mental disturbances in general: 1. Severe marital discord 2. Low social class 3. Large family size 4. Maternal mental health disorder 5. Paternal criminality 6. Foster placement. Rutter observed that the aggregate of these adverse factors, rather than the presence of any one factor, impaired development. Poverty and psychopathology: The Great Smokey Mountains study looked at groups of white American and American Indian children grouped into ‘poor’, ‘never-poor’ and ‘expoor’ (ex-poor were those whose income increased annually at later times due to a casino being built on American Indian land). The results showed that before the casino opened poor and ex-poor children had more psychiatric issues, but the levels in the ex-poor fell to the same as never-poor after the casino that produced good income for the ex-poor families opened. The most prominent psychiatric issues responding to poverty were conduct and oppositional defiant disorders while the prevalence of depression and anxiety remained the same. Sociology of mental illness Mental illness as deviance: Society tends to see odd and abnormal behaviour to be against acceptable norms and values and some of these are grouped as mental illnesses. Hence, the deviance becomes an important determinant of illness concept in psychiatry. Edwin Lemert developed the idea of primary and secondary deviance as a way to explain the process of labeling. Primary deviance is any general aberration from expected normality before the person showing such an aberration is identified as a ‘deviant. For example, primary deviance may refer to minor rule breaking in society such as over-speeding. With repeated instances of primary deviance, the subject gets labelled, and the institutions react to the deviant actions. This leads one to become secondary deviant. Secondary deviance refers to the actions carried out by a person identified as a ‘deviant’ by institutions such as the society or the justice system. This refers to the maintenance of primary deviance as a repercussion of the label given. © SPMM Course Thus, societal reaction initiates sociological/psychological processes which sustain deviance, making it more central to the life of the "deviant." Formal deviance includes breaking a written law or code of constitution as in criminal act; informal deviance includes breaking unspoken social rules of living. Deviancy amplification spiral: Originally applied to crime reporting, the theory identifies a spiral that starts with a ‘deviant’ act. The media report such acts as newsworthy and start regularly adding non-newsworthy items similar to this act (‘sensationalism’) setting up a bias against the so-called deviant act. As a result, minor problems look serious and rare events are perceived as common. A mounting public concern is the next stage in this spiral, forcing law enforcement to focus more resources on the particular deviancy than it actually warrants. Social construction theory explores how variations in human experience have come to be classed as illness categories; the method used for such investigation is ‘deconstruction’ or discourse analysis. According to the theory, the reality of mental illness is socially constructed and complicated by cognitive interests of social groups – doctors, lawmakers, politicians. Some examples include: 1. Agoraphobia as a concept developed around the time when the social emancipation of women occurred. The condition thus might be partly originated from problematized use of public space. 2. Sexual role stereotypes may play a role in anxiety disorder constructs and psychopathy. 3. Most major mental problems are circularly defined – e.g. a patient with schizophrenia is termed ‘psychotic’ as he hears a voice. When this patient enquires why he hears a voice, he gets told that he hears a voice because he is psychotic. Thus, most labels are circular descriptions constructed by the society. Social labelling or societal reaction theory: Labelling theory originated from the concept of symbolic interactionism. Each person plays many different social roles sanctioned by the society; in each role, interaction occurs with other people and meanings of such interactions are dependent on the role assumed. Thomas Scheff in his book Being Mentally Ill (1966) expanded labelling theory to mental illness.  According to Scheff, the social routine is made of numerous, uncategorisable residual rules. These are unspoken and taken for granted often.  Residual deviance occurs when these rules are broken, but often these are not noticed unless certain specific circumstances arise. Thus in certain circumstances rule breaking is accepted, ignored or normalised, but labelled deviant on other occasions. # 09 - Suicide and sociology # Suicide and sociology © SPMM Course  Thus societal-labelling may occur in one-off crises situations or as a gradual shift from acceptance to labelling, depending on contingencies i.e. the effect of such deviances on others concerned. This might explain the fact that numerous voice hearers live in the community without a diagnosis of schizophrenia and the results from community surveys always showing higher prevalence compared to clinical samples for almost all mental illnesses.  Once labelled as mentally ill, the labelled person takes up the role of being a mentally ill individual in the society. This new identity sanctions him certain privileges as a compensation for the loss of other privileges. Apart from the societal reaction, selflabelling will serve to strengthen beliefs with regard to the given role. Original labelling theory is empirical without much experimental support. A modified labelling theory is now used to explain the effect of stigma on relapses of mental illnesses. Suicide and sociology Durkheim, often adored as the father of sociology, described a sociological model of suicide and described 4 types of suicides. According to him, both an unusually ‘tight’ bondage and a weak adherence to defined societal values can contribute to suicide. These are called altruistic and anomic suicides respectively. Other 2 types are described below. The Social Origins of Depression Brown and Harris (1978) studied social & economic circumstances associated with the onset of depression in women living in inner London in 1978. They identified 4 ‘vulnerability factors’: 1. Absence of a close confiding relationship; 2. Loss of mother before age of 11; Durkheim’s model Explanation Altruistic suicide Individual is overly attached to social norms and dies for the sake of the society (i.e. for others in the society) e.g. self-molestation among Buddhist monks in Tibet Egoistic suicide Excessive individualism, but low social integration. No cohesive group attachment Fatalistic suicide Society’s control on the individual is very strong such that it interferes with moral values and personal goals Anomic suicide Individual feels that he has no guidance or regulations from the societal system; feels disillusioned © SPMM Course 3. Lack of employment outside home; 4. Having 3 or more children under 15 living at home. Brown et al.’s further work has revealed the following factors for depression (elaborated by Morris & Morris, 2000); 1. Predisposing factors: these occur before the age of 17. a. Sexual abuse b. Parental indifference c. Parental loss d. Physical abuse (See Brown & Harris original vulnerability factors above) 2. Precipitating factors include a. Acute severe life event b. Chronic stress more than 4 weeks c. Lack of social support 3. Maintaining factors include a. Further negative life events b. Persistent poor quality social support c. Poor coping style: i.Self-blame and helplessness ii.Denial of problems iii.Inability to solve problems iv.Blaming others or external forces d. Inability to obtain adequate social support: i.Fear of intimacy ii.Denial of need for intimacy iii.Enmeshed intimate relationship e. Low educational level 4. Relieving factors may include a. Positive life events such as i.Fresh or potential fresh start: new role, positive change ii.Removal from source of stress: e.g. separation from violent husband iii.Anchoring: role change and increased security iv.Difficulty neutralisation: ending a difficulty v.Goal attainment. b. Improved quality and consistency of support # 10 - Social factors in schizophrenia # Social factors in schizophrenia © SPMM Course Social factors in schizophrenia The significant social disadvantage (e.g. experience of racism, discrimination, economic and employment disadvantage, the perception of ‘outsider status’) is evident in populations with a higher risk of schizophrenia. According to the social defeat hypothesis, “long-term experiences of social disadvantage lead to sensitization of the... dopamine system and (or) to increased baseline activity of this system, thereby, to an increased risk for schizophrenia." Immigrant populations exemplify this link between social factors and schizophrenia. Stress and Social Adversity: Social adversity is associated with high degree of stress that can be exceptionally harmful in the context of vulnerability to psychosis. This has been demonstrated in many animal studies. Childhood Abuse and Family Dysfunction: While child abuse is not seen as a specific risk factor for schizophrenia, it is now accepted that childhood abuse may be a marker for other potential relevant risk factors, such as family dysfunction that increases the risk. Neighbourhood effect: In neighborhoods with ethnic minorities (non-white) that were at an increased risk, the risk reduced when the population of minorities increased. Similarly, natives had an increased risk in neighborhoods where minorities were larger in number, supporting the notion of social adversity in increasing the risk of schizophrenia. Urban Effect  There is a large deal of evidence now to support that in most parts of the globe, children born in urban environments are at an increased risk for psychosis (OR:1.61; CI: 1.4 – 1.8).  This urban-birth effect is not consistent among all countries; some Australian research has no increase in psychosis among urban areas.  Marcelis et al. (1998) (Dutch National Psychiatric Register study) found that the effect of urbanicity on all psychosis was greater for men than for women.  The effect of urban birth was greatest for individuals from the most recent birth cohorts and with an early-onset disease even after correcting for the length of followup.  Another study noted a positive correlation between admission rates for schizophrenia and degree of urbanization. There is a consistent dose–response relationship between urbanicity and risk of schizophrenia; the larger the town of birth, the greater the risk. © SPMM Course Immigration and schizophrenia Though the frequency of most mental illnesses are found to be higher in migrants that the natives, schizophrenia has been studied the most. Conflicting explanations have been offered to explain why migrants have more schizophrenia. Cooper has revisited and reappraised the data available and summarised the main findings as below: a. The excess risk is not specific for African—Caribbean immigrants. It is also present among African-born Black immigrants to the UK, and to a lesser extent among immigrants from Asian countries. Hence, any explanation cannot be purely biological and not simply race specific. b. Incidence rates of schizophrenia in Caribbean countries are similar to those found in the indigenous UK population; this excludes country of origin theory which proposes that the immigrants carry such higher incidence rates from where they come from. The rate for schizophrenia in second-generation African—Caribbean people born in the UK appears to be higher than in the first generation, which is strongly suggestive of an environmental rather than a genetic effect. c. According to this notion of prepsychotic segregation, individuals who are psychosis prone find it hard to survive in the countries of birth and so immigrate to other regions. There is no evidence for selective immigration from the Caribbean as part of a pre-psychotic segregation. Also notable is the fact that apart from 1st generation immigrants having higher rates of psychosis, the 2nd generation children of immigrants also have a very high rate of psychosis (in some cases, higher than their parents), negating the probability of psychosis-induced immigration. d. The immigrants’ pathways to psychiatric care are characterized by long delays in seeking professional help, a lower likelihood of psychiatric referral, and frequent involvement of the police and emergency services and high proportions of compulsory and intensive care and secure (locked) ward admissions. The long-term outcome tends to be correspondingly unfavourable for immigrants. Hospital admission rates are consistently noted to be higher among ethnic minority population as a whole but variations between groups. In UK, highest rates of hospital admissions were noted among Irish migrants followed by people born in Caribbean. The rate of mental illness among South Asian population is notably lower than UK-born white population. It is unclear if these are effects of migration or social disadvantage or organisational differences in pathways of care. Census of inpatients, 2005 showed that 9% of in-patients were black or mixed black-white ethnicity while black patients were 44% more likely to have been sectioned & 50% more likely to have been put in seclusion. Black # 11 - Social factors in addictions # Social factors in addictions © SPMM Course Caribbean men were 29% more likely to have been subject to control and restraint. It is speculated that an association with the use of substances may be a confounder. Schizophrenia and ethnicity: Aetiology & Ethnicity in Schizophrenia and other Psychoses (AESOP) study was conducted in London, Bristol and Nottingham. It reported 2-fold higher rate of incidence of psychosis in London compared to the other 2 centres. Afro-Caribbeans had a 9-fold increase in rates of psychosis. In addition, minority ethnic groups had a far higher likelihood to be detained on first presentation, accessing health often via police than GPs. Social factors in addictions Patterns of substance use across the world are strongly influenced by the sociocultural milieu of human communities. Several social factors shape the population prevalence of substance use behavior. Contextual factors such as neighborhood deprivation appear to be strong determinants of cigarette and alcohol use. Family and social network norms and social support are also important in the cessation of drug use. Factors that are consistently identified in association with substance use and alcohol are listed below (Galea et al., 2004) Smoking Smoking •Low school achievement •Young among peer cohort •Poorer relationships with their family •Low household income Alcohol use Alcohol use •Disruption of family structure •Social networks that use alcohol •Recent immigration •Small-area deprivation Illicit substances Illicit substances •Peer drug use •Single parenting •Homelessness •Poor educational attainment •Neighborhood disadvantage •Unemployment # 12 - 7. The sociology of institutions # 7. The sociology of institutions © SPMM Course 7. The sociology of institutions Goffman described a ‘total institution’ as one ‘whose character is symbolized by the barrier to social intercourse with the outside’. Total institutions share the following characteristics: 1. All aspects of life are conducted in the same premises and under the same unitary authority. 2. Each member’s daily activities are carried on in the immediate proximity of a large batch of others, who are also required to do the same set of activities. 3. All parts of a single day’s activities are strictly scheduled with one leading into the next. 4. The different enforced activities are based on a single plan whose purpose is the fulfilment of the proposed official (or statutory) aims of the institution. Goffman also described the ‘moral career’ of a mentally ill patient i.e. the process whereby a person with social ties, friends, and family in the community is institutionalized and converted into an inmate whose world is limited to his immediate hospital ambience (Peele et al. 1977). See the figure below for more details. © SPMM Course According to Goffman although the stripping process and privilege system are offered in the disguise of being in the patient’s best interests and on therapeutic grounds, the real purpose is to break his spirit and make him more manageable. The stripping process and privilege system introduce him to a therapeutic milieu and offer him a new identity – the patient identity. Batch-living: This refers to the pattern in which all inmates did ‘the same thing’ and led a very similar life inside institutions. Binary living: Lives of the staff are in stark contrast as they have power, connection with the outside world and could change their lives in the way they choose. A binary division exists between staff and inmates. Goffman considered ‘secondary adjustments’ as a direct result of institutionalization and as a hallmark of institutionalism. Secondary adjustments refer to the habitual arrangements used by patients who now act as if their major concern is to escape the pervasive control of the institution. These were usually unauthorized activities leading to obtaining of unauthorized ends. Step 1 Step 1 •BETRAYAL FUNNEL: People we trust most – family and friends – conspire against us when we are unwell, reporting our actions to doctors and mental health professionals (called the ‘circuit of agents’) who run the decision-making process. Step 2 Step 2 •ROLE STRIPPING: The institutionalization process begins with a series of assaults on the recruit’s self. The process of stripping inmates of their identity involves such initiation rituals as trading personal clothes and belongings for hospital issue Step 3 Step 3 •MORTIFICATION: Mortification procedures that consist of a series of assaults on the inmate's self-image. At the end of mortification one becomes a ‘full member’ of the institution. Private, personal activities go on public display; he must request permission for even the most minor activities that were purely volitional on the “outside,” such as smoking, shaving, or going to the toilet. This is termed as civil death. Step 4 Step 4 •PREVILEGE SYSTEM: The patient is then inserted into the lowest rung of an allembracing privilege system. This system is based on the house rules. The privileges are usually reductions in the institution’s control over the patient’s life. Freedom is a token of reward. © SPMM Course Russell Barton (1976) described 'institutional neurosis', characterized by apathy, lack of initiative, loss of interest and submissiveness. The proposed causes of institutional neurosis include loss of contact with the outside world, enforced idleness, brutality and authoritativeness of staff, loss of friends and personal possessions, poor ward atmosphere and loss of prospects outside the institution. Social reactivity and schizophrenia: Wing & Brown explored social etiology of negative symptoms of schizophrenia. They surveyed asylums (Mapperley Hospital at Nottingham, Netherne in south London and Severalls in Essex) that existed in the late fifties and concluded that social poverty and lack of stimulation were very much related to the severity of blunted affect, poverty of speech, and social withdrawal – these were termed as ‘clinical poverty’. But such relationship was found to be weak in a reappraisal in 1990. (Curson et al., 1992). It was also feared that too much stimulation could provoke positive symptoms in these patients. Thus, social reactivity is considered to be an important phenomenon in the phenomenology of schizophrenia. Morgan (1979) coined the term malignant alienation to describe a process characterised by a progressive deterioration in the relationship between carers (staff in a ward) and a patient, including loss of sympathy and support from members of staff, who tended to construe these patients' behaviour as provocative, unreasonable, or overdependent. In some instances, such alienation may precede suicide / attempted suicide of the patient # 13 - 8. Criminology and penology # 8. Criminology and penology © SPMM Course 8. Criminology and penology In simple terms, criminology is the study of crime, its origin and effects; in a broader sense criminology is said to include the study of: i) Attributes of a criminal. ii) Characteristics and extent of crimes. iii) Effects of crime on victims and society. iv) Methods of crime prevention. v) Types of crimes. 3 levels of explanation are often discussed with respect to the origin of criminal behaviorIndividual level (personal characteristics of the criminal), Situational or contextual level (immediate circumstances or situations), Social-structural level (social relationships, milieu and institutions). Different theories of criminology tend to construct their primary explanation for criminal behaviour at one of the above levels. Penology comes from the Latin word poena (punishment). Penology deals with the societal response and treatment of crime and criminals and thus focuses on the characteristics and workings of the Criminal Justice System. Also known as penal science, the broad goal of penology is to aid society repress criminality. In this sense, it mostly deals with the punishment of the offender but in the context of mental health issues, penology also covers medical treatment and education that aims at rehabilitation and social inclusion of the offender. Relationship between crime and mental health: It is difficult to have a clear-cut understanding of the relationship between crime and mental health. By definition, crime is understood in a social context; what is a crime in one setting may not be a crime in another time or place. So acquiring data relating crime and mental health is very difficult. Also, convictions are not same as crimes. Most data available pertains to conviction rates; nonconvicted or unregistered crimes are far too many. Also, it is not easy to study if the mental illness was directly related to an offence. A mentally ill person can commit a crime as everyone else could, but whether it is related to his mental illness is the most important but often unanswerable question. # 14 - 9. Stigma and prejudice # 9. Stigma and prejudice # 15 - Themes of stigma # Themes of stigma © SPMM Course 9. Stigma and prejudice Stigma is an attribute, trait or behaviour that that is considered shameful; that symbolically marks the possessor as unacceptable and inferior or dangerous. (Goffman) STIGMA TYPES Enacted stigma refers to a patient’s actual experience of discrimination Felt stigma refers to a patient’s fear of experiencing a discriminated act; it is more prevalent and more disabling than enacted stigma. Public stigma is the reaction that the general population has to people with mental illness. Self-stigma is the prejudice which people with mental illness hold against themselves; this internalized stigma develops from the prolonged societal response. Courtesy stigma refers to the stigmatization unaffected person experiences due to his or her relationship with a person who bears a stigma e.g. parents of children with psychiatric conditions. Not In My Back Yard or NIMBY opposition refers to the vehement disapproval by local authorities, and social groups for localization of a community mental health facility in a geographic area due to the fear and stigma against the mentally ill. Mind (National Association for Mental health) organized a survey to measure NIMBY opposition wherein more than 2/3rd of mental health services faced such opposition in England and Wales. Fear of children’s safety, falling house prices and violence were the main concerns for the opposers. Themes of stigma Hayward & Bright described 4 major recurring themes or beliefs behind the stigma against mental illness. These include: 1. Dangerousness 2. Attribution of responsibility 3. Poor prognosis 4. Disruption of social interaction These 4 themes formed the basis of an Office of National statistics survey in the UK measuring public attitudes towards mental illness. Schizophrenia and addictions were regarded most negatively; approximately 60% respondents thought addicted individuals have only themselves to blame for their problems. Most individuals knew the difference between various disorders and most felt that depression and anxiety are treatable. Little change was recorded over 10 years, with over 80% endorsing the statement that “most people are embarrassed by mentally ill people”, and about 30% agreeing, “I am embarrassed by mentally ill persons” (Huxley, 1993). © SPMM Course Surveys (e.g. Jorm et al., 1997) carried out on health professionals and the public with a case vignette show that: 1. Professionals give much higher rating than the public for the helpfulness of antidepressants for depression, and of antipsychotics and admission to a psychiatric ward for schizophrenia. 2. Public give much more favourable ratings to vitamins and minerals and special diets for both depression and schizophrenia, and to reading self-help books for schizophrenia 3. The beliefs that health practitioners hold about mental disorders differ greatly from those of the general public. Hagighat proposed a unifying theory of stigma, which states that stigma serves the selfinterest of the stigmatisers in different ways as follows:  Constitutional origins: Quick and easy stereotypes at the expense of sophistication and depth. The human brain weights negative evaluations preferentially to positive ones. Similarly, it is likely to interpret repeated episodes of violence by a few as independent episodes of violence committed by the ‘mentally ill’. It links negative (rarer than neutral or positive) events with rare objects (e.g. minority groups).  Psychological origins: Human tendency uses the example of the ‘unfortunate other’ to feel happier about themselves e.g. those rewarded the same as others feel less satisfaction than those in groups with others rewards less for the same work. Those with low self-esteem derogate others to bolster their self-esteem and sense of wellbeing. These psychological dividends benefit the stigmatisers in the presence of the stigmatised.  Economic origins: To increase one's access to resources, stigmatisation of rivals is used as a weapon in the socio-economic competition. Stigmatisation is likely to be more intense in more competitive, self-seeking societies.  Evolutionary origins: Stigmatisation may have an evolutionary advantage in some way. A strong discrimination includes avoiding such discriminated population from being chosen as mates of sexual function. How does stigma evolve? (Link and Phelan 2001) 1. Labelling: people distinguish and label human differences. 2. Stereotyping: dominant cultural beliefs are used to group and categorise labelled persons to undesirable characteristics— to negative stereotypes. 3. Separation: the labelled persons are placed in distinct categories with an observable degree of separation of "us" from "them." # 16 - Interventions against stigma # Interventions against stigma © SPMM Course 4. Status loss and discrimination follow soon after. According to Corrigan three different stigma components can be distinguished: stereotypes (e.g. schizophrenics are violent), prejudice (endorse negative stereotypes result in emotional reactions) which lead to social discrimination (the resulting behavioural reaction). Dimensions of stigma (Jones et al., 2000) 1. Concealability - how obvious or detectable the characteristic is to others. Less concealable problems are more stigmatised. 2. Course - whether the stigmatizing condition is reversible over time, with irreversible conditions tending to elicit more negative attitudes from others. 3. Disruptiveness - the extent to which a mark strains or obstructs interpersonal interactions. The degree of stigmatisation is directly proportional to the degree of disruption in social interaction produced by the condition. 4. Aesthetics - the attractiveness or pleasing nature of a presentation to one's perceptions; A disorder that elicits an instinctive, and strong reaction of disgust will be more stigmatised. 5. Origin - one’s understanding of causal factors. A condition thought to be self-inflicted will have a higher stigma. 6. Peril - feelings of danger or threat that a condition induces. Highly threatening problems are highly stigmatised. Interventions against stigma MIND after NIMBY survey proposed 3 types of antistigma interventions:  Rights based – legal methods  Normalising approach – popularising the fact about how common mental illness are – e.g. 1 in 4 film from Changing Minds campaign, improving contacts between mentally ill and the neighbours, etc  Educational media-based approach – highlighting the role of balanced reporting by media. Legislative intervention: Not much experimental evidence available to support that antidiscrimination legislation would or would not change public stereo-types. Legislation may reduce discriminatory acts but not the prejudice or stereotypes held. It may increase debate and self-questioning about stigma. People may change behavior to avoid legal sanctions. But there is a risk that suppressed discrimination will be shown in subtle, unpunishable forms. This may suppress but not eliminate stigma. Affective intervention: e.g. increasing contacts between local neighbourhood and the mentally ill patients living in a hostel. The generalization from a few hostel inmates in a © SPMM Course locality to the whole category of mentally ill cannot be drawn. It is also noted that when such contacts were encouraged, the mobility of neighbours of such hostels was higher than that of people in a control street. Such measures also have the risk of reinforcing a stereotype by sub typing the better ones and differentiating them from the ‘dangerous’ ones. Public education: had mixed results, but focussed interventions can increase socially desirable responses around stigma in the post-campaign survey but no improvement in behaviour. N.B. ignorance is not the only cause of stigma. Liz Sayce (‘Psychiatric patient to citizen’) provides four different models for addressing stigma and social exclusion. These are A. Brain disease model - also known as ‘no fault’ approach – it’s an illness like any other. This has the danger of lacking credibility, is too paternalistic and may make ill-person ‘a victim of fate’. B. Individual growth model - considers a continuum or spectrum of mental health and illness. In this model, good mental health, emotional distress triggered by bereavement and enduring psychosis are related experiences (dimensional). The continuum approach has been critiqued as advocating for the status quo rather than attitude shifts involving cultural change though it is a popular approach particularly in mental health promotion. C. Libertarian model - advocates equal rights and equal criminal responsibility for mental health service users. The biggest concern is that the net result will be a series of losses for people with mental health problems rather than gains particularly in the courts and workplace. D. Disability inclusion model - the favoured approach that promotes the concept of social inclusion on civil rights grounds and not just paternalistic ‘help’. Disability is the impairment plus the effects of socially imposed barriers and prejudices faced by the individual. Changing Minds was a 5 years campaign spearheaded by Kendell and colleagues at the Royal College of Psychiatrists. In the RCPsych 1998 survey, 70% believed that people with schizophrenia are violent and unpredictable. Various anti-stigma measures were devised and popularized. 1 in 4 is a short 2-minute film aimed at young adults aged 15-25 to challenge preconceptions about mental illness. 1 in 4 refers to how common mental illnesses are. ‘Every Family in the Land’ is a book on stigma published in conjunction. Various other methods such as tube cards, press articles and videos and road shows were also conducted Labelling and stigma: A survey of nearly 5000 German nationals revealed important findings regarding the effect of diagnostic labeling on the stigma (Angermeyer et al. 2003). Labeling as mental illness has an impact on public attitudes towards people with © SPMM Course schizophrenia. Endorsing the stereotype of dangerousness has a strong negative effect and increases the preference for social distance. By contrast, perceiving someone with schizophrenia as being in need of help evokes mixed feelings and affects people's desire for social distance both positively and negatively. Labeling has practically no effect on public attitudes towards people with major depression. Normalization is a concept that emerged in the context of the deinstitutionalization of people with developmental disabilities. It focuses on providing disabled individuals with a life in “normalized” settings in the community. It can be defined as “the utilization of means which are as culturally normative as possible in order to establish and/or maintain personal behaviours and characteristics which are as culturally normative as possible” (Wolfensberger 1972) Social role valorisation was formulated in 1983 by Wolf Wolfensberger to expand the scope of the principle of normalization. SRV aims to create social roles for devalued people to enhance their competencies. In other words, SRV deals with the enablement, establishment, enhancement, maintenance, and/or defense of valued social roles for people. SRV is primarily a response to the historically universal phenomenon of social devaluation and especially societal devaluation. # 17 - 10. Culture and mental health # 10. Culture and mental health © SPMM Course 10. Culture and mental health Comparative psychiatry refers to the study of mental illness in different sociocultural settings; Kraepelin traveled to Southeast Asia and developed the concept of comparative psychiatry. This is now referred to as transcultural psychiatry. Two perspectives of cultural studies often discussed:  Emic perspective (emic view): Used to refer to the perspective of an individual from a specific cultural group about his own group.  Etic perspective (etic view): Refers to the perspective of an individual outside a specific cultural group about the studied group. The etic approach, for instance, involves applying Western psychiatric concepts en bloc into a different culture and uses it for diagnosis. This approach assumes 1. Universality of illnesses 2. Invariance of core symptoms 3. Validity of diagnostic constructs Different views in etic / emic approaches: ETIC approach EMIC approach Diagnosis of mental illness Similar core symptoms in all cultures Linguistic and cultural variations acknowledged Classification system Common classificatory systems endorsed Locally derived systems endorsed Preferred measurement method Identical rating scales and measures across nations Preferred research method Quantitative methods emphasizing reliability are preferred Qualitative methods emphasizing cultural validity Treatment methods Biomedically driven Local belief driven Help seeking behaviour Provision of services most important Individual health belief and explanatory models most important Ethnicity is often defined by a set of cultural patterns (values, beliefs, roles, affective and cognitive styles, and norms), heritage, or ancestry shared by a social group of common national or geographic origin. © SPMM Course Term Characters Determined by Perceived as Race Physical appearance Genetic Permanent Culture Behaviour & attitudes Upbringing (enculturation) and choice Changeable (see acculturation) Ethnicity Group identity Social; pressures, psychological need for identification Partially changeable (From Seminars in Gen Adult Psych 1e. Pg. 783) Acculturation refers to the process of cultural change that takes place when an individual or a group comes in continuous contact with a culturally distinct group. Acculturation can result from immigration and can occur in either direction – hosts can get accultured; as evident in certain places in times of Colonial rule. Four types are described according to the degree of retention and adoption of the two cultures at ethnocultural group level: Berry’s model of acculturation High degree of retention of culture of origin Low degree of retention of culture of origin High degree of adoption of new culture INTEGRATION ASSIMILATION Low degree of adoption of new culture SEPARATION MARGINALISATION  Assimilation: This refers to partial adaptation of a new culture (seen in migrants or refugees) without retaining or giving up all of one’s culture of origin completely.  Integration refers to both high retention of one’s own cultural values and high adoption of the practices of the new culture.  Separation refers to high retention of one’s own cultural values and low adoption of the practices of the new culture.  Marginalisation refers to both low retention of one’s own cultural values and low adoption of the practices of the new culture. These individuals get marginalized by members of both culture of origin and culture of adoption. When someone loses the identity of one’s culture of origin voluntarily e.g. upon immigration but does not assimilate or integrate, then the risk of loss of cultural identity and subsequent increase in mental illness are noted. © SPMM Course Enculturation refers to culture being learnt through contact with family, friends, teachers and the media. This happens to everyone irrespective of migration. At a larger societal (as opposed to small group) level, Berry’s model is often mapped using the terms given below: Berry’s model of acculturation High degree of retention of individual culture identities Low degree of retention of individual culture identities High degree of relationship among various cultures MULTICULTURALISM MELTING POT Low degree of relationship among various cultures in the society SEGREGATION EXCLUSION Cultural bereavement refers to a self-limited grieving response developed by an individual on leaving his own culture. Cultural diffusion or syncretism refers to the spread of cultural traits (including psychiatric syndromes, treatment methods) through contacts across societies. This leads to creating innovations that are distinct from both groups. Sojourning refers to voluntary but brief exposure to different culture e.g. tourists, Peace Corps volunteers. Nostalgia or homesickness is common in sojourners and can be reduced by shortening length of stay, keeping in touch with family and friends at home and learning about a new culture before arrival. Segregation: This refers to removal of people from communities and placing them in an artificial community, which is more or less an institution. Goffman described 5 types of segregation: 1. Incapable harmless – orphanages and old age homes 2. Ill but threat to society – mental hospitals 3. Not ill, threat to society with malice – prisons 4. Occupation related – military barracks, boarding schools 5. Retreat from the world – monasteries, convents. What happens when a family emigrates? © SPMM Course 1. The elderly often find difficult to adapt and change – rejection of new culture happens 2. Complete assimilation is seen in young children 3. A bicultural pattern is seen among young adults in working age – at work they adapt to new culture, but at home they remain attached to the culture of origin. Function of culture in psychiatric practice The five elements of cultural formulation (American Psychiatric Association, 2002) 1. The cultural identity of the individual 2. Cultural explanations of the individual’s illness 3. The influence of the patient’s psychosocial environment and level of functioning within it 4. Cultural elements in the patient–professional relationship (this requires the psychiatrist to be knowledgeable of her own cultural values and beliefs) 5. The use of cultural assessment in deciding diagnosis and care. The concept of explanatory models  Patients’ explanatory models are not fixed and are influenced by the circumstances of their symptoms, age, gender, educational attainment, time point and context of assessment and importantly their cultural beliefs.  Explanatory models themselves can influence a physician’s assessments.  The process of exploring patient’s identity and explanatory model ensures improved understanding and informs the successful negotiation of different worldviews. This exploration does not require psychiatrists to enter into another culture as a participant observer. Idioms of distress Culture as an explanatory tool: This allows description of non-pathological behaviours in the context of one’s culture. Culture as a pathoplastic agent: This allows description of psychopathology that result from cultural practices. Culture as a diagnostic factor: This allows culture-specific, unique diagnostic framework e.g. culture-bound disorders Culture as a service instrument: This allows utilization of cultural knowledge in service delivery and resource distribution. © SPMM Course Idioms are well-structured and codified way expressing thoughts via language. Idioms in one language cannot be translated as such to another – they lose their meaning out of context. In cultural psychiatry, idioms of distress refer to somatic symptoms that serve as a code for expressing one’s mental distress in some cultures. Models of care in cultural psychiatry: Culturally sensitive care could be delivered using various models. Some of these include 1. Ethnic minority services: Separate services are set up for the growing minority population, but there is a risk of organizational marginalization in such models. 2. Cultural consultation model: This has been tested in Canada. It consists of a specialized multidisciplinary team which provides consultations to other clinical teams, sometimes to the families directly. They do not provide direct patient care. 3. Melting pot model: In this model, institutional factors promoting inequalities are addressed. Culture is not perceived as a problem area that needs special resources. Instead, mainstream services are commonly enriched by responding to all cultural groups’ needs. This guarantees equality of access in care. (Melting pot refers to regions or countries that accommodate other cultures in huge numbers, eventually paving way for a high degree of admixture and cultural mosaicism, e.g., United States). 4. A hedge-your-bets approach: Following both prescribed medication and ethnic, spiritual therapy may be the best hope for securing adherence. This encourages honest discussion with family and maintaining religious affiliations. # 18 - 11. Culture Bound Syndromes # 11. Culture-Bound Syndromes © SPMM Course 11. Culture-Bound Syndromes Culture bound syndromes are identified in both ICD and DSM classification systems. Most of these syndromes are merely locally flavoured varieties of illnesses found elsewhere. Most actually occur in many unrelated cultures. More than the symptom profiles of the syndromes, the explanatory mechanisms like witchcraft or humoral imbalances are the defining features. Such illness beliefs can lead to behaviours that would seem to indicate disordered thought processes outside their cultural context, which actually make sense within the context. For example, consider the Chinese syndromes of pa-feng and pa-leng below. © SPMM Course Culture-Bound Syndromes Amok ( F68 disorder of personality and behaviour) Mostly dissociative not psychotic in nature. Starts with sullen period, followed by outburst of violent, sometimes homicidal behaviour; A return to premorbid state occurs after the episode. Some instances of amok may occur during a brief psychotic episode or constitute the onset or an exacerbation of a chronic psychotic process. Seen in Malaysia, Laos, Philippines, Papua New Guinea, and Puerto Rico. Ataque de nervios (F45 somatoform) An attack of distress wherein sudden shouting, crying, beating oneself on chest with dissociation and panic attacks can occur with a sense of being out of control. May have loss of consciousness or amnesia afterwards. Related to acute stress (trauma or family conflict) A sense of heat arising from chest into head may be present Mechanism: dissociative trance. Berdache North America Term for a male who has assumed female gender role Bouffee delirante Seen in French-speaking nations where a sudden outburst of agitated and aggressive behaviour, confusion resembling an episode of brief psychotic disorder. West Africa and Haiti commonly. Brain fag West Africa – seen in students with difficulties in concentrating, remembering, and thinking. A type of somatoform illness. Dhat (F48 / F45: neurotic disorder / somatoform autonomic) India/SE Asia Refers to severe anxiety and hypochondriacal concerns associated with the seminal discharge accompanied by feeling weak and exhausted. Called shenkui in China (fear of loss of yang from men: see below) According to old Hindu tradition, it takes forty drops of blood to create a drop of bone marrow and forty drops of bone marrow to create a drop of sperm Frigophobia (Pa-Leng : fear of cold; Pa-Feng: fear of wind) (F40 specific phobias) A morbid fear of feeling cold / wind due to presumed yin-yang imbalance. Yin-yang refers to Oriental psychological notion of two opposing forces; yin is dark, female and negative force. Yang is bright, male and positive force. Excessive yin in males leads to pa-leng or pa-feng Affected men typically bundle themselves in warm clothing, avoid wind or drafts, and eat foods that are symbolically and calorically "hot' while avoiding foods that are "cold" Koro (Turtle Head) (F48 / F45: neurotic disorder / somatoform autonomic) Malaysia, SE Asia Refers to an episode of sudden and intense anxiety that the penis (or, in women, the vulva and nipples) will recede into the body and possibly cause death. Can occur as epidemics! Latah (F48 / F44: neurotic disorder / dissociative) Hypersensitivity to sudden fright, often with echopraxia, echolalia, command obedience, and dissociative or trancelike behaviour seen in middle-aged women. Malaysia and south East Asia © SPMM Course Mal de ojo Mediterranean concept of evil eye affecting children with physical symptoms mostly. Nerfiza or Nevra Egypt, Greece and Central America Common, often chronic, episodes of extreme sorrow or anxiety, inducing a complex of somatic complaints such as head and muscle pain, diminished reactivity, nausea, appetite loss, insomnia, fatigue and agitation. The syndrome is more common in women than in men. Often treated with traditional herbal teas Piblokto (F44 dissociative) Dissociative episode with excitement often followed by seizures and coma lasting up to 12 hours. May be withdrawn before the attack and usually has amnesia for the episode; they may tear off clothing, shout obscenities, eat faeces, jump into ice cold water naked etc. Seen in Arctic Eskimo communities (Inuits) Shinkeishitsu “Nervous traits’ in Japanese A syndrome of obsessions, compulsive perfectionism, social withdrawal, extreme sensitivity and neurasthenia. Susto (F48 / F45: neurotic disorder / somatoform autonomic) Attributed to a frightening event that causes the soul to leave the body and results in unhappiness and sickness. Tajin-kyofu-shou (F40.1 / 40.8 social phobia) Japanese psychiatric syndrome Fear of losing good will of others due to imagined shortcomings of oneself Social anxiety, tremulousness, self-consciousness and a sense of physical defect or deformity Can develop into anthropophobia (fear of people) – a severe form of social phobia four subtypes: sekimen-kyofu (the phobia of blushing – closer to social phobia), shubo-kyofu (the phobia of a deformed body- closer to body dysmorphic disorder), jikoshisen-kyofu (the phobia of eye-to-eye contact), and jikoshu-kyofu (the phobia of one’s own foul body odor). Ufufuyane, (singular), Amafufunyane, (plural), Seen in Kenya, Southern Africa; Bantu, Zulu; and affiliated groups Anxiety state attributed to the effects of magical potions (given to them by rejected lovers) or spirit possession Characteristic sobbing, repeated neologisms, paralysis, trance-like states, or loss of consciousness in young, unmarried women, who may also experience nightmares with sexual themes, and rarely episodes of temporary blindness. Windigo (F68 personality and behaviour) Involves an intense craving for human flesh and the fear that one will turn into a cannibal. Seen among Algonquian Indian cultures (Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC.) Piblokto Windigo Brain Fag Boufee delirante Mal-de-ojo, Ataque de nervios, susto © SPMM Course Pa-leng Tajin-kyofushou, Shinkeishitsu Amok, Koro, Latah Dhat Ufufuyane 40 © SPMM Course What effect can culture have on psychopathology? Tseng described 6 different effects: 1. Pathogenic: Culture is directly causative 2. Pathoselective: tendency to select certain culturally influenced reactions (e.g. culturally sanctioned suicide of wife when husband dies prematurely) 3. Pathoplastic: Culture influences the manifestation e.g. delusional content. Acute onset of schizophrenia was seen in 40.3% in developing nations compared to 10.9% of cases in West. WHO conducted a collaborative study in 4 countries (Montreal, Tehran, Nagasaki, Tokyo and Basel) using the Schedule for Standardised Assessment of Depression – this study observed that there was a significant similarity in the core symptoms across various nations, the differences were quantitative rather than qualitative in terms of depressive symptoms. 4. Pathoelaborating: Universal behavioural reactions that are selectively reinforced by a culture 5. Pathofacilitative: cultural beliefs affect the frequency of onset by facilitating risk factors. 6. Pathoreactive: culture affects the treatment, stigma and outcome. Interestingly, the prognosis of schizophrenia seems much better in developing than developed nations. But remission was achieved by 62.7% in developing countries compared to 36.8% in the West (IPSS Data – WHO). # 19 - 12. Philosophy in psychiatry # 12. Philosophy in psychiatry # 20 - Anti psychiatry movement # Anti-psychiatry movement © SPMM Course 12. Philosophy in psychiatry Philosophy concerns the framework of ideas within which we consider facts presented to us rather than the facts themselves. William James asserted “philosophy is an unusually stubborn effort to think clearly”. Several streams of philosophical enquiries are often invoked to provide clarity and enquire the concept psychiatric disorders. These include the issues of 1. Illness status of mental symptoms: Consider hypomania and its relationship with a cheerful disposition. Various mental symptoms have questionable illness status that blurs the clinical distinction of disease from normality. 2. Influence of morality, legality and mental health: In general psychiatric disorders are more value-laden than physical disorders e.g. psychopathy and its relationship with delinquency, alcoholism and its relationship with drunken behaviour, etc. Societal norms regarding expected functions and roles profoundly influence the identification and treatment of psychiatric disorders. 3. The issue of ownership or agency: This is especially relevant for symptoms of psychosis. 4. Variation of symptoms: The signs and symptoms of mental disorders are diverse with the variation spanning across different dimensions e.g. organic-functional, mind-body, statetrait, etc. 5. Similarities and differences with physical disorders: This has been a crucial issue in the debate between pro-psychiatry and anti-psychiatry groups. Anti-psychiatry movement David Cooper coined the term ‘anti-psychiatry’ in 1960s. The term refers to a confederation of psychiatrists, psychologists, nurses, social and welfare workers, lay people and patients who oppose the traditional mental health practice and treatment. The central contentions of the antipsychiatry movement are about the diagnostic labels used, lack of agreement and measurability among practitioners with regard to diagnosis, stigma carried by labeling and the problems with current treatments which are seen as more damaging than being useful. Invoking various streams of philosophical enquiries (see the list above) to study the concept of psychiatric disorders, we can identify five major themes of arguments in the pro- vs. antipsychiatry debate.  The psychological model: Mental disorders are learned abnormalities of behaviour; hence the disease model is inappropriate (Eysenck, 1968). # 21 - Philosophical basis of psychopathology # Philosophical basis of psychopathology © SPMM Course  The labelling model: The features of ‘so called’ mental disorders are, in fact, the response of an individual labelled as deviant (see the section on sociology above).  Hidden meaning model: Apparently irrational behaviours deemed as ‘symptoms‘ are indeed meaningful for the patient; thus they do not characterise a disorder at all.  Unconscious mind model: Apparently irrational behaviours representing ‘symptoms’ are indeed products of an unconscious process and thus can be made comprehensible (psychoanalytic view).  Political control models: The medical model of insanity is a socio-political scheme devised for the purpose of legitimizing the control of the ‘deviant, dangerous, or the undesirable’ (Also known as Foucault stance). Three major pioneers are 1. R.D. Laing, 2. Thomas Szasz and 3. Foucault. R.D.Laing wrote ‘The Divided Self’ (1959), ‘Sanity, Madness and the Family’ (1964). Thomas Szasz wrote ‘The Myth of Mental Illness’ (1961) and ‘The Manufacture of Madness’ (1971). Foucault wrote Madness and Civilization (1965). R.D. Laing famously said, “insanity need not always be a breakdown; it can also be a breakthrough”. He also said, “insanity sometimes is the sane response to an insane society.” Philosophical basis of psychopathology Human experience is varied and wide. In order to study the details of human experiences, a student of psychiatry must initially reduce such broad human experience into a simpler subject matter. Phenomenology is a method to define more clearly that which we seek to reduce, namely, the subjective essence of the given experience. (Broome, 2007) Karl Jasper: Karl Jaspers is widely considered a major figure in philosophy and psychiatry. Jaspers method of philosophical enquiry into symptoms of psychiatry has laid the foundation for descriptive psychopathology that we use today. He introduced phenomenology, a long regarded as a method of philosophic enquiry, to psychiatry. He also distinguished the difference between causal explanation (aetiology) and meaningful understanding (description) in psychiatry. In fact, he provided what Ghaemi (2007) regards as the first scientific foundation to psychiatry. The Understanding/Explanation Distinction: This dichotomy was clearly explained by Jaspers. By understanding (Verstehen), Jaspers referred to the psychological intuition that an individual could have about the meaning of a psychological state or event for another individual. By explanation (Erklären), Jaspers referred to the observable influence of one event or process on another that could be tested objectively. One can understand this distinction if one considers the © SPMM Course fact that ‘explanation’ applies best to natural sciences (physics, chemistry, biology) and understanding applies best to human sciences (like history and art). Psychiatry requires both understanding and explanation for further study. Descriptive psychopathology differs from explanatory psychopathology in that it does not attempt to explain causality; it restricts itself to ‘understanding’ human experience through the description of what is observed. For this to be practiced, one needs a common language or terminology. By studying the glossary of psychopathology, one can prepare oneself for further enquiries in psychiatry. Hence, it is clear that there are two components in descriptive psychopathology. The initial process is one of observation of behaviour; this is accompanied by an empathic assessment of subjective experience. The latter is referred to by Jaspers as phenomenology. To describe a phenomenon, it is important to appreciate the phenomenon from the beholder’s position. This attempt to ‘feel like how your patient might feel’ is very different from feeling sorry or pitiful for your patient. The former is called empathy while the latter is called sympathy. Empathy is an essential component of learning further about the pathological processes taking place in a patient. Phenomenology purports to employ various philosophical approaches to defining the symptoms of psychiatric disorders. 1. Ostensive: illustrating a concept by clinical experience; defining by examples 2. Conventional: defining a concept using conventional description e.g. legal definitions 3. Persuasive: deliberate employment of a term to persuade users to employ it in a specific manner 4. Declarative: formal explanation of the significance of a word or its constituent parts, as used in the dictionaries 5. Contextual: defining a concept by the contexts in which it generally occurs e.g. lack of energy is related to depression 6. Essential: defining the nature of an object 7. Semantic: defining what a word means using other words Explanatory psychopathology assumes causative factors based on theoretical constructs. Such explanations may be derived from experiments e.g. behaviourism or derived from arbitrary hypothetical theories e.g. psychoanalysis. # 22 - 13. Ethics in psychiatry # 13. Ethics in psychiatry © SPMM Course 13. Ethics in psychiatry Ethics provides guidance on decisions that we make in clinical practice. The first written book on medical ethics was authored by Ishaq bin Ali Rahawi. This book called Adab al-Tabib (Conduct of a Physician), is thought to be first published in 9th century Hammurabi code is the first attempt in history to codify medical competence and legal liability for negligence. It is mostly concerned with surgical negligence and imposes eye-for-eye sentences for assaults on noblemen though slaves can be ‘replaced if accidentally damaged’! Hammurabi cannot be regarded as a code of ethics. Charaka, an ancient Indian physician, proposed what seems to be the earliest of medical ethics relevant to modern medicine. This clearly outlined four ethical principles of a doctor:  Friendship  Sympathy towards the sick (Caring attitude)  Interest in cases according to one's capabilities and  No attachment to the patient after his recovery. Charaka also emphasised the personal values central to the nobility of the profession, thus: 'Those who trade their medical skills for personal livelihood can be considered as collecting a pile of dust, leaving aside the heap of real gold'. Furthermore, 'He who regards kindness to humanity as his supreme religion and treats his patients accordingly, succeeds best in achieving his aims of life and obtains the greatest pleasures'. Charaka also advised his fellow practitioners to “always strive to acquire knowledge” (i.e. Continuous Professional Development in modern terms) and highlighted the importance of confidentiality. Present day ethical principles: 1. Higher order principles: Deontology and teleology are two alternative higher-order ethical principles concerning current medical practice. The term Deontology derives from the Greek ‘Deon’ for ‘duty’ indicating the centrality of rules in governing medical practice. Accordingly, rights and duties determine action and so it is also called as absolutism. According to Ross, some duties are right because of their very nature (such as the duty to tell the truth); these are called prima facie duties. Others are right in particular circumstances, called duty proper. Whilst this approach (duty-based approach) provides security and clarity, there may be conflicts in managing particular problems and meeting the individual patient’s wishes and needs. Examples of rules include GMC Good medical Practice and the RCPsych code of ethics. © SPMM Course The term Teleology derives its name from the Greek ‘Teleon’, meaning ‘purpose’ and the central concept is that rather than rights, people have interests, whether these are concerns, desires or needs. Accordingly, the broad judgment of benefits and harm determine medical practice. It assumes that the right action is the one that has the best foreseeable consequences. It is also called as consequentialism or utilitarianism. Utilitarianism takes two forms:  Act utilitarianism deals with a specific act only (situational ethics).  Rule utilitarianism deals with general practices (for which rules can be established). Evaluation of utilitarianism: The strengths of utilitarianism lies in its practicality and clarity. It approximates the principle of ‘beneficence’ (see below) and fits well with approaches to public policy. Two factors extraneous to psychiatry influence utilitarianism's position in psychiatric ethics. First, legislated responsibilities of psychiatrists, particularly in relation to issues of public safety (e.g., when applying Mental Health Act). Such legal imperatives are invariably utilitarian in nature and have usually emerged in the context of social and political responses to issues such as public safety especially in relation to forensic patients. The other factor promoting utilitarian thinking in psychiatric ethics has been the profound changes to healthcare systems in the face of globalization and financial pressures (managed care settings). 2. Prima facie principles: American philosophers Tom Beauchamp and James Childress and British doctor & philosopher Raanon Gillon pioneered the following prima facie principles:  autonomy—respecting patients' wishes and freedom of choice  beneficence—acting in patients' best interests  Non-maleficence—avoiding harm – primum non nocere.  Justice—treating problems equally, with equitable distribution of resources to the needy. These four principles are the main guiding aspects of current practice, and most other related ethical discussions relevant to clinical practice can be brought under these topics. 3. Models of doctor – patient interaction:  The paternalistic model. It is assumed that the doctor knows best. It is an autocratic model where treatments are prescriptive. May be desirable in emergency situations. But often this approach results in a clash of values. # 23 - Landmark publications relevant for critique o # Landmark publications relevant for critique on ethics © SPMM Course  The informative model. The doctor is seen as a dispenser of information. Here the choice is left wholly up to the patient. May be useful in one-off consultations, but may not work well if strictly followed on long-term professional relationship.  The interpretive model. Here the doctor will be treating the patient for a long time and might know his/her patient well and understand the circumstances of their microenvironment. Here shared decision-making is established.  The deliberative model. The doctor here may act as a friend or counselor to the patient, where information dispensing is coupled with advice on a course of action. This is commonly used to enable lifestyle modification and to address maladaptive coping. 4. Other terms used:  Direct Ethics is about the action taken. To determine what ethical behaviour is, we should assess the act -- what has been done.  Indirect Ethics is about the actor -- the nature of the individual choosing those actions. The main concern here is the formation of character by a moral agent (a person).  Pragmatic ethics: Emphasis is on achieving success, on reaching a goal with relatively little concern for how that success is achieved.  Humanistic ethics: Emphasis is on doing what's best for society. This dominates ethical theory overwhelmingly; according to humanism, ethics is held as a virtue, with its goal being social improvement rather than personal success. Although some actions are always wrong (murder, for instance), in most cases, ethical behaviour lies between extremes, along a range between excess and deficiency. This is the idea of the golden mean of Aristotle. Landmark publications relevant for critique on ethics  Nuremberg Code 1974: Code of ethics following the Nuremberg Trials (post-World War II Trial concerning doctors experimenting on people detained in concentration camps). According to Nuremberg Code, human experimentation can be carried out only if  Voluntary consent is given  Research is intended for common good of the society  Avoidance of unnecessary pain and suffering is guaranteed for the subjects  Subject has liberty to withdraw at any point  Qualified researchers undertake research  Scientist must terminate a study if more harm is being caused than expected to the subjects # 24 - Landmark studies relevant for critique on eth # Landmark studies relevant for critique on ethics © SPMM Course  Declaration of Geneva 1948: Reaffirmation of humanitarian aims of medicine by World Medical Association. The Declaration of Geneva is a modification of Hippocratic Oath, intended to highlight the dedication of medical profession for the cause of humanitarian goals.  Declaration of Helsinki 1964: This was adopted by The 18th World Medical Association General Assembly in 1964 and has been amended five times since, most recently in 2000. Notes of clarification were added in 2002 and 2004. The current (2004) version is the only official one. The Declaration specifically addresses clinical research, reflecting changes in medical practice from the term 'Human Experimentation' used in the Nuremberg Code. Landmark studies relevant for critique on ethics Tuskegee Syphilis Study (1932-1972): Between 1932 and 1972, US public health service followed up nearly six hundred low-income African-American males, 400 of whom were infected with syphilis. All diseased subjects were periodically examined but were not informed of the disease that they were diagnosed with and the implications of such diagnosis, even after the introduction of penicillin in 1950s. In some cases, when other physicians diagnosed subjects as having syphilis, researchers intervened to prevent treatment, in order to study the natural course of syphilis. Many subjects died of syphilis during the study. The study was strongly criticized, and US government issued a public apology in 1997. As a result of this Belmont Report was produced. Important principles outlined: 1. Respect for persons i.e. Individuals should be treated as autonomous agents and those with diminished autonomy should be adequately protected for research purposes. 2. Informed consent should be obtained by providing full information, ensuring comprehension and maintaining voluntariness (can withdraw at any time). 3. During a research, beneficial effects must outweigh any harms caused, with a systematic assessment of benefits and risks carried out beforehand. Willowbrook School Study (1963 - 1966): Mentally handicapped children at Willowbrook State School were deliberately infected with hepatitis after parents gave consent for what they thought to be vaccinations. The study was looking at the course of hepatitis and effectiveness of viral inoculation. There is evidence to suggest only consenting families were admitted to the school. Jewish Chronic Disease Hospital: Studies to develop information about the nature of human transplant rejection. Chronically ill patients who did not have cancer where unknowingly injected with cancerous human liver cells. The defense argued that the administration did not want to scare patients and expected the cells to be rejected. © SPMM Course Tearoom Trade Study: During 1960s, a sociologist called Laud Humphries followed up many men who had anonymous sex in public places by tracing their number plates after falsely befriending them. The research was conducted without explicit informed consent and became a matter of debate, highlighting the important of ethics in scientific research in non-medical fields of enquiry. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgments have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information © SPMM Course Notes prepared using excerpts from:  Angermeyer MC, Matschinger H. The stigma of mental illness: effects of labelling on public attitudes towards people with mental disorder. Acta Psychiatr Scand 2003; 108:304–309.  Bebbington & Kuipers, 2003. Schizophrenia and psychosocial stresses. In Schizophrenia, Hirsch & Weinberger (Ed). Blackwell; Oxford.  Benbow, A. (2007) Mental Illness, stigma and the media. Journal of clinical psychiatry, 6; supp 2: 31 – 35  Bhugra & Gupta: Medical professionalism in psychiatry. Advances in Psychiatric Treatment (2010) 16: 10-13 http://apt.rcpsych.org/content/16/1/10.full  Bhui, K & Bhugra D. Communication with patients from other cultures: the place of explanatory models. Advances in Psychiatric Treatment 2004, 10 (6) 474-478;  Boyer, BA. & Paharia, MI. (Ed) Comprehensive Handbook of Clinical Health Psychology. 2008. John Wiley & Sons; NewYork  Chapter on Sociology and Psychiatry. Companion to psychiatric studies. 6th ed.  Cooper, B. Immigration and schizophrenia; the social causation hypothesis revisited. British Journal of Psychiatry (2005) 186: 361-36  Corrigan PW, Watson AC. Understanding the impact of stigma on people with mental illness. World Psychiatry 2002; 1: 6– 20.  Crisp, A. H., et al (2004) The College’s Anti-Stigma Campaign, 1998–2003: a shortened version of the concluding report. Psychiatric Bulletin, 28, 133 –136.  Curson DA, et al. Institutionalism and schizophrenia 30 years on. Clinical poverty and the social environment in three British mental hospitals in 1960 compared with a fourth in 1990. British Journal of Psychiatry 1992; 160: 230-241.  Galea et al. The Social Epidemiology of Substance Use. Epidemiol Rev 2004;26:36–52  Hashemi, A. H. & Cochrane, R. (1999) Expressed emotion and schizophrenia: a review of studies across cultures. International Review of Psychiatry, 11, 219–224  http://www.medschools.ac.uk/  Jorm AF, Korten AE, et al. Helpfulness of interventions for mental disorders: beliefs of health professionals compared with the general public. Br J Psychiatry 1997; 171: 233-237  Kendler, KS et al. Life Event Dimensions of Loss, Humiliation, Entrapment, and Danger in the Prediction of Onsets of Major Depression and Generalized Anxiety. Arch Gen Psychiatry. 2003; 60(8):789-796.  Kendler, KS et al. Stressful life events and genetic liability to major depression: genetic control of exposure to the environment? Psychological Medicine (1997), 27: 539-547  Link et al. Measuring Mental Illness Stigma Schizophrenia Bulletin, Vol. 30, No. 3, 2004. 30 (3): 511. (2004)  Morriss & Morriss. Contextual evaluation of social adversity in management of depressive disorder. Advances in Psychiatric treatment. 2000, 6, pp. 423–431  Muntaner C et al. Socioeconomic Position and Major Mental Disorders. Epidemiol Rev (2004) 26 (1): 53-62.  Peele et al. (1977). Asylums revisited. American Journal of Psychiatry, 134: 1077-81.  Weindling, P.J. (2005). Nazi Medicine and the Nuremberg Trials: From Medical War Crimes to Informed Consent. Palgrave Macmillan.  WMA Medical Ethics Manual. Last Accessed on 30 Jan 2015 at http://www.wma.net/en/70education/30print/10medical_ethics/ # 04 - 21_Human_Development # 01 - 1. Conceptualizing development # 1. Conceptualizing development © SPMM Course 1. Conceptualizing development In psychology, maturity refers to the ability to respond to the environment in an appropriate manner, usually with a learnt response. Maturity refers to the production of expected behaviour and actions in a given situation in an age-appropriate manner. Psychosocial maturity is a key factor in the development of a sense of autonomy and includes processes involving cognitive, emotional, social and moral development. Nature vs. Nurture: Development is influenced by both nature (genetic disposition) and nurture (environmental influences). But the proportional contribution of genetics and environment to the psychosocial development of personality, intelligence and sexuality is fiercely debated to date. Studies estimate a heritability of 40-50% for human IQ. But several observations warrant consideration in this regard. 1. Heritability of IQ varies with age: While the heritability is around 30% in children, it increases to 80% among adults. This suggests that either the genetic determinants of intelligence are age-specific or that the non-genetic maturational factors are much more influential in shaping human intelligence at younger ages. 2. Heritability of IQ is affected by demographics: Scarr et al. observed greater genetic effects on intelligence in middle-class white groups than in lower-class African American groups, suggesting that among lower socioeconomic groups, nongenetic influences operate on development. Irving Gottesman, the proponent of endophenotype concept, famously stated that genes are weaker than poverty. 3. Genetic influences are likely to be variable: For a construct such as intelligence, which is made of several sub-constructs, it is likely that no single gene or genetic complex will be sufficient to account for the variations. Furthermore, at various stages of development, the genetic factors operating to influence intelligence could vary. 4. Effect of the shared environment: genetic influences are often inferred from the observation that closer biological relatives (e.g. identical twins) are more similar in their intelligence than less closely related pairs (non-twin siblings). But, in fact, several observations suggest that there is indeed a greater similarity between pairs of family members than would be predicted on the basis of their biological relationship, indicating the effect of shared environment on intelligence (Deary et al., 2010). # 02 - Models and theories # Models and theories # 03 - Maturational tasks # Maturational tasks © SPMM Course Models and theories Developmental theories aim to explain how children grow and learn. Of these stage, theories refer to theories that consider development as a process that occurs over a 12- to the l5-year period in chunks of time called stages. Within each stage, a specific set of functioning and behaviour can be observed. Certain maturational tasks (motor, cognitive and perceptual) are also achieved in each stage, heralding transition to next stage of development. Piaget’s theory is a prototype stage theory focused on epistemology (the study of the development of knowledge or intelligence). According to Piaget, development 1. Occurs in hierarchical stages 2. Each stage is qualitatively different ( not just quantitatively) 3. The stages consist of invariant functions and all children undergo these sequentially Other stage theorists include Gesell, Freud and Erikson. Maturational tasks Age Motor Language Sensory Social development 4-6 weeks Smiles at the parent (social smile - 6 weeks); can recognise mum’s face apart; shows preference to human faces. 6-8 weeks Cooing 3 months Can hold head up. grasp reflex disappears Babbling Localises sound source Squeals with pleasure appropriately. Discriminates smile 5 months Reaches out; oral exploration Spontaneous babbling and sound experiments 6 months Hand to hand transfer rolling over Palmar grasp Double syllable sounds such as 'dada.' Localises sound 45cm lateral to either ear 9-10 months Cruises around and crawls. Sits unsupported. Picks up objects with pincer grasp Babbles tunefully Looks for toys dropped; Peek a boo Stranger anxiety followed by object permanence © SPMM Course game 1 year Stands alone momentarily One or two words Separation anxiety months Walks alone. Holds rails and climbs, can jump with both feet. Can build a tower of 3 or 4 cubes and throw a ball (1 X 3). Can use a spoon. Many intelligible words – up to 40 in some. Uses holophrases. Shows rapprochement ( hugs when coming back). 2 years Able to run. Builds tower of 6 cubes (2 X 3) Makes sentences – telegraphic initially. Parallel play. Dry by day 3 years Goes upstairs 1 foot per step and downstairs 2 feet per step. Copies circle, imitates cross and draws the man on request. Builds tower of 9 cubes (3 X 3) Speaks in sentences Cooperative play. Imaginary companions 4 years Can skip; copies a cross Toilet trained mostly 5 years Can hop; copies a triangle. Fluent speech with grammar use; uses function words Dresses and undresses alone 6 years Copies a diamond. Can count number of fingers Nearly adultlike speech © SPMM Course A brief outline of various developmental theories is presented in the table below. These will be considered in detail in later sections of this chapter. Theories Key Concepts Temperament theory (Thomas & Chess, Kagan) Temperaments are inherent biologically based traits varying from difficult to easy (or inhibited to uninhibited). Temperament elicits environmental response that perpetuates a pattern of behaviour Organismic stage theory (Piaget) Development occurs in stages with transition occurring as a result of interaction of the child with its environment (child as a scientist) Attachment theory (Bowlby) Innate tendency to seek relationships influence patterns of behaviours in later life. Social learning theory (Bandura) Observational learning in childhood influences later behaviour Psychosexual stage theory (Freud) Stage-specific behaviours are driven by inner conflicts and resulting anxiety signals. Successful resolution of conflicts aid in progressive maturation. Psychosocial stage theory (Erikson) Psychosocial developmental stages are characterized by conflicts, but the successful resolution is not mandatory for further development. Collaborative learning theory (Vygotsky) Development is not entirely private; child acts as an apprentice in social surroundings rather than a scientist. Parents and teachers carry out the role of scaffolding to introduce familiarity for the child to develop its own expertise (collaborative learning). Zone of proximal development refers to functions that are not yet fully achieved but are in the process ‘pipeline’ whose development is aided by scaffolding. Maturational Growth theory (Gesell) Maturation of the nervous system as the principal driver of the various aspects of human behaviour © SPMM Course Freud’s psychosexual stages: Gradual, the sequential emergence of genital sexuality from infantile sexuality is noted in Freud’s model. The stages discussed here reflect both biological and psychological maturation. Freud’s Psychosexual Stage Characteristics ORAL (0 to 1 ½ years) Drive discharge is via sucking; oral erotogenic zone. oral erotism (sucking, licking, etc.) in early stages; oral sadism (biting, chewing) in later stages. The ego develops at this stage. ANAL (1 ½ to 3 years) Anal erotogenic zone; drive discharge via sphincter behaviour. Anal erotism refers to the sexual pleasure in anal functioning. Anal sadism refers to the aggressive wishes linked to fecal expulsion. Anal fixation is characterized by OCD like pattern – also ambivalence and sadomasochistic tendencies are associated. PHALLIC/OEDIPAL (3 to 5 yrs) Genitals become organs of interest; masturbation-like activity noted. Oedipus complex – wish to have a libidinal relationship with opposite sex parent (Electra complex in girls) with a desire to exclude the rival parent. This lead to a fear of retaliation from the rival parent in the form of castration anxiety in boys and loss of mother’s love in girls. Electra complex in girls include penis envy, a wish to have penis is accompanied by blaming the mother for absence of penis; later this becomes a secret wish to displace mother as object of father’s love and bear his baby. At the resolution of Oedipus and Electra complexes, identification with the aggressor i.e. dad for a boy and mum for a girl occurs; superego develops from introjection of parental values. Abraham divided this into early partial genital (true phallic phase) and later mature genital phase. LATENCY (5 to puberty approx.11yrs) Socialization, interest in peers seen. Sexual energy sublimated towards school work, hobbies and friends GENITAL (puberty onwards) Biological maturation occurs; genital sexuality is born. # 04 - Adversities and development # Adversities and development © SPMM Course Adversities and development A critical period is a time point when an individual is acutely sensitive to the effects of external influences - both positive and negative. This is usually defined by biological and psychosocial events. This concept is related to the notion that there is a gradually decreasing plasticity in functioning across the life span. But this is challenged by some observations that suggest, for example, that maturational tasks such as an attachment can be formed even at later ages. Early life is the period of most rapid brain development. Therefore, this period is a sensitive phase for both positive and adverse factors to influence human development. Severe neglect (e.g. in relation to institutional care) produces adverse consequences if it occurs in early rather than later childhood. Similarly, the effects of toxins (e.g. lead and alcohol are far more dramatic when the exposure occurs in utero or in early life. Apart from early life, adolescence is also another critical period in life. Major life transitions influencing development occur during adolescence. On the basis of potential to cause enduring physiologic disruptions, 3 distinct types of stress responses are described in young children.  Positive stress response – brief, mild response moderated by the availability of a caring and responsive adult. e.g. getting an immunization, anxiety associated with the first day at a nursery. When buffered adequately positive stress responses are growth-promoting opportunities.  Tolerable stress response - associated with exposure to non-normative experiences with a greater magnitude of adversity. The e.g. death of a family member, a serious illness or injury. When buffered well the risk of physiologic harm and long-term consequences is greatly reduced. STRESS VULNERABILITY MODEL Zubin & Spring (1977) proposed the stress vulnerability model. According to this model mental illness, schizophrenia especially, is a result of two hits. The first hit is the vulnerability or predisposition of an individual that may be biologically or psychosocially determined. The second hit is the stress factor, which may act as a trigger or precipitant. This could also be biological, psychological or social. Low vulnerable individuals will require high degree of stress to develop an illness while highly vulnerable may respond to hairline triggers. In an interesting study of environment-gene interaction, Caspi et al (2003) noted that individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. # 05 - Methodology for studying development # Methodology for studying development © SPMM Course  Toxic stress response - strong, frequent, or prolonged activation of the body’s stress response in the absence of the buffering protection from supportive adults. e.g., child abuse or neglect, parental substance abuse, and maternal depression. Toxic stress disrupts the developing brain circuitry during sensitive developmental periods forming the precursors of later physical and mental illness. Methodology for studying development Children of different ages can be compared on a given behaviour in order to determine agespecific developmental features (cross-sectional design). But, in this case, inter-individual variations can distort the true picture. Longitudinal designs are often employed where the same children are studied twice or more over a prolonged period of time with respect to a developmental feature. This provides more reliable estimates of development though this can be time-consuming. As in other scientific disciplines, in developmental psychology, the identification of a risk factor does not necessarily imply causation as the relationship could be mediated by a third variable (mediator), the putative risk factor may indeed be the outcome (reverse causality) or due to the presence of multivariate relationships. Such multivariate factors that partially account for the relationship between a risk factor and a disorder are termed mediators. The mediator could be a protective factor or a buffer that reduces the risk in an individual. # 06 - 2. Attachment theory # 2. Attachment theory # 07 - Bowlby believed that attachment is innate and # Bowlby believed that attachment is innate and adaptive. We are all born with an inherited need to form attachments, and this is to help us survive. In his terms, the newborn infant is helpless and relies on its mother/caregiver for food, warmth, etc... © SPMM Course 2. Attachment theory Bowlby’s views: According to Bowlby, attachment begins in infancy and lasts throughout a lifetime. A newborn baby immediately needs someone to take care of them. This person may be a parent, a sibling, or a nanny, but whoever it is, there will be a bond formed between them. Bowlby believed that this primary caregiver is the one that will most shape the child's personality and character. The primary caregiver is usually the mother (but need not always be), and strong bonds are formed within minutes of giving birth. It is important for the new parents and baby to be alone together right after the birth to establish a strong bond. If there are too many individuals in the room right after birth, the natural process of attachment can be disrupted and this can have long-term effects on the relationship between the child and parents (Klaus, Kennell, & Klaus, 1995). The attachment formation needs caregiver’s presence in early stages; no difference is made if motherly care is provided late after 30m especially and not in early stages. Attachment behaviour is more evident when distress is present. According to Bowlby, the strong innate tendency to attach to one adult female is seen – this is called monotropy. This attachment is qualitatively different from later attachments made. But it is shown that multiple attachments are the rule rather than the exception. Around 18m, 87% infants have multiple attachments; 50% primarily attached to the mother, 18% to father and the rest to equally both. Attachment process itself is more important than who the attachment figure is. Bowlby believed that attachment is innate and adaptive. We are all born with an inherited need to form attachments, and this is to help us survive. In his terms, the newborn infant is helpless and relies on its mother/caregiver for food, warmth, etc. and hence the attachment behaviour is essentially adaptive. Attachment behaviour peaks between 12-18 months but various phases are notable during development. 1. Preattachment phase (birth to 8 or 12 weeks), babies orient to their mothers, 2. Indiscriminate attachment (attachment in making - 8 to 12 weeks to 6 months): Allows strangers to handle, infants become attached to one or more persons in the environment 3. Clear-cut attachment (6 through 24 months): Preferential attachment, separation anxiety, object permanence, stranger anxiety. At the later part, weakened stranger anxiety; other attachment figures may also present. 4. After 25 months, the mother figure is seen as independent. Harlow’s experiments: These experiments established the importance of contact comfort as basic as the need for food in developing mother-infant bonding. Harlow separated rhesus monkeys # 08 - This classification below correlates highly w # This classification below correlates highly with 1. Responsiveness and sensitivity of the mothers to the needs of their children and 2. Total amount and quality of stimulation (holding) provided by the mothers. © SPMM Course from their mothers during their first weeks of life. Harlow substituted a surrogate mother made from wire or cloth for the real mother. The infants preferred the cloth-covered surrogate mother, which provided contact comfort, to the wire covered surrogate, which provided no contact comfort. This preference was observed irrespective of feeding, i.e. the terry-cloth soft-surrogate mother was preferred even if it did not have a feeding nipple attached to it. Ainsworth’s experiments: Ainsworth constructed a strange situation experiment with separation and 2 reunion episodes. An infant is observed in the presence and absence of its mother and a stranger in the vicinity in seven different combinations. According to the infant’s behaviour it is classified as type A, B or C. This classification below correlates highly with 1. Responsiveness and sensitivity of the mothers to the needs of their children and 2. Total amount and quality of stimulation (holding) provided by the mothers.  Type A: Anxious avoidant: 15%. Indifferent attitude to the mother is leaving the room or entering the room; keeps playing indifferent to mother’s presence. Distress when alone, not when the mother is leaving. Stranger can comfort the child easily. Highly environment directed, low attachment behaviour. Greater in the West. Perpetrators of bullying mostly have this pattern.  Type B: Secure: 70%. Plays independently when the mother is in the vicinity (secure base effect). Distress when the mother is leaving; seeks contact on the return of the mother and gets quickly comforted by the mother, not a stranger.  Type C: Anxious resistant: 15%. Fussy and cries a lot and cannot use the mother as a secure base to explore around. Very high levels of distress are seen when the mother is leaving. But not comforted easily even on her return; appears ambivalent about her return. Active resistance to stranger’s efforts to pacify. Highly caregiver directed low play behaviour. Greater in Japanese and Israeli families. Furthermore, this pattern is also common among victims of bullying. Strange Situation Experiment Situation 1 Both mother and infant enter the room Situation 2 A stranger joins them Situation 3 Mother leaves now; infant left with stranger Situation 4 Mother returns; stranger leaves Situation 5 Infant left alone; mother leaves now Situation 6 Stranger comes back and tries to comfort the child Situation 7 Mother comes back and comforts, stranger leaves. © SPMM Course  In some cases a fourth type D - disorganised type - is also seen. This is seen in maltreated or maternally deprived children. The child has an insecure, dazed look and acts as if it is frightened of the mother. This pattern may be a precursor to later personality difficulties or dissociative experiences. Mother may have an experience of being abused as a child. Attachment style may differ with different caregivers; it is a function of the quality of caregiving and NOT the temperament of a child. Main devised a semi-structured adult attachment interview with 15 items (AAI). This is based on the fact that infantile attachment pattern can be predicted reasonably accurately using discourse analysis of adults when recollecting their childhood. Accordingly 4 patterns are noted.  Secure autonomous: Those who had secure attachment provide spontaneous and coherent answers with the ability to talk freely about negative experiences in childhood type B Ainsworth.  Dismissing of experiences: Those who had an avoidant (insecure) pattern often minimise their experiences, do not elaborate on them and do not use colourful metaphors during the discourse– type A (avoidant)  Entangled: Those who had insecure but ambivalent (enmeshed) attachment use multiple emotionally laden responses and ramble excessively, – type C resistant.  Unresolved disorganised: Broken continuity and interrupted the logical flow of thoughts is seen in those who had insecure disorganised attachment pattern– type D. The secure attachment appears to be a protective factor for the development of childhood disorders, and insecure attachment is best conceptualized as a risk factor for a number of childhood disorders. It has been demonstrated in various studies that insecure attachment during early childhood is associated with the development of behavioural problems especially oppositional defiant disorder at school age. Insecure attachment in combination with other vulnerability factors such as family dysfunction, difficult child temperament, and poor parental management can give rise to later childhood disorders Spitz – anaclitic depression or hospitalism: When children are hospitalised for physical problems, a short period of separation from primary caregiver ensues; this loss of loved one is called anaclitic (object loss) depression. It is counterproductive to child’s development. But recovery is good if the maternal deprivation is kept minimum i.e. less than 3 months. Rare if prolonged. Surrogate mothering helps the infant when having the anaclitic depression to some extent. © SPMM Course Margaret Mahler described the development of a sense of identity in young children, independent of their mothers. This is called separationindividuation theory, and the proposed stages are supposed to be universal in all children. Rutter distinguished deprivation from privation.  Deprivation: Attachment is formed but lost temporarily. If it is for a short time then protest – despair – detachment phases (similar to grief) are seen. This is more common in 8m to 3 yr. old. Boys show more deprivation features than girls. It is more noticeable if aggressive caregiving e.g. physical abuse was present before separation. In prolonged deprivation, separation anxiety sets in. Increased clingy behaviour, psychosomatic complaints, vacillation and aggression are seen in the child.  Privation refers to the non-formation of attachment; this is very rare and can lead to what Rutter termed as ‘affectionless psychopathy’ and developmental retardation. Attention seeking, lack of guilt, antisocial behaviour and indiscriminate attachment patterns are noted. This is reversible but only to some extent. Ethology is the systematic biological study of animal behaviour. Greek ethos - custom or habit. It was coined by Heinroth. Imprinting is a special primitive form of learning wherein during the early period of development (called critical or sensitive phase) a young animal is highly sensitive to a certain stimulus that provokes a specific behaviour pattern. Lorenz described the imprinting in goslings where a moving object in the early period of development provokes the following behaviour of that moving object. This is useful as almost always mother is the first moving object for goslings and hence they learn to follow the mother; but when Lorenz disrupted MAHLER’S STAGES 1. Normal autism (0 to 2 m): Child spends most time in sleep as if the intrauterine aloofness continues. 2. Symbiosis (2 to 5m): Inner and outer world studied via senses but perceives mother and self as one unit. 3. Separation – individuation phase: (DPRO) a) Differentiation sub-phase: (5 to 10m) slowly appreciates the difference between mother and self b) Practicing sub-phase: (10 to18m) A gradual increase in interest on the environment; practices exploration. c) Rapprochement sub-phase: (18 to 24m) Alternating drives to be autonomous and dependent; Able to explore alone but requires comfort and reassurance on return. d) Object constancy sub-phase: (2 to 5yrs) Understand that the mother will not be lost if temporarily away; hence able to function independently. # 09 - Object relations theory # Object relations theory © SPMM Course this by presenting himself as the moving object, the goslings imprinted by Lorenz followed him and refused to follow mother goose. Imprinting is particularly resistant to change. Innate releasing mechanism (IRM) refers to the sensory mechanism selectively responsive to a specific external stimulus and responsible for triggering the stereotyped motor response. Fixed action pattern (FAP) is an inherent pattern of behaviour initiated by specific stimuli. It consists of species-specific, stereotyped movements e.g. following behaviour in goslings. Object relations theory According to object relations theory – the ego exists only in relation to other objects, which may be external or internal. ‘Object’ refers to both living persons and non-living concepts. Melanie Klein was a major proponent of what came to be known as Object relation theory later. Other prominent theorists include Fairbairn, Kernberg, Guntrip, Winnicott and Balint. Kleinian theory:  Play interpretation was the major technique employed  Maintained that oedipal development occurred earlier than what Freud envisaged  According to Klein, an infant possessed instinctual knowledge of the body.  Weaning is symbolically equivalent to castration  Klein’s stages are not age specific – but the PSP and DP are said to occur between 0-3 months (very early)  Kleinian defenses – SIPDOG i.e. Splitting, introjection, projective identification, Denial, omnipotence and grandiosity Winnicott’s concepts:  Children’s psychological development occurs in a zone between reality and fantasy called transitional zone. Play is an important aspect of development of a child.  Transitional object refers to a soft toy, towel or any such objects that help in transition from ideal objects of fantasy to real objects which are not as reliable as those in fantasy. These serve as buffers against the loss, get invested with primary object’s qualities e.g. mother’s contact but remain under the control of the child.  Good enough mother concept refers to the fact that a mother need not be perfect – but good enough to provide growth sustaining environment (holding).  Parental control and impositions can lead to the development of a false self-different from the real self (theory of multiple self-organizations). © SPMM Course A flowchart describing Kleinian theory of infant’s (‘object-‘) relationship with the mother Soon after birth, fear of annihilation is present. This cannot be tolerated by the child and projects this destructive impulse to external objects. Projection of both bad and good impulses occurs followed by splitting of the external world into good and bad. Cannot unify these elements into one. Bad objects include nongratifying bad breasts (parts). This leads to persecutory anxiety, and the child is said to be in Paranoid –schizoid position. Later the child realizes that both good and bad things emanate from the unified single object (whole). At same time weaning occurs – perceived as a loss. Subsequent guilt develops for having destructive impulses against the mother. Depressive position – fear of loss of the love of object. Reparation phase – creativity emanates as an attempt to repair damage done by ‘destructive impulse’. Continues lifelong. In the absence of reparation, a maladaptive defense called manic defense can emerge characterized by denial of reality (refusal to take guilt), omnipotence and grandiosity. # 10 - 3. Parenting practices # 3. Parenting practices © SPMM Course 3. Parenting practices Parenting style is a psychological construct representing standard strategies that parents use in child rearing and includes the demands of children and response of parents. With respect to parenting, quality of care is more important than quantity of time spent. Parenting practices are specific behaviours. Types of parenting: Maccoby and Martin described four parenting styles given in the table below. Corresponding to this classification, Baumrind described 3 response patterns in parents.  Authoritative parenting: parents are demanding but responsive; fits propagative parenting and concerted cultivation  Authoritarian parenting: restrictive and punishment heavy; follow rules without explanation. High demand and low responsiveness.  Indulgent parenting: Low demand, high response, the parents are permissible and lenient with few behavioural expectations placed on the child – parents try to be friends with a child. As adults, those with indulgent parents pay less attention to avoiding behaviours which cause aggression in others.  Neglectful parenting: low demand, low response. These parents are detached and dismissive, not involved in the child’s life. Also dismiss child’s emotions and opinions. Authoritative Authoritarian Permissive Neglecting Control Good degree of control High control Low or absent control Low or absent control Nurturance Adequate warmth and nurturance Poor nurturance High degree of nurturance and leniency Low nurturance; no warmth Maturity demands Ageappropriate demands expected High degree of demands placed on growing child No demands placed on growing child No demands placed Communication Free flowing, positive Poor flow of communication Inadequate communication Poor communication Birth order is shown to have an effect on development through varying parenting practices. Demanding Undemanding Responsive Authoritative/Propagative Indulgent (Permissive) Unresponsive Authoritarian/Totalitarian Neglectful # 11 - Effect of family dysfunction # Effect of family dysfunction © SPMM Course  First-borns - get more parental time and have higher IQ, are more achievement driven and are more authoritarian, conservative and conformist  Middle-borns - receive the least attention at home - have strong peer relationships  Last-borns – receive most attention, get ‘spoiled’; independent and rebellious Effect of family dysfunction Family structure has been known to impact the behaviour of children where those with single parents or large family sizes have been shown to increase behavioural issues. Single-sex couples and extended family involvement in upbringing do not cause the same issues. Dysfunction in families cause discord, rejection of children due to processes such as disengagement and/or overprotection and over-involvement resulting in enmeshment. According to the landmark Cambridge study of Delinquent development by Farrington et al, the most important childhood predictors (during age 8-10) of delinquency were antisocial child behaviour, impulsivity, low intelligence, low attainment, family criminality, poverty and poor parent child rearing behaviour. Parental loss: Most children adapt well to parental divorce if financial support, reasonable contact with non-custodial parent and successful remarriage of single parent take place. If not, poor academic achievement, low self-esteem, 2-3 times more antisocial behaviour and higher rates of later life depression are seen.  Children of all age groups are prone to short term behavioural difficulties after parental divorce – evident even in infants who may show changes in eating, sleeping and bowel patterns, with fearful or anxious responses.  3 – 6 age group often assume responsibility for parental separation  7 - 12 age group show decline in school performance  Adolescents feel hurt, become angry and critical of their parents; they spend most time away from home as a reaction.  Recovery usually takes 3 to 5 years.  One third of all children have lasting psychological effects  Boys are more affected than girls due to parental divorce; Among boys, physical aggression is a common sign of distress.  Recent divorce or separation of the parents predicts suicide in children.  25% step families dissolve in 2 years, whereas 75% are harmonious.  ADHD, Antisocial PD and conduct problems are more at homes without father. © SPMM Course  Children of divorced parents undergo divorce themselves twice more than children of undivorced parent.  Academic and social aptitude suffers due to divorce; asthma, injuries, headaches and speech defects are more common in divorced families.  Divorce has more impact than death of a parent on psychological make up of a child  Suicide rates for children of divorce are very high  25 % have adjustment problems at teenage.  Parental death has somewhat lesser impact than parental conflict and separation. Bereavement causes increase in temper tantrums, depressive reaction (sadness, irritability), sleep disturbance. Divorce can cause all of the above but protective factors include positive temperament, relationship with other siblings & joint access. Day care: Providing day care for more than 4 months at less than 1 year age for >20hrs a week can increase insecure attachment. If not, day care does not affect development adversely. Adoption: Research shows that the earlier the age of adoption, the better is the outcome for the child. When a child is adopted during early childhood, then the chances of forming new attachments are better. Therefore early adoption is recommended as a matter of social policy. Children adopted before the age of 4 or 5 have been shown to do well generally. Although late adoption after the age of eight, does not necessarily lead to problems in adjustment, such children are more vulnerable and are at risk of developing future problems, like behavioural problems at home and school (Tizard and Hodges 1978). Adopted children become aware of their adopted status most often between 2 to 4 years. Parental disclosure to children about their adoption reduces later psychological trauma. Institutional care: Tizard and Hodges followed up a group of children who had been in institutions from infancy, adopted at age 4 and had been looked after by a number of carers who changed often. At age 8, most children had formed reasonably good attachment with their adoptive parents. At age 16, although the adolescents appeared to be functioning rather well, they showed a constellation of features termed as ex-institutional syndrome. These young people related better to adults than to their peers, were less likely to have a special friend, were less likely to be selective in choosing their friends and turned to peers less often for emotional support. Intrafamilial abuse: Sexual abuse perpetrated by a parent can result in anxiety related symptoms, sexualized behaviour in the child, borderline personality disorder, substance misuse, dissociation and depression. # 12 - 4. Temperament # 4. Temperament © SPMM Course 4. Temperament This is an aspect of personality studied in infants. It describes individual differences in behavioural style. Certain aspects of temperaments remain stable over many years. Infant’s negative emotionality (e.g. fear), and reactions to new situations (inhibition or neophobia) are the two most stable temperaments. New York Longitudinal Study is a key study on childhood temperament conducted by Thomas & Chess. It is a thirty years (initially 6 years) longitudinal study of 138 children, observing childhood temperaments. It employed parental interviews to ascertain temperamental dimensions – 9 such dimensions have been used: 1. Activity 2. rhythmicity 3. approach/withdrawal 4. adaptability 5. intensity 6. threshold 7. mood 8. distractibility 9. attention span / persistence Three behavioural styles were identified using the above 9 dimensions 1. Easy – rhythmic pattern of needs, adapts well, and active – 40% 2. Difficult – less predictable, uncomfortable with new experiences, negative mood, react intensely to stimuli, difficult to comfort – 10% 3. Slow to warm up children – adapts poorly to change, but less active and responds at low intensity – 15% 4. Ungrouped – 35% Difficult temperament may offer some survival benefits as mother pays more attention – especially in tribal populations. Inhibition (approach/withdrawal dimension), according to Keagan, is a strongly inborn trait. Behavioural inhibition may be a precursor for later neurotic disorders including anxiety and depression. In an extreme form of inhibition called neophobia, a child appears frozen and withdrawn in novel situations. Goodness of fit (Thomas & Chess) describes the reciprocal relationship between a baby’s temperament and its social environment whereby a good match between the both results in positive development later. Chess and Thomas used the term especially to refer to the harmonious interaction between a mother and a child. # 13 - Resilience to mental illness # Resilience to mental illness © SPMM Course (Note that the concept of Good-Enough Mothering was proposed by Winnicott; according to him mothers provide a holding environment. A mother does not need to be perfect, but she must provide good-enough mothering.) EAS model (Buss & Plomin 1984) describes three major dimensions: Emotionality – Activity – Sociability in children. EAS is a strongly biological model that views temperament as inherited personality traits exhibited in early life. Resilience to mental illness Resilience refers to the ability of children to function well in the face of adversity. There are 2 ways of considering resilience. 1. Resilience as a positive psychological outcome in the face of adversity. 2. Resilience as a dynamic process of psychological functioning that increases positive and reduces adverse outcomes in the face of adversity (Cummings, Davies, & Campbell, 2000). Masten and Coatsworth (1998) reported that when children are faced with highly adverse situations (e.g. parental mental illness, family violence, poverty, natural disasters etc.), personal characteristics such as good intellectual functioning; appealing, sociable, easygoing disposition; self-efficacy, self-confidence, high self-esteem; talents; and faith can produce a positive psychological outcome despite adversity. Certain family characteristics also convey resilience. These include having a close relationship with a caring parent figure, authoritative parenting (e.g., warmth, structure, high expectations), higher socioeconomic status and having extended family networks. Extrafamilial factors that increase resilience include having bonds to supportive adults outside the family, being attached to prosocial organizations, and attending efficient schools/institutions. # 14 - 5. Cognitive Development # 5. Cognitive Development © SPMM Course 5. Cognitive Development Erikson’s stages Erikson proposed psychosocial developmental stages. These coincide with Freud’s psychosexual stages but extend well beyond adolescence. It is not necessary that each stage must be resolved entirely before further progress. A mixture of positive and negative outcomes is noted for most people. However, if predominantly negative experiences accumulate at various stages of development, this may predispose to difficulties in life. In Erikson’s model autonomy refers to children gaining more control over activities and acquiring new skills. This is crucial for building self-esteem, failing which a sense of shame is felt. During 6 to 12 years of age we are capable of learning, creating and accomplishing numerous new skills and knowledge, thus developing a sense of industry. This is also a very social stage of development, and if we experience unresolved feelings of inadequacy and inferiority among our peers, we can have serious problems in terms of competence and self-esteem. Identity vs. role confusion. This stage occurs during adolescence between the ages of approximately 12 to 18. Up to this stage, according to Erikson, development mostly depends upon what is done to us. But from teenage onwards, our development depends primarily on what we do. Teens need to develop a sense of self and personal identity. During adolescence, children explore their independence and start to form a sense of self. This phase of transition from dependent child to an independent adult is associated with confusion and insecurity. Teens also experiment with different social roles at this stage. According to Erikson, this is important to the process of forming a strong identity and developing a sense of direction in life. The inherent strength of young adulthood is love, and the major task is intimacy and formation of a future bond partner. A middle aged adult seeks satisfaction through productivity in career and family / social network. This is referred to as generativity. Crisis Approximate Age 1. Basic trust vs. basic mistrust Birth to 12-18 months 2. Autonomy vs. shame 18 months to 3 years 3. Initiative vs. guilt 3 to 6 years 4. Industry vs. inferiority 6 to 12 years 5. Identity vs. role confusion Adolescence 6. Intimacy vs. isolation Young adulthood 7. Generativity vs. stagnation Middle adulthood 8. Ego integrity vs. despair Late adulthood © SPMM Course An older adult reviews/cherishes life accomplishments prepares for end of life by pursuing lifelong interests etc. This is referred to as integrity Piaget’s model of cognitive development According to Piaget, a schema is defined as the basic building block or unit of intelligent behaviour. Schemas consist of organized past experiences to understand future experiences. We have physical schema such as bike riding schema and mental schemas such as addition, multiplication and division schema. Within each developmental stage, functioning is generally internally consistent and stable and thus said to be in equilibrium. Stage-to-stage transformation occurs as a result of interaction with environment, whereas existing schemas cannot solve the environmental realities. Adaptation is the process of fitting schemas to environmental information. Adaptation can occur either as assimilation or accommodation. In assimilation new information is incorporated into existing schemas without restructuring the schemas. In accommodation, the schemas are restructured to ‘accommodate’ newly learnt information. Equilibration is achieved when all information properly fit into the schemas via either processes of adaptation. During each developmental stage, the child will experience cognitive disequilibrium, which through adaptation, gets solved, and equilibration results. Each time that equilibration occurs, the child produces more effective schemata or mental structures. Approx. AGE (not delineated by Piaget) STAGES FEATURES 0 to 2 years Sensorimotor Exercising reflexes (0 to 1 m) to smoothen them; Primary circular (1 to 4 m) reactions where reflexes extend to objects; secondary circular ( 4 to 10 m) where goal direction seen; object permanence starts by 9m; coordinated actions with added element of curiosity forms tertiary circular ( 12 to 18 m) reactions – here novelty is sought. Mental combinations occur; thoughts dominate actions. 2 to 7 years Preoperational Preconceptual stage 2 to 4 years; intuitive stage 4 to 7 years. 7 to 11 years Concrete operational Ability to decentre, conserve, seriate and declining egocentrism noted. Perspective taking starts to develop. But transitivity tasks still pose a challenge. E.g. ‘4>2, 2>1, which is the greatest of all?’ - is still difficult. # 15 - Sensorimotor stage (SPIRO) # Sensorimotor stage: (SPIRO) # 16 - Preoperational stage (FAT PILES) # Preoperational stage: (FAT PILES) © SPMM Course > 11 years Formal operational Here manipulation of ideas and propositions are seen – 1st order operations; soon, reasoning solely based on verbal argument construction develops – 2nd order operations. Hypotheticodeductive reasoning develops in a proportion of children after age 12. Sensorimotor stage: (SPIRO)  Symbolic thought: Language starts developing and thought starts to dominate actions.  Representational Play: Mimics one object with another e.g. cup for a hat.  Deferred Imitation: remembers an act and replays it later.  Recognition of self: Primitive self recognition begins.  Object permanence: Understanding that object that disappears from field of perception has not ceased to exist; if searched well this object can be found or it will reappear. Hence peek-a-boo games are understood and enjoyed. Initially this is limited as the hidden objects are searched at where they were last seen (around 9 to 12 months); not at where they were hidden. Around 18 months invisible displacements are inferred and object permanence is completed. Preoperational stage: (FAT PILES)  Functional attribution: Objects are referred to by their function rather than appearance.  Artificialism: ‘Sky is blue because someone painted it’ o & Animism: Inanimate objects are treated as living objects.  Transductive reasoning: Cats have 4 legs, Dogs have 4 legs. So cats and dogs are the same (called Von Domarus law). o & Telegraphic speech: No functional propositions noted but verbs and nouns are used  Phenomenalistic causality: In a similar logic to transductive reasoning, causality is inferred if two events occur with some temporal association e.g. lightning and rain come together; hence lightning brings rain.  Imminent justice: See moral development  Lack of seriation, conservation, and reversibility: o Seriation is the ability to sort or categorise based on dimensional variations of items. In centration only single dimension can be focussed at one time (akin to syncretic thought, see below). Conservation refers to the ability to perceive that a quantity (such as count, weight, volume etc) is unchanged if the same amount of a material is # 17 - Concrete operational stage # Concrete operational stage: © SPMM Course transformed into a different shape or structure. E.g. 1 litre of water remains the same 1 liter irrespective of whether it is present in a half full 2 litre bottle or two complete 500ml bottles. Concept of compensation refers to the fact that magnification in one dimension and reduction in another dimension can nullify each other’s effect. Reversibility refers to the ability of mentally calculating and understanding that what is done can be undone without loss of material.  Egocentrism: This does NOT refer to self-centredness or selfish attitude. It refers to the restricted ability of viewing the world from a single point of view at this developmental stage. This was demonstrated using the Mountains task where a child at this age group could not say what a person would see from other side of the desk when only one side of a toy mountain was visible from each view.  Semiotic function: Signifiers are symbols and signs that represent or stand for something else. For example, drawing a matchstick man. Thus signifiers represent a meaning, serving semiotic function. This is vital for developing play activities.  Syncretic thought: Links neighbouring objects and events on the basis of common instances e.g. red square with red sphere with blue sphere with blue cube etc. Concrete operational stage: Conservation of liquid develops around 6 years, followed by conservation of length, count, weight and volume (around 11 to 12 years) in a vertical decalage fashion (i.e. not parallel but one by one development of these abilities). Note that if the same question about quantity is asked before and after manipulation of materials in front of a child, the child answers differently for the second question as he/she interprets that the question is asked twice as the answer given was wrong in the first instance. If the pre-transformation question is dropped, the conservational ability could be demonstrated at earlier stages. Also using an external ‘accident’ such as naughty teddy that disturbs a heap of coins, conservation could be demonstrated earlier than what Piaget thought. # 18 - 6. Language development # 6. Language development # 19 - Stages of language development # Stages of language development: © SPMM Course 6. Language development Basic speech sounds are called phonemes. In English language, there are 46 speech sounds. Most children can differentiate speech sounds before being able to produce them. The basic meaningful part of the language is called morpheme. The rules for combining words into phrases and sentences are called syntax. Language is slower to develop in boys, in twins, in large families, in those from social classes 4 and 5 and those that lack speech stimulation e.g. deaf and neglected children. Stages of language development: The pre-linguistic state (0 to 12 m): Crying is an important form of communication. A onemonth-old child is able to distinguish speech sounds although these phonemes are almost identical sounds. This categorical speech perception is supposed to be innate. By six weeks, the child starts cooing. By six months, babbling is seen. Babbling is nothing but the repetitive production of speech sounds. Spontaneous babbling refers to the situation when the child enjoys making these sounds alone. All babies around same age irrespective of the culture start bubbling. Even the deaf babies of the deaf-mute parents start marbling but stop at 9 to 10 months. The phonemic expansion refers to the expansion of production of phonemes even if such phonemes are not seen in the native language. One word stage (12 m to 18 m): Jargon words and babbling continue up to 18 months. First words are often self-invented but carry meaning and consistently match with the same meaning. There is a clear intention to communicate. Earliest words are context bound; sometimes they do not have any communicative purpose but are used as performatives to refer to actions. A child says ‘teddy’ only when the teddy is thrown up into the air while playing; thus teddy refers to ‘throw up’ action rather than the doll. Holophrases are one-word substitutes for whole phrases or sentences. At this stage, a child understands more words than it could produce. Gradually words get decontextualised and fall into one of the following functions; 1. Nominals – specific e.g. Sarah, or general – e.g. ball pen 2. Action words e.g. bye, look. 3. Function words e.g. the for, what, etc. propositions and grammatical functions. 4. Modifiers – e.g. red, big, etc. 5. Personal and social function – e.g. oops, ouch, etc. Two-word sentences / stage 1 grammar (18 to 30m): Telegraphic speech is seen where meaningful words are used without connecting words. At this stage adults interact with children © SPMM Course in a ‘motherese’ – short simple raised pitch paraphrased language directed at infants. As object permanence is achieved by this stage, words start to have representational functions. Stage 2 grammar (> 30m): Mean length of utterances increase largely due to the use of function words – propositions, etc. Noam Chomsky: Children are born with an innate language acquisition device. Transformational grammar is important in understanding language development. All languages have a surface structure where the syntax is accurate and actual words are used to construct language; and a deep structure where the most semantic sense is made without similar syntactical rules. A single surface structure can have several deep structures. Children are born equipped with the ability to decipher the transformational grammar of deep to surface structure conversion. Hence, years up to puberty are sensitive though not critical fro language development. Social interaction view of language development: Adults such as mother act as LASS (language acquisition support system). This is essential for the function of language is social interaction. The elaborate language code is characterized by longer, complex sentences that are contextindependent. It focuses on the past and future, employs pronoun ‘I’ commonly and allows for the expression of abstract thought. Restricted language code is characterised by short, incomplete sentences, which tend to be context-dependent, frequently uses like ‘you know’, focuses on the present, employs pronoun I rarely and has little room for expressing abstract thinking. People in lower socioeconomic classes more commonly use the restricted code whereas the middle class and upper class children often use elaborate language code. Such differences emerge from the influence of social interactions in language development. AGE & LANGUAGE DEVELOPMENT 3 months-babbling 9 months-repetitive babbling 12 months-speaks three words 18 months-speaks up to 40 words. 24 months-telegraphic speech, grammatically pairs words and vocabulary more than 240 words 36 months-early comprehension of grammar and syntax 48 months-correct use of grammar 60 months-language akin to adult speech # 20 - 7. Social competence and peer relationships # 7. Social competence and peer relationships © SPMM Course 7. Social competence and peer relationships Through friendship, children learn cooperation, sharing and conflict management. They also learn empathy and group belonging. Studies suggest that peer rejection can later result in depression, school drop out and other psychiatric issues. (Cairns, Cairns and Neckerman, 1989) Social competence is a complex concept involving social, emotional, cognitive and behavioural skills. It is the foundation upon which ability to interact with others is built and also perceptions of own behaviour is developed. There are several approaches involved. Peer regard/status Define social competence based on popularity amongst peers Social skills Behaviours demonstrating social skills are used to determine social competence Relationship Social competence is based on the ability to form and quality of relationships Functional Context-specific, it is concerned with the identification of social tasks Peer groups are comprised of children of similar age, background, social status and often with similar interests. This primary social group can influence several behaviours and beliefs. Children look to join peer groups that accept them, even if they are involved in negative activities disapproved by parents. Peer acceptance: the extent to which a child I viewed by peers as worthy and likeable companion. This is assessed using sociometric techniques Popularity: Popularity is not the same as having many friends - many popular children do not count having a large number of friends. 1. Popular children: liked by many disliked by few 2. Rejected children: disliked by many liked by few 3. Neglected children: neither liked nor disliked (few nominations in sociometric measurements in a classroom) 4. Controversial children: liked by many but also disliked by many 5. Average-status of acceptance: nearly 1/3rd of the class – liked or disliked by a moderate number of peers Popular children show the following characteristics:  Respond positively in unfamiliar environments © SPMM Course  Initiate interaction in new social groups  Comment constructively in groups  Blend smoothly with new peers  Pleasant temperament  Academic skills  Display ease when interacting with opposite gender # 21 - 8. Moral development # 8. Moral development © SPMM Course 8. Moral development Freudian theory: According to Freud, boys have unconscious wishes to compete with the father for mother’s love. This leads to castration anxiety as fear of being punished for competing sets in. This anxiety drives the repression of such desire and leads to identification with one’s father from whom the superego morality is incorporated; thus moral development is achieved via the development of the superego. In girls Oedipus complex is not seen; instead penis envy (Electra complex) is noted. Father is the love object here, and unconscious wish for having a baby from the father is present, but without a strong anxiety as seen in boys, the identification with mother and imbibing of superego occurs. Hence, Freud claimed that superego or morality is weaker in women than men. Piaget described qualitative differences in older vs. younger children in terms of morality that was based on the ability of older children to have social perspective (an extension of the Theory of Mind concept); he did not describe stage-by-stage development of morality. Cognitive development is essential but not sufficient for moral development. Moral development lags 2 years behind the cognitive development. Piaget’s Moral Development Theory 5 to 9 years Older than 10 years Unilateral respect for the external law: seniors make rules; they are sacred and should not be broken, but get violated periodically for pleasure. External responsibility holds for crime; severity of outcome or loss decides the degree of punishment warranted. Moral realism: Strong penalty should be paid for any crime; can accept collective punishment to deliver justice (punishing the wrongdoer is more important than not hurting the innocent) Imminent justice: Wold is just – a misfortune will punish the deserved for a misdeed. Heteronomous morality: Subject to rules written by others. Mutual respect for the self-invented law: could be changed by consensus and for fairness. Internal responsibility holds for crime; intent or motivation decides the degree of punishment warranted. Moral relativism: Punishment should match the crime; does not accept collective punishment. No imminent justice. Autonomous morality: Rules can be self-made. © SPMM Course Kohlberg’s theory of moral development: This is a stagewise process where reasons for making a judgment in a hypothetical experiment (Heinz Dilemma) are studied in children; reasons are more important than the actual judgment made. On this basis, Kohlberg identified 3 levels and 6 stages.  Level 1 Pre-conventional morality (7-12 years to middle childhood): In this stage, the children decide right or wrong according to the consequences. If an action leads to punishment it must be bad and if it leads to reward it must be good. i. Punishment and obedience orientation: Obedience to rules to avoid punishment ii. Reward orientation/ Instrumental relativism: What brings rewards is right. ‘tit for tat’ approach seen.  Level 2 Conventional morality (approximately 13-16 years): Here the children believe that social rules and the expectation of the others determine what acceptable or unacceptable behaviour is. iii. Concordance orientation: What pleases others is right. What the majority thinks right is right. Also called Good boy/good girl orientation. Conforms to avoid disapproval and meet expectations of others. Being good is important and having good motives and showing concern iv. Social order or Authority orientation: Upholds laws and social rules to avoid the censure of the authorities and feelings of guilt about not doing one’s duty. Maintaining social order is the goal.  Level 3 Postconventional morality (approximately 16-20 years)- Here what is right is based on an individual’s understanding of universal ethical principles. These are often abstract and ill-defined, but it might include the preservation of life at all costs and the importance of human dignity v. Social contract or legalistic orientation: Actions guided by principles commonly agreed by one’s group on as essential to public welfare (relative values) and democracy is upheld while individual’s life is given more respect than written codes of law. vi. Universal Ethical orientation: Actions guided by self-chosen ethical principles. Laws and social principles usually valid because they are based on these principles. Social rules can be broken if universal morality is not upheld. Level 3 cannot be considered a part of the normal or expected course of development and instead represents a philosophical ideal. Only 15% eventually achieve level 3. Formal operational thought is necessary but not sufficient to achieve level 3 morality. Kohlberg’s stages are criticized to be © SPMM Course androcentric (all male sample) and Eurocentric. Though they are well correlated with ‘moral reasoning’, they are not so well associated with actual behaviour. Eisenberg’s stages: Both Kohlberg’s and Piaget’s theories were based on the prohibition of the wrong; Eisenberg’s was based on prosocial reasoning where helping or altruistic behaviour was studied. Social learning theory argues that while actual reinforcement is not needed for ‘learning‘ about morality, the performance of a moral deed can be reinforced (either directly or vicariously). Vicarious punishment is more effective than vicarious positive reinforcement in this regard. # 22 - 9. Emotional literacy and fears # 9. Emotional literacy and fears # 23 - In a detailed longitudinal study, (Developmen # In a detailed longitudinal study, (Development of Toddlers Study (D.O.T.S.)) Cole et al. observed the child in spontaneous situations at 4 time points (18, 30, 36, 42 months). Their observations are tabulated below: © SPMM Course 9. Emotional literacy and fears Emotional literacy is a term used interchangeably with emotional intelligence (Steiner, 1997). Components of emotional literacy includes: 1. Knowing your feelings 2. Having a sense of empathy 3. Learning to manage our emotions 4. Repairing emotional problems 5. Emotional interactivity – putting it together Emotion regulation describes an individual’s ability to gauge the appropriate level of emotional response required and respond to environmental stimuli with a range of emotions in a controlled manner (Panfile and Laible 2012). Emotion regulation develops throughout the lifespan (Cole et al., 2009). Infants have limited emotional regulation, shown by gaze aversion and vocalising. Around 1 year of age children are able to unconsciously regulate their emotions. Between 3 and 5 years (at kindergarten) children may tolerate ordinary, brief frustrations and handle minor disappointments
(Cole, 1986; Cole et al., 2003). In a detailed longitudinal study, (Development of Toddlers Study (D.O.T.S.)) Cole et al. observed the child in spontaneous situations at 4 time points (18, 30, 36, 42 months). Their observations are tabulated below: # 24 - Developmental fears # Developmental fears © SPMM Course Imaginary companions are often a part of emotional development.  Preschool years mostly (between 3 to 10 yrs age, 50% may have),  Usually in children with above-average intelligence  Usually in the form of persons rather than animals/things  Usually friendly and help to reduce loneliness and anxiety.  Mostly disappear by age 12, occasionally persist into adulthood. Developmental fears  Fear of animals-age 3  Fear of the dark-age 4 or 5  Fear of imaginary creatures - 5 plus  Fear of open spaces arises in later childhood or adult life  Fears that arise in late childhood or adult life: fear of sex/open spaces.  Teenage onwards-failure, illness and death  Fears that show no particular age trend-fear of snakes or storms Simple fears are often linked to early negative childhood experiences or learnt from other family members (such as a sibling’s fear of spiders may influence a child). Maintenance of phobias is due to avoidance of the anxiety-provoking stimuli relieving unpleasant emotions, which becomes a reward itself. Children of age 3 to 6 yrs are aware of their body and show a preoccupation with illness or injury, - every injury must be examined and cared for – hence this phase is also called Band Aid Phase. •were quick to express anger •slow to distract themselves •might try to distract themselves but only briefly •bid to mother but angrily 18 to 24 months 18 to 24 months •quickly bid to mother (but thru words not anger) •were somewhat quicker to distract •anger was briefer, distractions longer 36 months 36 months •quickly & briefly bid to mother (verbally) •quickly distracted themselves •eventually focused on gift & then showed anger 48 months 48 months # 25 - 10. Sexual development # 10. Sexual development # 26 - Theories of Gender Identity development # Theories of Gender Identity development © SPMM Course 10. Sexual development Gender identity typically forms around the age 3-4 and remains established. Gender typing describes the process where an individual acquires a sense of gender-related traits within the society they are born. It usually starts with clothing at a young age. Gender role: behaviour an individual engages in that identifies with their gender e.g. use of cosmetics. Theories of Gender Identity development  According to Social Learning Theory of gender development, girls and boys learn to behave differently because the society treats them differently (pink dresses for girls, Barbie dolls for girls, etc.). Fathers treat children in a more gendered way than mothers. This sex typing is reinforced by further observational learning by the child and reinforcement that results on accomplishing gender specific developmental tasks.  Cognitive Developmental Theory stresses the importance of child’s participation in gender identity. A child’s discovery about his/her biological sex leads to identification with a group and conformity as a result. Thus three stages have been identified: 1. Basic gender identity / gender labelling: Around age three, a child understands she/he is female or male. 2. Gender stability: By age 4 – 5 recognise that gender is retained life-long and will not change! 3. Gender constancy / consistency: Age 6 -7 understand that gender is immutable even if physical changes are carried out. It is a type of conservation achieved akin to Piaget’s cognitive development  According to Gender Schema Processing Theory, gender identity alone provides children the motivation to assume sex-typed behaviour. Following this they observe and learn to be of a specific gender in the society. Thus, a gender schema of the particular culture gets deeply incorporated and serves as a standard for comparison. Sex drive exists from birth but increases in adolescence due to raised androgen secretion. Sexual orientation is explored during adolescence. There are arguments for and against the biological determination of sexual orientation vs. shaping in childhood. © SPMM Course Sexual Behaviours in Childhood Preschool (age <4 years)  Exploring private parts through touch and rubbing or showing to others  Trying to touch women’s breasts (including mother)  Exposing oneself and attempting to see other exposed people (adults and children) Young Children (approximatel y 4-6 years)  Stimulating genitals (masturbating) sometimes when others are present  Kissing, or holding hands  Talking about genitals without grasping the meaning in full  Exploring private parts with peers e.g. “playing doctor”, “I’ll show you mine if you show me yours.” School-Aged Children (approximatel y 7-12 years)  Masturbating privately  Playing courtship games (“mummy and daddy”)  Gazing at pictures of naked people; viewing sexual content in media (  Wanting more privacy  Showing reluctance to discuss sexual issues with adults  Being sexually attracted to peers # 27 - 11. Adaptations in adolescence & adult life # 11. Adaptations in adolescence & adult life # 28 - Puberty trends # Puberty trends: © SPMM Course 11. Adaptations in adolescence & adult life Adolescence is the period between childhood and adulthood and is described in many of the developmental models (Piaget – formal operational, Freud - genital stage, Erikson – identity vs. role confusion). Conflict with parents is common during this time due to developing a sense of self and autonomy. This could be attributed to a second separation-individuation phase. Anna Freud described affective instability as the oscillation between behavioural and affective excess and scarcity during adolescence induced by endocrine changes, sexual maturity and instability of ego defenses. Erikson described adolescent turmoil as a temporary maladaptive state that was due to identity diffusion. According to him all adolescents passed through this state. But later studies (Offer & Offer 1975) showed that while upheaval and turmoil are common in adolescence, they might not occur in all adolescents. Nearly 23% showed continuous linear development during adolescence, while 35% were late bloomers who were less introspective and had some frictions with their families. Around 21% had recurrent conflicts with their parents and chose less competitive careers. Marcia’s theory on adolescence: A mature self-identity is possible only if an individual experiences several crises, finally arriving at a stage of commitment. Successful maturation during adolescence depends on both the degree of crises faced and commitment achieved, with different levels of maturation as shown in the table below. Degree of crises Degree of commitment HIGH LOW HIGH Identity achievement Foreclosure LOW Moratorium Role confusion  Identity achievement: Most mature achievement – most desirable.  Foreclosure: Avoids anxieties by prematurely committing to safe and conventional parental and societal goals and beliefs.  Moratorium: Experiences height of crises but postpones decisions until alternative identities are tried.  Role confusion: a unresolved state of adolescence Puberty trends: © SPMM Course  In the UK the average age of onset of puberty in males is 11.2 years; for females it is 11 years. Menarche on average is at 12.5 years for females.  There is a general trend for falling in menarcheal age globally over last 50 years. Compared to US and other European countries this falling trend is smaller in UK (by about 6 months in 30 years).  Social stress is also a puberty accelerator, with familial disruption and father absenteeism, being one of the most effective stressors.  Precocious puberty is suspected in boys before age 9, and girls before age 8. As children develop through adolescence into adulthood, they hold increasingly complex orientations to the self and to the interpersonal world. Jane Loevinger described 9 stages of ego and personal identity development involving childhood, adolescence and adulthood. 1. Presocial – the baby is unable to differentiate itself from the world 2. Impulsive – the child is concerned with bodily impulses 3. Self-protective – the child has a notion of blame but externalises to the situation or other people 4. Conformist – around school age, they conform to socially approved codes/the norm 5. Self-Aware – (conscientious-conformist) transitional stage – increased self-awareness and self-criticism; deepened interest in interpersonal relations 6. Conscientious – internalisation of rules is complete; goals/ideals are acknowledged, and there is a new responsibility – feel guilt for hurting others rather than rule-breaking 7. Individualistic – respect for individuality and interpersonal ties 8. Autonomous – ‘synthesizers’ – able to conceptually integrate ideas 9. Integrated – rarely attained stage “learning is understood as unavoidable…the unattainable is renounced.” Pairing occurs often within the same cultural and socioeconomic background (homogamous mate selection). Equity theory suggests that individuals consider the cost-benefit ratio for each person in a relationship; reinforcement theory suggests that individuals chose their partners on the basis of reinforcement of attraction with rewards. The midlife transition occurs around age 40 to 45. The term ‘Midlife Crisis’ was coined by Elliot Jacques who distinguished it as a critical phase in development as the transition between the forties and early sixties, and is often associated with coming to realise mortality, unrealized goals, menopause or children leaving home. Downshifting refers to voluntary opting out of a © SPMM Course pressurized career and giving up well-paid job for more fulfilling life (anti-urbanism). Empty nest distress refers to the feeling of loneliness when children leave home. Bereavement is usually used to describe loss if a person, but can be loss of anything e.g. marriage, employment, and refers to being in a state of mourning (a process influenced by culture and society in which grief is resolved). The classic work on stages of grief came from Erich Lindemann, who studied 101 bereaved people and published in 1944; an article titled “Symptomology and Management of Acute Grief”. In this article he described a set pattern of reaction to a loss event (grief): After an unexpected death, there is the initial shock that lasts 10-14 days. After the initial shock comes a period of intense sadness, and the grieving person may withdraw from social contact. Next comes anger, as the grieving person seems to ‘protest’; the unexpected death. Finally, within a year or so, the grief is resolved, and the person returns to normal. These stages were further refined by Parkes. 5 stages of bereavement (Parkes) 1. Alarm 2. Numbness 3. Pining for the deceased (illusions or hallucinations of the deceased can occur) 4. Depression 5. Reorganisation (recovery) Physiological events such as pregnancy and childbirth could also be stressful in adult life. The psychological stress during pregnancy can have physiological implications on the growing fetus. Release of corticotrophin releasing hormone (CRH) from the placenta increases with stress, and with this an increased risk of intrauterine infection, preterm labour and low birth weight is seen. Pre-term infants are susceptible to complications later such as developmental delay and increased rate of mortality. Babies subject to stress in utero can have the difficult temperament and are irritable. There is additional data to suggest that stress in utero can result in increased risk of chronic health issues in adulthood e.g. hypertension and diabetes. Psychological symptoms following childbirth include intrusive thoughts, avoidance, anxiety, depression, social dysfunction and somatisation. Significant psychological distress is noted in 37% of mothers and 13% of fathers. Factors predicting acute maternal psychological distress included being a single parent, multiparity and previous traumatic birth. At six week and six months, psychological distress symptoms fell to that of general population level indicating that in most people, this is a short-term distress. # 29 - 12. Adaptation with ageing # 12. Adaptation with ageing # 30 - Phases of retirement # Phases of retirement: © SPMM Course 12. Adaptation with ageing Age is the first social category learnt by a child even before number concept develops. The effect of ageing on cognitive abilities: The mass of the brain reduces with ageing (in some cases this can be pathological). Memory is often cited as the cognitive function most susceptible to decline with age – particularly working memory and incidental memory. Attention also declines with age. The effect of ageing on body physiology: Bone loss results in a reduction of mechanical strength, collagen fibres deteriorate causing loss of elasticity of the skin, and the efficacy of organs deteriorates with age. Ageing and socioeconomic independence: Older adults are an economically vulnerable group and with an increasing older population, there are concerns they may outlive their financial resources. The decline in socio-economic status can result in a decline in their physical and mental health. Reduced mobility from physical health problems impacts their independence and ability to maintain social ties. Old age – theories of role change: 1. Social disengagement theory: Mutual withdrawal of society and the individual occurs; increased individuality and shrinking life space are inevitable moves towards death. 2. Social (non) reengagement theory (aka activity loss theory): Ageist society reduces the social interaction that older adults can have; withdrawal is not mutual but forced. 3. Social exchange theory: Age robs people of the ability to engage in reciprocal roles; retirement is a special social contract wherein productivity is exchanged for increased leisure and decreased responsibilities. 4. Socio-emotional selectivity theory: Wise investment of social energy in old age is to limit social interaction to those who are most familiar. Phases of retirement: 1. Pre-retirement phase: Increasing anxiety with the retirement of friends and colleagues. 2. Honeymoon phase: Immediate post retirement phase where increased freedom is enjoyed. 3. Disenchantment: Slowing down occurs, feels let down, worse if inadequately prepared for retirement. 4. Reorientation – explores new avenues, more realistic. 5. Stability –makes choices, mastery attained in chosen leisure. 6. Termination – frailty, death. # 31 - 13. Genetic influences on development. # 13. Genetic influences on development. © SPMM Course 13. Genetic influences on development. Brain development is genetically programmed. For example, the cortical thickness in lateral prefrontal, medial prefrontal, parietal, and temporal cortices is highly heritable. Regions crucial for evolutionarily advanced functions (such as higher‐order cognition, sociality, and language) show both high heritability and an increase in heritability with age during development. This pattern is similar to the age-related increase in heritability for traits such as IQ (discussed earlier). This could be either due to an age‐dependent gene expression or due to gene‐environment interaction. Gene-environment interaction refers to the influence of the relationship between genotype and the environment in shaping a phenotype. Consider the example of phenylketonuria, a genetic condition caused by the lack of an enzyme that breaks down the amino acid phenylalanine, resulting in intellectual disabilities. However, the usual dietary environment of a child can be altered by the use of phenylalanine-free foods, which results in normal development. Waddington proposed the concept of canalization in developmental genetics. Certain behaviour traits are strongly genetically determined (canalized), so development follows these behaviours (e.g. crawling). Other behaviours are poorly canalized (e.g. cycling), so environmental factors will influence these traits. Further, some traits appear to be heavily canalized early in development (e.g., language development), but less so later on (e.g., reading ability). Gottesman put forward the notion of a range of reactions. The genetic make-up of a child does not shape any behaviour in its entirety; instead genes only set limits (or range) within which the individual variability is shaped by the environment. Scarr & McCartney proposed the concept of ‘niche-picking’ in developmental genetics (1983). The genetic make-up of a child does not contribute to skills or behaviours as such; instead genes only contribute to propensities toward certain skills and abilities; children then seek activities that are compatible with their genetic endowment Three types of G-E interaction are notable:  Passive GE‐Interaction: A child’s environment is influenced in part by parental genes which are in turn correlated with the child’s genes. Thus, the phenotype is not a direct result of the child’s genotype; but results from environmental influences that are indirectly associated with the parental genes. This kind of passive G-E will show decreasing influence over development. e.g. a boy who does not inherit the same tallness and © SPMM Course physique as his father may still develop into a good basketball player in line with the father due to repeated exposure to basketball sessions.  Evocative GE‐Interaction: A child’s environment is influenced in part by genetically shaped behaviour. Thus, the phenotype is not a direct result of the child’s genotype; but results from environmental influences evoked by the child’s own genes. This kind of evocative G-E will show stable influence over development. e.g. a girl who inherits impulsivity may evoke an abusive parental reaction, leading to later depression, though depression itself is not inherited.  Active GE‐Interaction: A child’s environment is influenced in part by an active choice of the child to complement genetically shaped interests. Thus, the phenotype is not a direct result of the child’s genotype; but results from environmental influences that are actively associated with the child’s own genes. This kind of active G-E will show increasing influence over development. e.g. a girl who inherits impulsivity may choose to gamble, losses in which may lead to later depression though depression itself is not inherited. # 32 - 14. Neuroimaging and neurodevelopment # 14. Neuroimaging and neurodevelopment © SPMM Course 14. Neuroimaging and neurodevelopment (This section is best read in conjunction with the section on neuroimaging in the Clinical Examination chapter) A neural tube is seen 2-3 weeks after the formation of the human fetus. By week 5, the ectodermal tissues differentiate to precursors of different brain regions. This is followed by birth neurons from stem cells (at ventricular proliferative zone, by week 8), neuronal migration (week 12-20), formation and pruning of axons, dendrites and synaptic contacts, myelination of axons and apoptotic removal of excess cells. One of the earliest neurodevelopmental events that can be visualized using neuroimaging in human fetuses is the migration of neurons. Around 17 weeks’ of gestation, a transient layer of cortical subplate of migrating neurons is visible beneath the cortex; by 20 weeks the subplate withers away and replaced by more permanent cortical sheet at 24 to 28 weeks. A cortical folding pattern consisting of sulci and gyri become visible on fetal MRI by 20 weeks. Around the 28th week of gestation, the neuronal count in the human brain is at its peak - around 40% greater than in the adult. Dendritic formation accelerates at this time (but cannot be seen in MRI), and along with the disappearance of the proliferative zone and cortical subplate, an increase in cortical thickness is notable on fetal MRI. Synaptogenesis peaks around 34th week of gestation in (~ 40,000 new synapses formed per second) and continues in postnatal life alongside active synapse elimination; eventually the net number of synapses begins to decrease at puberty (pruning). Synaptic pruning cannot be observed directly with neuroimaging, but a prominent progressive cortical thinning of frontal and parietal cortices is noted in MRI studies during adolescence and is attributed to synaptic pruning. An indirect indicator of synaptic removal is the glucose metabolism measured using positron emission tomography (PET). Myelination of the visual cortical white matter begins prenatally (last trimester); by 9 months of postnatal life, myelination extends to frontal cortex (posterior-to-anterior maturation starting with sensory pathways motor pathways, and finally the higher-order association areas). Landmark longitudinal studies of brain volumes in children were conducted in the Child Psychiatry Branch of the NIMH, USA. These studies report the following observations 1. White matter volume increases linearly up to age 20 years in all brain regions; 2. Frontal, parietal, and temporal gray matter volumes follow an “inverted U-shaped” developmental curve (increase before adolescence, frontoparietal peak at 12 years and temporal peak at 16 years of age, followed by universal reduction thereafter) © SPMM Course 3. The cortical thickness decreases with advancing age in “back-to-front” progression starting from sensorimotor areas, progressing to the dorsal parietal, superior temporal, and dorsolateral prefrontal cortices later. In other words, sensorimotor area mature earlier than higher-order regions. Cortical thinning may occur either due to synaptic pruning or myelination (with myelination, the brain tissue that is identified as white matter in MRI scans increase in proportion, reducing the relative grey matter thickness). Diffusion Tensor Imaging, a technique used to study the integrity of white matter tracts, reveals that in children, with advancing age, the directionality of diffusion in white matter pathways continues to increase especially in the prefrontal regions and in basal ganglia. This suggests that frontostriatal systems myelinate progressively during adolescence. DTI studies also show that the frontotemporal pathways may continue to myelinate until age 30 years. Magnetic Resonance Spectroscopic measure of N-Acetyl-Aspartate, an indicator of neuronal integrity, reveals low levels around birth that increase rapidly during the first 2 years of life, slowing down thereafter; this may represent synaptogenesis during childhood. Functional MRI studies reveal age-related increases in activation left frontal and temporal cortices (language areas) supporting the expansion of reading and phonological skills during childhood. © SPMM Course Notes produced using excerpts from:  Burman, E. (2007). Deconstructing developmental psychology. Routledge.  Cole, P. M., Martin, S. E., & Dennis, T. A. (2004). Emotion regulation as a scientific construct: Methodological challenges and directions for child development research. Child development, 75(2), 317-333.  Deary IJ, Penke L& Johnson W (2010). The neurosciences of human intelligence differences. Nature Reviews Neuroscience 11, 201-211.  Farrington, D. P. (1995) The development of offending and antisocial behaviour from childhood: key findings from the Cambridge Study in Delinquent Development. Journal of Child Psychology and Psychiatry, 36, 929–964.  http://www.learning-theories.com/eriksons-stages-of-development.html  http://www.personalityresearch.org/papers/lee.html  Marsh, R et al. Neuroimaging Studies of Normal Brain Development and Their Relevance for Understanding Childhood Neuropsychiatric Disorders. J Am Acad Child Adolesc Psychiatry. 2008 Nov; 47(11): 1233–1251.  Shonkoff, J. P., Garner, A. S., et al. (2012). The lifelong effects of early childhood adversity and toxic stress. Pediatrics, 129(1), e232-e246.  Sigelman, C., & Rider, E. (2014). Life-span human development. Cengage Learning.  Skari H, Skreden M, et al. Comparative levels of psychological distress, stress symptoms, depression and anxiety after childbirth--a prospective population-based study of mothers and fathers. BJOG. 2002 Oct;109(10):1154-63.  Slee, P. T., & Shute, R. (2014). Child Development: Thinking About Theories Texts in Developmental Psychology. Routledge.  Thambirajah MS. Psychological Basis of Psychiatry. Churchill Livingstone, 2005 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information. # 05 - 31_Neuroanatomy # 01 - 1. General anatomy of the brain # 1. General anatomy of the brain # 02 - A. Cortical structures # A. Cortical structures # 03 - Hemispheric lateralisation # Hemispheric lateralisation © SPMM Course 1. General anatomy of the brain A. Cortical structures The cerebrum has four major lobes (frontal, temporal, parietal and occipital lobes). The lobar surface is heavily folded forming sulci (valleys) and gyri (ridges). Primary (major) sulci are more invariant in their appearance than the secondary (minor) sulci. The central sulcus divides frontal lobe from the parietal lobe. Precentral gyrus (part of the frontal lobe) is the primary motor cortex. The representation of different body parts in this region is often termed as a homunculus. Postcentral gyrus (part of the parietal lobe) is the primary somatosensory cortex with a similar homunculus representation. The lateral sulcus (Sylvian fissure) divides frontal lobe from the temporal lobe. The insula, a structure that is sometimes regarded as the fifth lobe of the cerebrum, is located deep in the Sylvian fissure. Insula is the seat of the primary gustatory cortex. Other major primary sulci include 1. Superior and inferior frontal sulci: In between these sulci is the middle frontal gyrus constituting the dorsolateral prefrontal cortex, often considered to be responsible for executive functions of the human brain. 2. Cingulate sulcus on the medial side of the frontal lobe. The anterior portion of the adjoining cingulate gyrus is considered to be the seat of motivation. 3. Olfactory and orbital sulci on the inferior surface of the frontal lobe. The orbitofrontal cortex is often considered to be the seat of associative learning and decision-making. 4. The Superior temporal sulcus is forming superior temporal gyrus, the seat of primary auditory cortex. 5. The interparietal sulcus separates superior and inferior parietal lobes. The inferior parietal lobe is made of the angular gyrus and supramarginal gyrus and is considered to be important for visuospatial attention. 6. Calcarine sulcus in the medial occipital cortex, the seat of primary visual (striate) cortex Hemispheric lateralisation  Most fundamental brain functions are represented bilaterally. Higher levels of associative functions usually lateralize to one or other hemisphere. For example, language comprehension is localized to the left temporal cortex while prosody (tonal modulation of speech) seems limited to the right hemisphere.  The hemisphere contralateral to the dominant hand is the dominant hemisphere, and it mediates language and speech functions.  Dominance can be tested using Annette’s handedness scale or Edinburgh handedness inventory. But handedness is not always same as dominance. # 04 - B. Subcortical structures # B. Subcortical structures # 05 - Limbic system Papez circuit # Limbic system/ Papez circuit # 06 - Medial temporal structures # Medial temporal structures # 07 - Basal Ganglia # Basal Ganglia © SPMM Course  In right-handed people, the left hemisphere is mostly dominant. In 10% of right-handed people, the right hemisphere is dominant. Among left-handed people only about 20% are right hemisphere dominant, with 64% left hemisphere dominant and 16% showing bilateral dominance.  Size asymmetry: The planum temporale is a triangular region on the upper surface of the superior temporal gyrus. It is important for language processing and is larger on the left than the right hemisphere in 65% brains. It is probably the most asymmetrical structure in the human brain, with some individuals having a five times larger planum temporale on the left than on the right. This asymmetry is reportedly reduced or reversed (right>left) in schizophrenia. B. Subcortical structures Limbic system/ Papez circuit  Broca first described the limbic lobe. Papez and later Maclean assigned the function of emotional processing to limbic structures though this view is challenged in recent times.  The Papez circuit consists of the hippocampus → fornix → mammillary bodies → mammillothalamic tract → anterior thalamic nucleus → genu of the internal capsule → cingulate gyrus → parahippocampal gyrus → entorhinal cortex → perforant pathway → back to hippocampus  The boundaries of the limbic system were subsequently expanded outside of the Papez circuit to include the amygdala, septum, basal forebrain, nucleus accumbens, and orbitofrontal cortex.  The limbic system is thought to be involved in various functions such as mediation of emotional responses (through amygdala), influencing neuroendocrine responses (via hypothalamus) and reward system regulation (via nucleus accumbens).  The limbic system is often considered to be evolutionarily older than the higher cortical centres. Medial temporal structures  Include the hippocampus, amygdala, entorhinal and parahippocampal cortex.  Hippocampus appears to play an important role in memory processes. It is one of the few brain regions where the continuous production of new neurons is noted even in adult life.  Amygdala appears crucial for fear conditioning and emotional regulation Basal Ganglia  The basal ganglia are a group of gray matter nuclei forming the largest subcortical structure in the brain. They are involved in the planning and programming of movement, and also have a role in the processes by which an abstract thought is converted into voluntary action Left Hemisphere lesions Right Hemisphere lesions Aphasia Visuospatial deficits Right-left disorientation Anosognosia Finger agnosia Neglect Dysgraphia (aphasic) Dysgraphia (spatial, neglect) Dyscalculia (number alexia) Dyscalculia (spatial) Limb apraxia Constructional apraxia Dressing apraxia Face recognition (bilateral) # 08 - Thalamus # Thalamus © SPMM Course  They include striatum made of the caudate nucleus and putamen and pallidum made of globus pallidus. Putamen and globus pallidus are sometimes called lenticular/lentiform nucleus.  The subthalamic nuclei and the substantia nigra are both functionally related to the basal ganglia but are not considered to be a part of this structure.  Basal ganglia receive crucial inputs from glutamatergic corticostriatal projection. Alexander described five important circuits involving the basal ganglia. These are  Motor circuit  Oculomotor circuit  Dorsolateral prefrontal circuit (executive)  Anterior cingulate circuit (motivation)  Lateral orbitofrontal circuit (social intelligence) Disorder Nature of basal ganglia dysfunction OCD Volumetric changes and higher blood flow to the caudate nuclei. Increased caudate metabolism in untreated subjects reduces after effective treatment. Tourette’s syndrome Striatal dopaminergic dysfunction Huntington chorea Degeneration of the striatum (mainly caudate nucleus) & selective loss of GABAergic neurons Wilson disease Copper deposits in the lenticular nuclei CO poisoning Acute bilateral anoxic damage to basal ganglia Hemiballismus Subthalamic nucleus damage (especially infarction) Parkinsonism Depigmentation of Substantia Nigra; Lewy bodies are seen. Striatal overactivity associated with bradykinesia Fahr's disease Progressive calcium deposition in the basal ganglia. (early onset cases present with schizophreniform psychoses and catatonia; later onset cases exhibit dementia and choreoathetosis) Thalamus  A large oval mass of grey matter nuclei in the subcortical region, relaying all types of sensory information onto cortex (except olfaction).  It also relays cerebellar and basal ganglia inputs to the cerebral cortex.  The thalamus is said to play a crucial role of filtering sensory information in preparation for cortical processing.  The anterior thalamus is a part of the limbic system. It receives the mamillothalamic tract and fornix and connects to the cingulate cortex. Thus, it relays information from hypothalamus and hippocampus onto the frontal cortex.  Pulvinar is associated with visual attention. Sleep spindles are generated in the reticular nucleus of the thalamus. # 09 - Hypothalamus # Hypothalamus # 10 - C. Cerebellum # C. Cerebellum # 11 - D. Brain stem and cranial nerves # D. Brain stem and cranial nerves © SPMM Course Hypothalamus  The hypothalamus regulates physiological functions such as eating, drinking, sleeping, and temperature regulation.  The hypothalamus has chemoreceptors that respond to variations in glucose levels, osmolarity, acid balance, etc. It also plays a major role in neuroendocrine control.  The ventromedial hypothalamus acts as the satiety centre while the lateral hypothalamus is the feeding centre. In animals with a lesion of ventromedial hypothalamus hyperphagia and obesity are noted. C. Cerebellum The cerebellum has the important role of preparing a motor plan and predicting balance needed between muscle groups to carry out the intended action smoothly. Cerebellar lesions produce ataxia and coarse intentional tremors, along with hypotonia, past pointing and pendular knee jerk. Increasingly the role of the cerebellum in cognitive processes has been appreciated. The term cognitive dysmetria (Andreasen) refers to the difficulty in coordinating and monitoring the process of receiving, processing, and expressing information that could result from disrupted cortico-cerebellar circuitry in schizophrenia. D. Brain stem and cranial nerves The brain stem is made of the midbrain, pons and the medulla. Most of the cranial nerves (9 out of 12) enter or exit the brain from the brainstem. The midbrain consists of superior (conjugate gaze control) and inferior colliculi (auditory source localization). The substantia nigra is also located in the midbrain along with periaqueductal grey matter that plays an important role in vocalization and freezing response to threat and in pain suppression. Pons is positioned beneath the cerebellum and surrounds the upper half of the 4th ventricle Medulla surrounds inferior part of the 4th ventricle and is continuous with the spinal cord. No. Name Anatomical features I Olfactory Runs on the basal surface of frontal cortex without passing through the thalamus. Formed as an outgrowth of forebrain II Optic Also an outgrowth of the forebrain. Relays via thalamus (geniculate body) III Oculomotor Purely motor function. Supplies four of the six ocular muscles IV Trochlear Purely motor function. Supplies superior oblique (ocular muscle) V Trigeminal Both sensory and motor. Transmits facial sensation and controls jaw muscles VI Abducens Purely motor function. Supplies lateral abducens (ocular muscle) INFERIOR OLIVARY NUCLEUS Inferior olivary nucleus is located in the brainstem and aids in motor coordination by projecting climbing fibers to the contralateral cerebellar cortex via inferior cerebellar peduncle. Inferior olivary lesions lead to appendicular ataxia due to motor incoordination of the contralateral arm and leg. Patients with inferior olivary lesions will fail the finger-nose test, mimicking cerebellar lesion. But unlike cerebellar lesions that result in ipsilateral motor incoordination, the contralateral side is affected in olivary lesions. # 12 - E. Spinal Cord # E. Spinal Cord # 13 - F. Cerebrospinal fluid # F. Cerebrospinal fluid © SPMM Course VII Facial Both sensory and motor. Transmits taste sensation and controls facial muscles VIII Vestibular Transmits auditory sensation Cochlear Transmits balance sensation IX Glossopharyngeal Motor control of pharynx; parasympathetic control of the parotid gland; taste from the back of the tongue. X Vagus Motor control of larynx and pharynx; parasympathetic control of the viscera; visceral sensations. XI Accessory Motor control of neck muscles XII Hypoglossal Motor control of tongue muscles E. Spinal Cord Unlike cerebrum where grey matter is on the outer surface, in spinal cord grey matter occupies the deeper aspect forming an H shaped column surrounding the CSF. The white matter bundles form anterior, lateral and dorsal columns around the grey matter zone. The dorsal column carries proprioceptive sensory fibres; the anterior and lateral columns are made of ascending spinothalamic tracts carrying touch, pressure, pain and temperature sensations. F. Cerebrospinal fluid CSF is secreted by the choroid plexus in the lateral, third and fourth ventricles and at a rate of 300 ml/day, which is almost protein free. Route: From lateral ventricle to 3rd ventricle via interventricular foramina of Monroe; From 3rd to 4th ventricle via cerebral aqueduct of Sylvius; From 4th ventricle to subarachnoid space via foramen of Magendie (single) and foramina of Luschka (two lateral). The body of the lateral ventricle lies immediately below the corpus callosum, and the two lateral ventricles are separated by septum pellucidum. The third ventricle lies between thalamus and hypothalamus. The fourth ventricle lies above the pons and just below the cerebellum. Obstruction to CSF circulation commonly occurs within third or fourth ventricle (foramen of Monroe), leading to non-communicating hydrocephalus. Impairment of CSF reabsorption in the subarachnoid space due to partial occlusion of the arachnoid villi leads to communicating hydrocephalus. # 14 - 2. Blood supply to the brain # 2. Blood supply to the brain # 15 - A. Major branches # A. Major branches # 16 - B. Effect of lesions # B. Effect of lesions © SPMM Course 2. Blood supply to the brain A. Major branches The internal carotid artery enters the circle of Willis and divides to form the anterior cerebral and middle cerebral arteries. The anterior cerebral artery supplies the medial and superior strip of the lateral aspect of the cerebral cortex up to the parietal/occipital border. The middle cerebral artery supplies most of the lateral aspect of the cerebral cortex. This includes the Broca’s and Wernicke’s areas in the dominant hemispheres. The posterior cerebral artery arises from basilar artery and supplies the inferomedial temporal lobe and the occipital lobe. The medulla is supplied by posterior inferior cerebellar arteries and anterior spinal branches of vertebral arteries. Pons is supplied by the basilar artery that runs along the midline of the pons. B. Effect of lesions Artery Supply Lesion effects Anterior Cerebral Artery (ACA) Medial surface (ventromedial frontal lobe, the cingulum, the premotor cortex, and medial motor strip) Bilateral infarct produces quadriparesis (legs weaker than arms) and akinetic mutism (ventromedial or cingulate syndrome) Recurrent artery of Huebner (branch of ACA) Head of the caudate nucleus Initially an agitated, confused state; evolves to akinesia, abulia, with mutism and personality changes Anterior branches of the upper division of the Middle Cerebral Artery Lateral prefrontal cortex Planning deficits, impairment of working memory, and apathy. (DLPFC dysfunction) Anterior communicating artery Basal forebrain Akinesia and personality change (orbitofrontal dysfunction) with a confabulatory amnesia resembling Wernicke-Korsakoff syndrome. Posterior inferior cerebellar artery (PICA) thrombosis Lateral medulla Wallenberg's lateral medullary syndrome. Acute vertigo with cerebellar signs. Ipsilateral face numbness, diplopia, nystagmus, Horner’s syndrome and IX/X nerve palsy with contralateral spinothalamic sensory loss and mild hemiparesis. Carotid system TIA Carotid system TIA •Amaurosis fugax (due to blockade of retinal arteries) •Aphasia •Hemiparesis •Hemisensory loss •Hemianopic visual loss Vertebrobasilar TIA Vertebrobasilar TIA •Diplopia, vertigo, vomiting •Choking and dysarthria •Ataxia •Alexia without agraphia •Hemisensory loss •Hemianopic visual loss •Transient global amnesia •Tetraparesis •Loss of consciousness (rare) # 17 - 3. White matter pathways # 3. White matter pathways © SPMM Course 3. White matter pathways There are 3 major types of white matter pathways. Projection fibers run vertically connecting higher and lower centres of the brain. Association fibers interconnect different regions within the same hemisphere of the brain. Commissural fibers interconnect similar regions in 
the opposite hemisphere. Corpus callosum is the largest bundle of fibres that connect the two cerebral hemispheres; the other such bundles are anterior commissure (interconnects olfactory bulbs), posterior commissure (interconnects midbrain pretectal nuclei), hippocampal commissure and habenular commissure (interconnects posterior dorsal thalamic nuclei). The pericallosal artery derived from the anterior cerebral artery provides blood supply to the anterior aspect and most of the body of the corpus callosum. Left sided apraxia and agnosia may be seen in cases of vascular disruption. Posterior cerebral artery territory supplies splenium (posterior aspect of the corpus callosum) and disrupted supply here prevents right visual cortex accessing the dominant hemispheric processes such as language resulting in alexia and color anomia but with preserved ability to copy words as motor information is relayed via anterior corpus callosum Fornix is an important white mater tract that connects hippocampus to the hypothalamus via mammillary bodies. Thus, it relays cortical input to regulate neuroendocrine and autonomic systems. Arcuate fasciculus connects Broca’s and Wernicke’s areas. Damage results in conduction aphasia. Uncinate fasciculus is a major frontotemporal tract that connects orbitofrontal cortex to the anterior temporal lobes. It plays an important role in social cognition and language. # 18 - 4. Cell types in the nervous system # 4. Cell types in the nervous system # 19 - A. Cortical layers # A. Cortical layers # 20 - B. Special neuronal cell types # B. Special neuronal cell types © SPMM Course 4. Cell types in the nervous system A. Cortical layers The human brain contains approximately 1011 neurons (nerve cells) and approximately 1012 glial cells. According to the distribution of the various types of neurons (i.e. the cytoarchitecture), Brodmann divided the cortex into 47 ‘specialised’ areas. The neocortex (most of the cerebrum) is made up of six layers, with pial surface above layer 1 to the white matter below layer 6. Layers 2 and 4 are mainly afferent (receiving inputs) while 5 and 6 are mainly efferent (sending outputs). The pyramidal neurons with their triangular-shaped cell bodies make up nearly 75% of the cortical neurons. Stellate cells (25%) are present in all the layers except layer 1. Layer Name Predominant cells Molecular/agranular Glial cells, dendrites from neurons of deeper layers and the horizontal cells of Cajal. External Granular layer Granule cells and small pyramidal cells (these get larger as you move down) External Pyramidal layer Small and medium sized pyramidal cells. Internal Granular layer Some pyramidal cells, mostly granule cells. Receives thalamocortical inputs. Internal Pyramidal layer Largest pyramidal cells (esp. in motor cortex: Betz cells) Multiform layer A mixture of all cells, spindle cells, Martinotti cells. The major source of corticothalamic fibres. Gives rise to association/commissural and projection fibres. The cerebellar cortex is three layered. The molecular layer consisting of basket cells and stellate cells, Purkinje layer consisting of Purkinje cells and a Granular layer consisting of granule and Golgi cells. B. Special neuronal cell types Purkinje cells are a class of GABAergic neurons located in the cerebellar cortex only. Purkinje cells form the sole output of all motor coordination in the cerebellum they connect to the deep cerebellar nuclei via inhibitory projections. Granule cells are found within the granular layer of the cerebellum, layer 4 of the cerebral cortex, the dentate gyrus of the hippocampus, and in the olfactory bulb. Large pyramidal cells called Betz cells are seen in the primary motor cortex. Betz cells are pyramidal cell neurons located within the fifth layer of the grey matter in the primary motor cortex. These neurons are # 21 - C. Glial cells # C. Glial cells © SPMM Course the largest in the central nervous system, sometimes reaching 100 μm in diameter. Betz cells represent about 10% of the total pyramidal cell population in layer V of the human primary motor cortex. Stellate cells are found in layer IV of the cerebral cortex (from thalamus feeding forward to pyramidal cells) and also in the cerebellum. C. Glial cells These are cells with supportive metabolic functions; they also participate in modulating neuronal functions e.g. via the production of neurosteroids. There are 3 types of glial cells: 1. Astrocytes are the most numerous of the three types. These are star-shaped cells that enable nutrition of neurons, breakdown of some neurotransmitters, and maintaining the blood-brain barrier. 2. Oligodendrocytes are seen in CNS (not in peripheral nerves, where Schwann cells replace them). They produce myelin sheaths that help in saltatory conduction (pole to pole jumping), which quicken the process of signal transmission. 3. The microglia are descendants of macrophages. They are scavenger cells that clear neuronal debris following cell death. 4. Ependymal cells are a special type of glia that cover the ventricles and facilitate CSF circulation via their ciliary processes. BLOOD BRAIN BARRIER The blood- brain barrier is located in endothelial cells of capillaries of the brain. Unlike the endothelial cells found elsewhere, brain’s endothelial cells have tight junctions with high electrical resistance providing an effective barrier against molecules. In addition, brain capillaries are in contact with foot processes of astrocytes that separate the capillaries from the neurons. Lipid soluble molecules (ethanol and caffeine) can penetrate the barrier relatively easily via the lipid membranes of the cells. In contrast, water-soluble molecules such as sodium and potassium ions are unable to transverse the barrier without using specialized carrier-mediated transport mechanisms. Inflammation such as meningitis weakens the blood brain barrier. There are some areas of the brain that do not have a blood- brain barrier. These are so called circumventricular organs e.g. subfornical organ, area postrema (chemo receptor trigger zone), median eminence and posterior pituitary. # 22 - 5. Major neurochemical pathways # 5. Major neurochemical pathways # 23 - A. Dopaminergic pathways # A. Dopaminergic pathways # 24 - B. Cholinergic pathways # B. Cholinergic pathways © SPMM Course 5. Major neurochemical pathways A. Dopaminergic pathways Depending on the length of the projections, dopaminergic pathways can be classified into 1. Long paths: Nigrostriatal, mesocortical and mesolimbic pathways. 2. Short paths: Tuberoinfundibular and incertohypothalamic pathway. 3. Ultrashort paths: These are found in the amacrine cells in the retina and in the olfactory system. The nigrostriatal pathway is the extrapyramidal pathway that is crucial for motor control; this accounts for most of the brain’s dopamine. Pathway Origin and destination Effect of dopamine (DA) blockade Nigrostriatal Substantia Nigra to striatum and amygdala via medial forebrain bundle DA deficiency (e.g Parkinson’s) or blockade due to antipsychotics can cause extrapyramidal side effects Mesolimbic Ventral tegmental area (VTA) to Nucleus accumbens and hippocampus via medial forebrain bundle Blockade of DA in this tract produces the desirable antipsychotic effect by controlling positive psychotic symptoms Mesocortical Ventral tegmental area (VTA) to cingulate cortex and prefrontal regions via medial forebrain bundle Low levels of DA or DA blockade in this tract is associated with negative symptoms (alogia, anhedonia, amotivation and apathy) Tuberoinfundibular Hypothalamus to the pituitary via portal vessels Dopamine acts as PIH – prolactin inhibitory hormone. DA blockade will serve to increase prolactin levels. Incertohypothalamic Internal connections within hypothalamus Disturbed thermoregulation and possibly weight gain B. Cholinergic pathways The two major cholinergic pathways are 1. Brainstem pathway: This forms a part of the ARAS - ascending reticular activating system that is important to maintain wakefulness and REM sleep state. It originates from pedunculopontine and laterodorsal tegmental nuclei and innervates thalamic relay neurons and reticular nuclei. 2. Basal forebrain pathway: Originates at the Nucleus Basalis of Meynert in basal forebrain and projects to the hippocampus, frontal cortex and amygdala. Degeneration of this pathway is implicated in Alzheimer's disease. # 25 - C. Serotonergic pathways # C. Serotonergic pathways # 26 - D. Noradrenergic pathways # D. Noradrenergic pathways # 27 - E. Glutamatergic system # E. Glutamatergic system # 28 - F. GABAergic system # F. GABAergic system © SPMM Course C. Serotonergic pathways Most of the brain’s serotonergic neurons originate in the midbrain dorsal and median raphe nuclei and ascend to innervate the entire cortex, basal ganglia, thalamus, and also descend to the spinal cord. D. Noradrenergic pathways Noradrenergic projection originates at the locus coeruleus (pons) and ascends to most of the cortex via medial forebrain bundle. Similar to the serotonin system, noradrenergic projections also descend to the spinal cord. E. Glutamatergic system Glutamate is the most common excitatory neurotransmitter in the brain. As a result, almost all cortical descending tracts (from pyramidal cells) rely on glutamate for neurotransmission. This large output of corticofugal fibres makes up most of the corona radiata. All of the association and commissural fibres also use glutamatergic transmission. Many thalamic neurons are also glutamatergic. Thus thalamocortical projections are also glutamatergic. In addition cerebellar output from deep nuclei, subthalamic nuclei to globus pallidus projections, and brainstem to spinal cord projections are also predominantly glutamatergic. F. GABAergic system GABA is the primary inhibitory neurotransmitter in the brain. Unlike other neurotransmitters, there are no specific neurochemical pathways where GABA is dominant. Instead, GABA is the major transmitter for cerebral interneurons that are ubiquitous throughout the cortex. Interneurons are usually short neurons that serve to connect two other neurons, thus forming an essential part of the complex wiring pattern of the cortex. They carry neither motor nor sensory information but serve to modulate local neural circuitry. 2 major cortical interneuron subtypes are noted: parvalbumin (PV)-expressing interneurons (~40% of all interneurons) and somatostatin (SST)-expressing interneurons (30% of interneurons, also called Martinotti cells). A reduction in the expression of PV-interneurons in the frontal cortex is now a well-replicated feature of schizophrenia. PV-interneurons are of 2 subtypes: Basket cells and Chandelier cells. Basket cells receive direct input from thalamocortical projections. They form synapses with the soma or dendrites of the pyramidal neurons and serve to provide the excitatory-inhibitory balance to the cortex. Chandelier cells form synapses with the proximal axonal hillock of pyramidal neurons. They may have an overall excitatory role by serving to short-circuit the action potential propagation though their role is still unclear. © SPMM Course Notes prepared using excerpts from: Heide et al. Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis. Brain. 2013 Jun;136(Pt 6):1692-707. Ruigrok TJ. Cerebellar nuclei: the olivary connection. Prog Brain Res. 1997;114:167-92. Lewis DA et al. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends in Neurosciences 2012 Jan;35(1):57-67.  Andreasen NC et al. "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull. 1998;24(2):203-18. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 06 - 32_Neurophysiology # 01 - 1. Physiology of Neuronal Activity # 1. Physiology of Neuronal Activity # 02 - A. Action Potentials # A. Action Potentials # 03 - B. Synaptic activity # B. Synaptic activity © SPMM Course 1. Physiology of Neuronal Activity A. Action Potentials An action potential is initiated at the axonal hillock when the synaptic signals received by the dendrites and soma are sufficient to raise the intracellular resting membrane potential from -70 mV to the threshold potential of - 55mV. At -55mV, the Na+ channels present at the axon’s initial segment will open. The subsequent Na+ influx causes rapid reversal of the membrane potential from the negative values to +40 mV. When the membrane potential reaches +40mV, the Na+ channels close and the voltage-gated K+ channels open. As K+ ions move out of the axon, the cell membrane gets “repolarized”. B. Synaptic activity A synapse is a junction between 2 nerve cells. Three types of synapses are noted in the nervous system.  Chemical synapses: Presynaptic neuron releases a chemical molecule on stimulation. This molecule acts on the next neuron to bring on a molecular effect or to propagate the impulse further downstream. o Depending on the effects noted on the postsynaptic neuron, a chemical synapse could be classified as either excitatory or inhibitory. Postsynaptic neurons are depolarized by activity at the excitatory synapses; inhibitory synaptic activity serves to hyperpolarize them. o In some instance the postsynaptic changes induced by an excitatory synapse may be sufficient to induce an action potential, but may serve to facilitate the likelihood of generating an action potential with further stimulation. This process is called facilitation. Due to this, additional input from several other presynaptic cells through other synapses may result in a spatial summation effect leading to an action potential. Similarly recurrent stimulation by the same synapse can result in temporal summation that leads to an action potential.  Electrical synapses: They bring on the response by electrical communication without chemical exchange.  Conjoint synapses: These have both electrical and chemical properties. # 04 - 2. Neural basis of physiological functions # 2. Neural basis of physiological functions # 05 - A. Eating # A. Eating # 06 - B. Temperature # B. Temperature # 07 - C. Pain # C. Pain © SPMM Course 2. Neural basis of physiological functions A. Eating The hypothalamus has 2 centers that control feeding behaviour. Ventromedial hypothalamus acts as the satiety centre while lateral hypothalamus acts as the feeding centre. Neurochemical substances such as ghrelin and neuropeptide Y act as mediators of increased appetite (orexigenic). Leptin, cholecystokinin and serotonin act as mediators of satiety (anorexigenic). Ghrelin is the only orexigenic substance produced outside of the CNS – it is synthesized in the gastric mucosa; adipose cells synthesize leptin. Food and food cues increase dopaminergic activity in nucleus accumbens (reward centre). Destruction of dopamine pathways reduces eating behaviour. In obesity, D2 receptors are reduced in the striatum. B. Temperature The hypothalamus has 2 centers that control body temperature. Preoptic anterior hypothalamus acts as a hypothermic centre while posterior hypothalamus acts as a hyperthermic centre. Stimulating preoptic anterior hypothalamus results in parasympathetic-mediated sweating and vasodilation, resulting in hypothermia. Stimulating posterior hypothalamus results in sympathetic drive, shivers and vasoconstriction, leading to hyperthermia. Body temperature varies diurnally; Lesions in the median eminence reduces the diurnal temperature variation. Certain drugs can induce malignant hyperthermia, but not through hypothalamic mechanism. An abnormal excitation-contraction coupling in skeletal muscles is responsible for this defect. Hyperthermia is also seen in Neuroleptic Malignant Syndrome (NMS) induced by neuroleptic use or levodopa withdrawal. C. Pain Thalamus plays a crucial role in pain perception while higher cortical centres are central to the localization and interpretation of pain signal. Thin unmyelinated C fibres or sparsely myelinated A-delta fibres carry pain sensation to dorsal horn of the spinal cord. Fast transmission takes place along lateral spinothalamic route to aid localization while slow transmission takes place through reticulothalamic tract to aid subjective sensation. Opioid receptors in dorsal horn and possibly those in brain stem (periaqueductal grey mater) modulate pain intensity. Descending fibres from serotonergic raphe nuclei also modulate pain perception; this may explain the role of tricyclic drugs in reducing chronic pain. # 08 - D. Thirst # D. Thirst # 09 - E. Abnormalities in physiological drives # E. Abnormalities in physiological drives © SPMM Course Thalamic pain syndrome can occur in cases of stroke involving thalamoperforating branches of posterior cerebral artery. Patients have contralateral loss of sensation with burning or aching pain triggered by light cutaneous stimulation. D. Thirst Subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs playing a crucial role in the perception of thirst. The hypothalamic paraventricular nucleus is also involved in the regulation of thirst. Angiotensin II acts as a neurotransmitter to propagate thirst signals to hypothalamus. Hypotension also stimulates thirst through pathways originating from the baroreceptors on aorta and carotid. Anti diuretic hormone (ADH) increases water reabsorption at renal tubules and thus helps maintain body’s fluid balance. The syndrome of inappropriate secretion of ADH (SIADH) may result from damage to paraventricular and supraoptic hypothalamic nuclei, or due to the use of drugs such as carbamazepine or chlorpromazine. Some tumours such as carcinoma of lung can also produce excess ADH. Low sodium and reduced osmolarity is noted in the presence of normal renal excretion of sodium and high urine osmolality. E. Abnormalities in physiological drives Disorder Clinical features Kluver-Bucy syndrome Bilateral lesions of amygdala and hippocampus results in placidity with decreased aggressive behaviour. Prominent oral exploratory behaviour and hypersexuality. Hypermetamorphosis (objects are repeatedly examined as if they were novel) is also seen. LaurenceMoon-Biedl Syndrome Obesity and hypogonadism along with low IQ, retinitis pigmentosa, and polydactyly. Diabetes insipidus is also seen. Autosomal recessive with genetic locus at 11q13 in most cases. No hypothalamic lesions have been found. Prader-Willi Syndrome Hypotonia, obesity with hyperphagia, hypogenitalism, mental retardation, short stature, impaired glucose tolerance. Abnormal control of body temperature and daytime hypersomnolence is related to hypothalamic disturbances. A reduction in oxytocin neurons and satiety neurons is noted. Associated with paternal deletion (genomic imprinting) at 15q11-q13 Kleine-Levin Syndrome Compulsive eating behaviour with hyperphagia, hypersomnolence, hyperactivity, hypersexuality and exhibitionism. A hypothalamic abnormality sometimes preceded by a viral illness; often resolves by the third decade of life. Psychogenic polydipsia Excessive water consumption in the absence of hypovolemia or hypernatremia. May lead to water intoxication and serious electrolyte imbalance. # 10 - 3. Neurodevelopment # 3. Neurodevelopment # 11 - A. Neurogenesis # A. Neurogenesis # 12 - B. Neuronal MigrationMyelination # B. Neuronal Migration/Myelination # 13 - C. Synaptic pruning # C. Synaptic pruning © SPMM Course 3. Neurodevelopment A. Neurogenesis Early fetal life is a prolific period of neurogenesis. An active zone of nerve cell production is seen immediately around the ventricles of the neural tube. This is called a subventricular zone. Neurons produced here migrate outwards to the cortical plate. Thalamic axons that project to the cortical plate initially synapse on a transient layer of neurons called the subplate neurons. In normal development, the axons subsequently detach from the subplate neurons and proceed superficially to synapse on the true cortical cells. The subplate neurons then degenerate. In some patients with schizophrenia an abnormal persistence of subplate neurons has been noted, suggesting a failure of axonal path-finding. It is now known that continuous neurogenesis takes place in certain brain regions (particularly the dentate gyrus of the hippocampus and olfactory bulb) in adults. Stress reduces hippocampal neurogenesis; enriched environments, exercise and antidepressants promote hippocampal neurogenesis. There is some controversy around whether adult neurogenesis is observed in other brain regions. B. Neuronal Migration/Myelination Neuronal migration takes place in the first 6 months of gestation. Two types of migration are noted: radial and tangential. Radial migration is the primary mechanism by which excitatory neurons reach the cortex. Radial glial cells form scaffolding through their foot processes to guide the migrating neuronal cells. Successive populations of migrating neurons travel past the previously settled neurons (inside out pattern) to form radial stacks of cells (Rakic’s cortical columns). Most inhibitory interneurons in the external and internal granular layers are tangentially migrated neurons. Abnormalities in neuronal migration result in neurons failing to reach the cortex and residing in ectopic positions. This is called heterotopia. Myelination begins prenatally at around 4th gestational month; it is largely complete in early childhood (by 2 years), but does not reach its full extent especially in association cortices until late in the third decade of life. C. Synaptic pruning Synaptogenesis occurs very rapidly from the second trimester through the first ten years of life. The peak of synaptogenesis occurs within the first 2 postnatal years. By mid-childhood, more neurons and cellular processes are established than required for adult's brains. Thereafter a process of pruning or synaptic elimination takes place to select and preserve the most useful while eliminating the unnecessary neuronal connections in the adult's brain. This synaptic pruning continues through the early teen years. Neuronal numbers can be studied using a wide variety of markers including the density of D2 receptors. Before 5 years of age, D2 receptor density is greater than adult levels but regresses during the second # 14 - D. Cerebral plasticity # D. Cerebral plasticity © SPMM Course decade. Dopamine receptors continue to decrease in adult years, but at a considerably slower rate of 2.2% reduction per decade. This rate is faster in males than in females. In schizophrenia, the rate of D2 receptor loss is faster (6.0% loss per decade) than in healthy men. While excessive or prolonged pruning is associated with schizophrenia, relative under-pruning is implicated in autism, wherein the size of certain brain regions may be larger than in healthy controls. D. Cerebral plasticity Cerebral plasticity refers to the capability of the brain to be molded. Cortical sensory maps change with variations in sensory input. Patients with phantom limb also show reorganization of sensory maps after amputation so that the representation of the amputated limb may occur on the cortical face area. Repeated practice also leads to a reorganization of brain’s functional regions. Such an effect is seen in musicians, jugglers and other professionals who repeatedly undertake a learned motor task. # 15 - 4. Neuroendocrinology # 4. Neuroendocrinology # 16 - A. Pituitary gland # A. Pituitary gland © SPMM Course 4. Neuroendocrinology A. Pituitary gland The pituitary gland has an anterior and posterior lobe. The anterior lobe secretes many hormones that are regulated by regulatory neurohormones produced by parvocellular neurons of the hypothalamus. The posterior lobe releases 2 hormones that are synthesized in the magnocellular cells of supraoptic nuclei and paraventricular nuclei of the hypothalamus.  Growth hormone excess causes acromegaly in adults or gigantism in children; low levels are associated with dwarfism. Exercise, sleep and stress increase GH release. The GH response to GHRH and the normal sleep-associated release of GH are altered in depression and anorexia nervosa.  Prolactin release is inhibited by dopamine from the hypothalamus; TRH, on the other hand, may facilitate the release of prolactin. Prolactin levels are increased during pregnancy, nursing and during sleep and exercise. Antipsychotics remove the inhibitory control of dopamine by blocking D2 receptors in the tuberoinfundibular tract. This leads to hyperprolactinaemia, gynecomastia in males and galactorrhea in females. Long standing prolactin increase may lead to osteoporosis.  Vasopressin (ADH) and oxytocin are peptides differing from each other in only two amino acids in their sequences. Vasopressin is thought to play a role in attention, memory, and learning. Release of vasopressin is increased by pain, stress, exercise, morphine, nicotine, and barbiturates and is decreased by alcohol. Oxytocin is implicated in mammalian bonding behavior, particularly in the initiation and maintenance of maternal behavior, social bonding, and sexual receptivity. Region Hormonal output Anterior pituitary o GH - growth hormone o LH - luteinizing hormone (a gonadotrophin) o FSH - follicle stimulating hormone (a gonadotrophin) o ACTH - adreno corticotrophic hormone (corticotrophin) o TSH - thyroid stimulating hormone (thyrotropin) o Prolactin Posterior pituitary o Vasopressin (ADH – antidiuretic hormone) o Oxytocin Hypothalamus o CRH - corticotrophin releasing hormone o GHRH - growth hormone releasing hormone o GnRH - gonadotrophin releasing hormone o TRH - thyrotrophin releasing hormone o SST – somatostatin (inhibits GH) o PIF - prolactin inhibitory factor (dopamine) # 17 - B. Thyroid gland # B. Thyroid gland # 18 - C. Adrenal Cortex # C. Adrenal Cortex © SPMM Course B. Thyroid gland TRH from the hypothalamus stimulates the secretion of TSH from the pituitary. TSH in turn stimulates the thyroid gland to synthesize and release thyroxine T4 and triiodothyronine T3. T4 is the predominant form of thyroid hormone, but T3 is biologically more potent. T4 is converted into T3 by target organs as well as the brain. Exogenous administration of TRH produces a brisk response by increasing TSH concentration. In patients with depression, a blunted response to TRH administration is seen. Mania, alcohol withdrawal and anorexia can also cause blunted TRH response. The addition of T3 and T4 as supplements to antidepressant treatment has been shown to accelerate response in some patients, particularly women. Exogenous administration of thyroid hormones (e.g. in resistant depression) increases serotonergic transmission with decreased 5-HT1A sensitivity and increased 5-HT2A sensitivity Nerve growth factor genes are activated by T3 during early development but not in the adult's brain. Lithium produces hypothyroidism especially in middle-aged women who are predisposed to carry antithyroid autoantibodies. Hypothyroidism is sometimes implicated in rapid cycling mood pattern in previously stable bipolar patients. Hyperthyroidism is associated with symptoms of generalized anxiety disorder. Hyperthyroidism Hypothyroidism Physical symptoms: Tachycardia, weight loss, heat intolerance, sweating Physical symptoms: Fatigue, weight gain, cold intolerance, dry skin Mental symptoms: Anxiety, irritability, poor concentration, agitation, emotional lability. Mental symptoms: Depression, reduced activity (psychomotor retardation), reduced libido and poor memory C. Adrenal Cortex CRH from the hypothalamus stimulates ACTH release from the anterior pituitary. ACTH in turn stimulates the release of cortisol from the adrenal cortex. Cortisol thus produced in turn inhibits both CRH and ACTH in a negative feedback loop to maintain homeostasis. This is called Hypothalamic-PituitaryAdrenal (HPA) axis. HPA axis is involved in regulation of stress response. With chronic stress the HPA feedback fails and continuous excess of cortisol is produced with deleterious consequences to the hippocampus where glucocorticoid receptors are abundant. Decreased hippocampal neurogenesis with atrophy of hippocampal dendrites results in shrinkage of the hippocampus. This disrupts long-term potentiation (LTP) and leads to impaired memory performance. A compensatory increase in dendritic arborization of # 19 - Dexamethasone suppression test (DST) # Dexamethasone suppression test (DST) © SPMM Course neurons in the basolateral amygdala may occur, contributing to a memory bias towards negative events in chronic stress. Hypercortisolism (Addison's disease) Hypocortisolism (Cushing's syndrome) Physical symptoms: Apathy, fatigue, and depression Physical symptoms: Fatigue, weight gain, cold intolerance, dry skin Mental symptoms: Anxiety, irritability, poor concentration, agitation, emotional lability. Mental symptoms: Depression, mania, confusion, and psychotic symptoms. A diurnal variation in cortisol levels occurs in humans, with peak cortisol levels occurring around 6:007:00 AM. Hypercortisolemia with the loss of the normal diurnal variation have been reported in depression (especially in melancholic depression with the somatic syndrome), in some patients with mania (especially psychotic), obsessive-compulsive disorder and schizoaffective disorder. In PTSD hypocortisolemia is seen in a subgroup of patients; this may be due to aberrant feedback to the pituitary due to excessive glucocorticoid receptors – probably a genetic vulnerability. Low cortisol is also seen in chronic fatigue and fibromyalgia. Dexamethasone suppression test (DST) o Exogenous corticosteroids such as dexamethasone will suppress endogenous cortisol production if the HPA axis is intact. o In DST, 1mg dexamethasone is given at 11PM with baseline cortisol sampling; on the next day at 8AM, 4PM and 11PM cortisol levels are measured again. If any one sample has >5mcg/L of cortisol, this indicates DST non-suppression. This demonstrates the failure of feedback suppression of ACTH/CRH and continuous production of endogenous cortisol despite administration of exogenous steroid (dexamethasone). o DST non-suppression is seen in depression and other psychiatric hyper cortisol emic states (also in organic hyper cortisol emic states such as Cushing’s). o The sensitivity of the DST for detecting major depression is modest (about 40%- 50%) but is higher (about 60%-70%) in very severe depression with psychotic as well as melancholic features. o DST non-suppression is non-specific to depression and is also seen in mania and schizoaffective disorder. In addition, a number of major medical conditions, pregnancy, severe weight loss and use of alcohol and certain other drugs (hepatic enzyme inducers that reduce dexamethasone availability - barbiturates, anticonvulsants, and others) can also produce DST non-suppression. o Despite the presence of depression, DST may suppress cortisol if the patient has Addison’s or hypopituitarism or taking steroids, high-dose benzodiazepines or indomethacin. o DST non-suppression does not increase the likelihood of antidepressant response. A negative test is not an indication for withholding antidepressant treatment. o Some data suggest that patients with DST non-suppression are less likely to respond to a placebo than those who show a suppression response. # 20 - D. Pineal gland # D. Pineal gland © SPMM Course o Continued failure to suppress cortisol despite the apparent recovery from depression suggests an increased risk for relapse, poor prognosis and possibly later suicidal behaviour. D. Pineal gland The pineal gland is also called epiphysis. It contains pinealocytes that secrete both serotonin (in the day) and melatonin (in the night). The gland also contains calcium deposits that become more prominent with age (corpora arenacea or brain sand). The pineal gland contains the highest concentration of serotonin in the body. Melatonin is synthesized from serotonin by the action of serotonin-N-acetylase and 5-hydroxyindole-O-methyltransferase. The major regulator of melatonin synthesis is the light-dark cycle, with synthesis increased during darkness. The pineal gland is regulated by a major -adrenergic mechanism, and -antagonists such as propranolol decrease melatonin synthesis. Melatonin regulates circadian rhythms. It has both synchronizing and phase-shifting properties in the regulation of biological rhythms. ENDOCRINE CHANGES & SLEEP Start of sleep – increased testosterone Slow wave sleep – increased GH & SST; reduced cortisol REM sleep – reduced melatonin Early morning sleep – increased prolactin. Circadian rhythm development in the first 1 month involves the emergence of the 24-hour core body temperature cycle; by 2 months progression of nocturnal sleeping is noted and in 3 months, melatonin and cortisol rhythms are established. # 21 - 5. Physiology of sleep # 5. Physiology of sleep # 22 - A. Measurement # A. Measurement # 23 - B. Architecture # B. Architecture # 24 - NREM sleep # NREM sleep: © SPMM Course 5. Physiology of sleep A. Measurement  Actigraphy: This is used to quantify circadian sleep-wake patterns and to detect movement disorders during sleep; it uses a motion sensor.  Polysomnography (PSG): This includes EEG, electromyogram (EMG), electrooculogram EOG. ECG, oximetry and respiratory monitor can also be added. PSG helps in the diagnosis and monitoring of sleep apnoea, narcolepsy, restless legs & REM behavioural disorder. Some of the terms used in PSG are o Sleep latency: time from ‘lights out’ to sleep onset. o REM latency: Time from sleep onset to first REM episode. Normally ~90 minutes in adults. o Non-REM latency: Time from sleep onset to first Non-REM episode. o Sleep efficiency: (Total sleep time/total time in bed) X 100. o Multiple sleep latency test: This is used to assess daytime somnolence and daytime REM onset in narcolepsy. B. Architecture The average length of sleep is approximately 7.5 hours per night. Sleep is made up of non-rapid eye movement (NREM) and rapid eye movement (REM) phases. NREM sleep: o 75% of adult sleep is NREM. Most physiological functions are markedly lower in NREM than in wakefulness (decreased muscle tone, respiration, temperature and heart rate). o NREM is classified as stages 1 to 4 with increasing amplitude and decreasing frequency of EEG activity. Stages 3 & 4 together constitute slow wave sleep (SWS). SWS dominates initial part of the sleep. o Features of non-REM sleep includes  Increased parasympathetic activity (decreased heart rate, systolic blood pressure, respiratory rate, cerebral blood flow)  Abolition of tendon reflexes  The upward ocular deviation with few or no movements. • 5% of sleep • Drowsy period. When awoken from this stage one denies being asleep. • Shows low voltage theta activity, sharp V waves. Stage 1 NREM sleep Stage 1 NREM sleep •45% of sleep •Shows the development of sleep spindles and K complexes. Stage 2 NREM sleep Stage 2 NREM sleep •12% of sleep •Shows <50% delta waves. Stage 3 NREM sleep Stage 3 NREM sleep •13% of sleep •Shows >50% delta waves. •Physiological functions are at the lowest Stage 4 NREM sleep Stage 4 NREM sleep DREAMS Dreaming occurs at all stages of sleep, but the content varies. In non-REM sleep the dreams are thought-like as though the person is solving a problem. In REM sleep the dreams may be illogical and bizarre. # 25 - REM sleep # REM sleep # 26 - C. Brain activity # C. Brain activity © SPMM Course  Reduced recall of dreams if awaken. (Sleep terror is an NREM disorder. When awake after sleep terror episodes, children appear confused and do not recall what terrified them). REM sleep o 25% of adult sleep is REM. Darting eye movements are noted in REM despite other muscles being paralysed. REM sleep is characterized by a high level of brain activity and physiological activity similar to those in wakefulness. o In REM sleep behavioural disorder, muscular paralysis does not occur resulting in violent movements coinciding with brain activity. o EEG shows low-voltage, mixed-frequency (theta and slow alpha) activity similar to an awake state. Sawtooth waves are also seen. o In a typical night, a person cycles through five episodes of non-REM/REM activity. The REM episodes increase in length as the night unfolds. o Features of REM sleep:  Increased sympathetic activity (increased heart rate, systolic blood pressure, respiratory rate, cerebral blood flow)  Autonomic functions are active with penile erection or increased vaginal blood flow  Increased protein synthesis  Maximal loss of muscle tone with occasional myoclonic jerks  Vivid recall of dream if awaken. (Nightmares occur in REM sleep – hence they are well recollected). C. Brain activity Apart from various oscillatory patterns, some specific patterns of electrical activity are also noted during sleep.  Sleep spindles  Waves with upper alpha or lower beta frequency, seen in many stages but especially in stage 2. The waveform resembles a spindle with an initial increase in amplitude that decreases slowly  Duration usually <1second.  They usually are symmetric and are most obvious in the parasagittal regions.  K complex:  K complex waves are large-amplitude delta frequency waves, sometimes with a sharp apex.  They can occur throughout the brain but more prominent in the bifrontal regions.  These may be mediated by thalamocortical circuitry.  Usually symmetric, they occur each time the patient is aroused partially from sleep.  Semiarousal often follows brief noises; with longer sounds, repeated K complexes can occur.  Runs of generalized rhythmic theta waves sometimes follow K-complexes; this pattern is termed an arousal burst.  V waves:  V waves are sharp waves that occur during sleep. They are largest and most evident at the vertex bilaterally and are usually symmetrical.  Multiple V waves tend to occur especially during stage 2 sleep. # 27 - D. Regulation # D. Regulation # 28 - Hypothalamic controls # Hypothalamic controls # 29 - Ascending Reticular Activating System Neurotr # Ascending Reticular Activating System - Neurotransmitters © SPMM Course  Often they occur after sleep disturbances (e.g., brief sounds) and, like K complexes, may occur during brief semiarousals. D. Regulation Hypothalamic controls  The master clock of the brain is the suprachiasmatic nucleus (SCN) located in the anterior hypothalamus - this orchestrates circadian rhythms and is synchronized by signals from the retina.  SCN is reset each day by signals of light from the retina. Specialized melanopsin-containing retinal ganglion cells project via retinohypothalamic tract to the SCN. This provides light input independent of vision.  In the absence of solar guidance, the 24-hour sleep-wake cycle will gradually increase to approximately 26 hours –this is called freerunning.  Pineal melatonin secreted during darkness can also reset the SCN. Thus, melatonin promotes sleep in those with delayed sleep onset or jet lag.  The ventrolateral preoptic nucleus (VLPO) is called the sleep switch nucleus. It has projections to the main components of the ascending arousal system. The VLPO induces sleep by putting the brakes on the arousal nuclei. People with damage to their VLPO have chronic insomnia.  The VLPO must be inhibited so that people can wake up. This is brought about by a negative feedback from the monoaminergic system. The switching to arousal is then stabilised by orexin (also called hypocretin) neurons in the hypothalamus. Orexin neurons are mainly active during wakefulness and reinforce the arousal system. Patients with narcolepsy have reduced number of orexin neurons, leading to repeated somnolence during the day. Ascending Reticular Activating System - Neurotransmitters Neurotransmitter Cell Bodies Function Cholinergic Midbrain-pons nuclei REM on neurons. Activation brings on REM sleep Noradrenergic Locus coeruleus REM off neurons. Activation reduces REM sleep. Dopaminergic Periaqueductal gray matter D2 possibly enhances REM sleep Serotoninergic Raphe nuclei 5HT2 stimulation possibly maintains arousal Histaminergic Tuberomammillary nucleus H1 stimulation possibly maintains arousal SLEEP & AGEING Newborns sleep about 16 hours a day. They spend >50% of sleep time in REM sleep. Sleep onset REM is also seen in neonates. By 3-4 months of age, the pattern shifts so that the total percentage of REM sleep drops to less than 40, and entry into sleep occurs with an initial period of NREM sleep. By late teens adult pattern of sleep is established. This distribution remains relatively constant until old age. Absolute reduction occurs in both slow-wave sleep and REM sleep in older persons. An increase in frequency of awakenings after sleep onset also occurs with age. # 30 - E. Drugs and Disorders # E. Drugs and Disorders © SPMM Course E. Drugs and Disorders Disorder / drugs Changes Alcohol  Increase SWS (chronic use – loss of SWS)  Reduce initial REM but increase second half REM Alcohol withdrawal  Loss of SWS  Increased REM  Intense REM rebound Anxiety disorders  Increased stage 1 sleep (light sleep)  Reduced REM, normal REM latency  Reduced slow wave sleep Benzodiazepines  Decrease sleep latency  Increase sleep time  Reduce stage 1 sleep  Increase stage 2 sleep  Reduce REM and SWS  REM rebound on cessation  Prevent the transition from lighter stage 2 sleep into deep, restorative (stages 3 and 4) sleep. Cannabis  Increase SWS  Suppress REM Carbamazepine  Suppresses REM and increases REM latency  Increases SWS Dementia  Increased sleep latency & fragmentation  Reduced sleep time Depression  Loss of SWS slow wave sleep (first half)  Increased REM (leading on to Early awakening)  Reduced REM latency Lithium  Suppresses REM and increases REM latency  Increases SWS Opiates  Decrease SWS & REM  Withdrawal REM rebound Schizophrenia  Inconsistent reduction in REM latency and slow wave sleep.  N.B.: Antipsychotics have variable effects SSRIs  Alerting due to 5HT2 stimulation  May reduce REM latency  Variable effects of REM suppression Stimulants  Reduce sleep time by decreasing both REM sleep and SWS  REM rebound on cessation (except modafinil) Tricyclics  REM suppression (especially Clomipramine)  Increased SWS and stage 1 sleep Z hypnotics  Less effect on sleep architecture; Zopiclone may increase SWS # 31 - 6. Neurophysiological measurements # 6. Neurophysiological measurements # 32 - A. EEG # A. EEG # 33 - Wave forms noted in EEG # Wave forms noted in EEG © SPMM Course 6. Neurophysiological measurements A. EEG  EEG records the electrical activity of the brain. In psychiatric practice, it is primarily used to rule out seizures, monitor ECT and in polysomnogram for sleep disorders.  Standard EEG uses 21 electrodes placed on the scalp. Placement of the electrodes is based on the 10/20 International System of Electrode Placement. This system measures the distance between readily identifiable landmarks on the head and then locates electrode positions at 10 percent or 20 percent of that distance in an anterior-posterior or transverse direction.  Activation procedures could be used to bring up abnormal discharges.  Strenuous hyperventilation (most common, safe)  Photic stimulation using an intense strobe light  24 hours of sleep deprivation can lead to the activation of paroxysmal EEG discharges in some cases  EEG recording during sleep (natural or sedative induced) can also be used when the wake tracing is normal. Wave forms noted in EEG Waves Frequency Notes Beta >13Hz Some seen at frontal, central position in the normal waking EEG Alpha 8 to 13 Hz Dominant brain wave frequency when eyes are closed and relaxing; occipitoparietal predilection. Disappears with anxiety, arousal, eye opening or focused attention. Dominance reduces with age. Theta 4 to 8 Hz A Small amount of sporadic theta seen in waking EEG at frontotemporal area; prominent in drowsy or sleep EEG. Excessive theta in awake EEG is a sign of pathology. Delta <4 Hz Not seen in waking EEG. Common in deeper stages of sleep; the presence of focal/generalized delta in awake EEG is a sign of pathology. Mu 7-11 Hz Occurs over the motor cortex. It is related to motor activity, characterized by arch like waves; gets attenuated by movement of the contralateral limb Lambda Single waves A single occipital triangular, symmetrical sharp wave produced by visual scanning when awake (e.g. reading) or in light sleep  Beta and alpha are called fast waves; theta and delta are slow waves. Newborns Newborns •Dominant delta and theta waves Infants Infants •Irregular medium- to high-voltage delta activity Early childhood Early childhood •Alpha range develops in posterior areas Midadolescence Midadolescence •EEG essentially has the appearance of an adult tracing by 1214 years. Adults Adults •Normal dominant alpha rhythm # 34 - Abnormalities in EEG # Abnormalities in EEG © SPMM Course Abnormalities in EEG EEG in various disorders Absence seizures (petit-mal) Regular 3 Hz Complexes Alzheimer’s dementia Rarely normal in advanced dementia; may be helpful in differentiating pseudodementia from dementia Angelman’s syndrome 1. EEG changes are notable by the age of 2. 2. Prolonged runs of high amplitude 2–3 Hz frontal activity with superimposed interictal epileptiform discharges – all ages 3. 3. Occipital high amplitude rhythmic 4–6 Hz activity facilitated by eye closure, is seen under the age of 12 years. 4. 4. There is no difference in EEG findings in AS patients with or without seizures Antisocial personality disorder Increased incidence of EEG abnormalities in those with aggressive behaviour ADHD Up to 60% have EEG abnormalities (spike/spike-waves) Borderline personality disorder Positive spikes: 14- and 6 per second seen in 25% of patients CJD Generalised periodic 1-2 Hz sharp waves are seen in nearly 90% patients with sporadic CJD. Less often in familial / hormonal transplant-related forms. NOT seen in a variant form. Closed head injuries Focal slowing (sharply focal head trauma) Focal delta slowing (subdural hematomas) Diffuse atherosclerosis Slowed alpha frequency and increased generalized theta slowing Herpes simplex encephalitis Episodic discharges are recurring every 1-3 seconds with variable focal waves over the temporal areas. Huntington’s dementia Initial loss of alpha; later flattened trace Infantile spasms (seen in tuberous sclerosis) Hypsarrhythmia [diffuse giant waves (high voltage, >400 microvolts) with a chaotic background of irregular, asynchronous multifocal spikes and sharp waves]. Clinical seizures are associated with a marked suppression of the background - called the electrodecremental response Infectious disorders Diffuse, often synchronous, high voltage slowing (acute phase of encephalitis) Metabolic and endocrine disorders Diffuse generalized slowing. Triphasic waves: 1.5 to 3.0 per second highvoltage slow-waves especially in hepatic encephalopathy. Neurosyphilis The non-specific increase in slow waves occurring diffusely over the scalp. Panic disorder Paroxysmal EEG changes consistent with partial seizure activity in one-third; focal slowing in about 25% of patients Seizures Generalized, hemispheric, or focal spike/ spike-wave discharge. Stroke Focal or regional delta activity Structural lesions Focal slowing / focal spike activity # 35 - Effect of drugs on EEG # Effect of drugs on EEG # 36 - B. MEG # B. MEG # 37 - C. ERP # C. ERP © SPMM Course  Diffuse slowing of background is the most common EEG abnormality; it is nonspecific and signifies the presence of encephalopathy. Focal slowing suggests local mass lesions; e.g. edema, haematoma or focal seizure.  Epileptiform discharges when seen interictally, can be considered as hallmark of seizure disorder. But this is not a common finding. If this is lateralized and periodic, it may suggest an acute destructive brain lesion. Effect of drugs on EEG B. MEG  Magnetoencephalography (MEG) is used to measure the magnetic fields produced by electrical activity in the brain  In contrast to electric fields, magnetic fields are less distorted/impeded by the skull and scalp.  The scalp EEG is sensitive to both tangential and radial components of a current source in a spherical volume conductor, MEG detects only its tangential components. Thus, MEG may selectively measure the activity in the sulci, whereas scalp EEG measures activity both in the sulci and at the top of the cortical gyri. C. ERP  An ERP is a change in electrical brain activity stereotyped and time-locked to an event (e.g., stimulus), although it can also occur for the omission of an expected stimulus. ERPs allow the investigation of specific types of information processing by the brain.  ERPs are small relative to the spontaneous brain activity (background EEG) that is they have a low signal-to-noise ratio. To increase the signal-to-noise ratio, an often-used method is ERP averaging Psychotropics Antipsychotics Slowing of beta activity with increase in alpha, theta and delta activity Antidepressants Slowing of beta activity with increase in alpha, theta and delta activity Lithium Slowing of alpha or paroxysmal activity Anticonvulsants No effect on awake EEG Primarily sedating drugs – decrease alpha Barbiturates Effects are opposite to that of alcohol. Increased beta activity upon intoxication; generalized paroxysmal activity and spike discharges (even without overt fits) in withdrawal states. Benzodiazepines Increased beta; decreased alpha. Overdose leads to diffuse slowing Opioids Decreased alpha activity; increased voltage of theta and delta waves; in overdose, slow waves are seen. Primarily recreational drugs – increase alpha Alcohol Increased alpha activity; increased theta activity. Withdrawal increases beta. Delirium tremens has beta (fast) wave activity – other deliria have increased slow waves. Marijuana Increased alpha activity in frontal area of brain; overall slow alpha activity Cocaine Same as marijuana; longer lasting. Nicotine Increased alpha activity; in withdrawal, marked decrease in alpha activity Caffeine In withdrawal, increase in amplitude or voltage of theta activity © SPMM Course  ERPs have polarity (positive [P] or negative [N]) and latency (the moment of peak occurrence after stimulus presentation, which is often indicated by the number attached to the labels of ERP activity).  The temporal resolution of EEG, MEG and ERP analysis is much higher than that of other neuroimaging methods like functional MRI, SPECT and PET, but these techniques lack the high spatial resolution of the MR techniques.  According to the time of occurrence ERPs, can be classified as early, mid latency and late.  The P300, a positive late ERP component around 300 ms after stimulus presentation, is typically generated when a rare target stimulus is imbedded with more frequent stimuli e.g. (auditory ‘oddball’ protocol). The P300 is related to the maintenance of working memory. Decrease in P300 amplitude is well established as a biological trait marker in schizophrenia.  The Mismatch Negativity or MMN is a negative ERP component that is recorded between 100-200 ms in response to low-probability deviant sounds (oddball) in a sequence of standard sound stimuli, when the participant is not actively attending to the deviants. The MMN is best seen in the difference wave between the ERP in response to the standard and deviant sounds. The MMN reflects involuntary information processing in auditory context, i.e. the mnemonic comparison of a given stimulus with a previous one that has already built up a trace in memory. The violation of the previously formed memory trace produces the MMN. Decreased MMN amplitude is noted in schizophrenia.  The Contingent Negative Variation (CNV) is a slow negative shift in the interval between two paired stimuli presented one after the other (S1 being the cue, S2 being the imperative stimulus prompting to respond). CNV reduction in central (midline) electrodes is noted in schizophrenia patients especially with long duration of illness with positive symptoms. •Basic sensory pathways can be studied by recording early ERPs. •These are also called ‘evoked potentials’ (EPs) or brain stem evoked responses (BAER) •They occur in response to sounds (Auditory EP, AEP), flashes (Visual EP, VEP) or electrical stimulation (Somatosensory EP, SEP). Early ERPs Early ERPs • These occur after BAER. •The three well known midlatency ERPs are N100, P50 and P200. •Their amplitudes reduce with repetition (habituation response / sensory gating). Midlatency ERPs Midlatency ERPs •Cognitive pathways can be studied by recording of ERPs related to the execution of psychological events such as attention, emotion or memory tasks. •P300 and MMN are late ERPs Late ERPs Late ERPs © SPMM Course Notes prepared using excerpts from:  Seeman P. Pruning during development. Am J Psychiatry 1999’ 156:168.  Martin et al. Repetitive transcranial magnetic stimulation for the treatment of depression: systematic review and meta-analysis. British Journal of Psychiatry, 2003: 182, 480 -491.  The APA Task Force on Laboratory Tests in Psychiatry. The dexamethasone suppression test: an overview of its current status in psychiatry. Am J Psychiatry 1987; 144:1253-1262  http://www.emedicine.com/neuro/TOPIC275.HTM  http://emedicine.medscape.com/article/1139332-overview  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition  George, MS et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biological Psychiatry, 2000: 47, 287 -295  Kaplan & Sadock Comprehensive Textbook of Psychiatry 9th ed – Pages 199-200.  Boyd et al. The EEG in early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr 1988: 147; 508–513  Ohayon MM et al. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan. Sleep. 2004; 27[7]: 1255-1273.  Walter et al. Contingent Negative Variation: An Electric Sign of Sensori-Motor Association and Expectancy in the Human Brain. Nature 1964: 203, 380 - 384 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 07 - 33_Neurochemistry # 01 - 1. Synaptic transmission # 1. Synaptic transmission © SPMM Course 1. Synaptic transmission  The presynaptic neuron synthesises, transports and stores the chemical messenger (neurotransmitter). Synthesis takes place in cell body / soma which contains the essential protein synthesis machinery. From here axonal transport occurs, and the neurotransmitter reaches the synaptic terminal. Before its eventual release, the neurotransmitter is stored within the synaptic vesicle. The release takes place through the process of membrane fusion and exocytosis.  Upon release, the neurotransmitter occupies receptors present on the surface of the postsynaptic neuronal membrane. Some of the neurotransmitter molecules will also act on autoreceptors that are present in the presynaptic neuronal membrane. Such autoreceptor activity is considered to be crucuial for feedback inhibition of the neurotransmitter synthesis and release.  Neurotransmitters exhibit specificity in receptor interaction. One neurotransmitter can have more than one receptor types, but within a given receptor site only a particular chemical conformation can be accommodated (lock and key).  Receptors have a finite number and thus get saturated if there is an over secretion of neurotransmitter.  Receptor binding is often competitive; relative synaptic concentrations of competing molecules decide the eventual degree of receptor activity. Most receptors are bound reversibly i.e. following dissociation of the neurotransmitter; the receptor falls back to its physiological status quo. Some molecules can act irreversibly producing structural alterations in the protein of receptor complexes.  After synaptic release and activity, cessation of neurotransmitter action takes place via 1. Reuptake back to presynaptic neuron via special transporters (e.g. monoamine transporters) 2. Enzymatic breakdown at the cleft (e.g. via COMT/MAO-A enzyme) 3. Removed by glia or plasma circulation (e.g. glutamate shuttle)  Feedback control of a neurotransmitter may exist at various points 1. Control of presynaptic synthesis 2. Regulation of release 3. Reuptake regulation 4. Autoreceptor mediated presynaptic inhibition 5. Independent postsynaptic inhibition via a different neuronal network Neurotransmitters Monoamines Amino acids Peptides Dopamine Norepinephrine Epinephrine Serotonin Acetylcholine Histamine GABA Glycine Glutamate Endorphins Cholecystokinin Neurotensin Neuropeptide Y Leptin Ghrelin # 02 - 2. Classification of receptors # 2. Classification of receptors © SPMM Course 2. Classification of receptors Receptors may be categorized into three categories: (1) Ligand-gated channels (ionotropic), in which binding of a chemical messenger alters the probability of opening of transmembrane pores or channels; (2) Those in which the receptor proteins are coupled to intracellular G proteins as transducing elements (metabotropic); (3) Those termed ligand-dependent regulators of nuclear transcription (nuclear receptors). Ionotropic or ion channel receptors result in fast response (GABAA benzodiazepine); G protein coupling (metabotropic) is comparatively a slower process (most antipsychotics, antidepressants). Ion channel receptors are made up of four or five protein subunits making up a pore like structure. The GABA-A receptor's structure is typical of most ligand-gated (ionotropic) receptors [‘doughnut with a hole in the centre’ or ‘rosette’ shaped]. Each protein subunit is a string of amino acids which passes in and out of the cell membrane four times. At the extracellular end of this string is a large N-terminal; this end-chain is thought to mediate GABA-channel interactions. In the middle of the string is a large intracellular loop of amino acids with four sites where phosphorylation occurs. Inhibitory neurotransmitter action leads to the entry of Cl- while excitatory action results in the entry of Ca2+ or other cations. Ionotropic receptors include GABAA, NMDA, the 5HT3 subtype of serotonin receptors. G-protein-coupled metabotropic receptors are proteins that span the cell membrane seven times (serpentine receptors). G protein-coupled receptors act via cyclase mediated second messenger activation (GTP, ATP, etc.). Gs-proteins are stimulatory; Gi-proteins inhibit the adenylate cyclase. A third variant of G-protein receptors acts via phospholipase C. Metabotropic receptors influence protein synthesis eventually thus producing longer lasting effects. Metabotropic receptors include DA receptors, most 5HT receptors except 5HT-3, NEN and neuropeptides including opioid receptors are G coupled. Nuclear receptors such as glucocorticoid receptors are part of a superfamily of receptors that have a cysteine-rich DNA-binding domain, a ligand-binding domain, and a variable amino terminal region. Upon appropriate ligand binding, a nuclear receptor becomes a transcription factor and binds in turn to DNA via zinc fingers. Other nuclear receptors include the receptors for progesterone, androgen, and 1,25dihydroxycholecalciferol (Vitamin D). Many receptors of this family are orphan receptors, for which the ligands are still unidentified. The glucocorticoid receptor is located mainly in the cytoplasm but migrates to the nucleus as soon as it binds its ligand. In contrast, the estrogen and the triiodothyronine (T3) receptors are retained in the nucleus and bind hormones directly in the nucleus itself. # 03 - 3. Dopamine # 3. Dopamine © SPMM Course 3. Dopamine •tyrosine l-dopa  dopamine Source Source •tyrosine hydroxylase Rate limiting step Rate limiting step •Monoamine oxidase (MAO) & Catechol-o-methyl transferase (COMT). •MAO-A more selectively metabolizes norepinephrine and serotonin •MAO-B more selectively metabolizes dopamine. Breakdown enzymes Breakdown enzymes •Homovanillic acid Breakdown product Breakdown product •Dopamine transporter (cocaine inhibits this transported) Reuptake Reuptake •Motivation, novelty seeking, reward circuitry (addictions), arousal and motor movement gating in basal ganglia Function Function •5 types; D1 to D5 . All are G protein coupled •D1-like  D1 & D 5; increase adenylate cyclase (stimulatory). D1 exclusively postsynaptic; resistant to antagonism. D5 more limbic in distribution; 10 times higher dopamine affinity •D2-like  D2,3 & 4 ; decrease adenylate cyclase (inhibitory). D4 is found primarily in the frontal cortex and clozapine has a high affinity. D4-selective antagonists do not have antipsychotic efficacy. Receptors Receptors •Levels low in Parkinson’s; high in psychosis especially at mesolimbic area; may be low in anhedonia and negative symptoms in mesocortical area. Disorders Disorders # 04 - 4. Noradrenaline # 4. Noradrenaline © SPMM Course 4. Noradrenaline •tyrosine l-dopa dopamine  norepinephrine  epinephrine Source Source •tyrosine hydroxylase Rate limiting step Rate limiting step •dopamine-b-hydroxylase modulates norepinephrine production; phenylethanolamine-N-methyltransferase modulates conversion of NEN to epinephrine. Synthetic enzymes Synthetic enzymes •Monoamine oxidase (MAO – A especially) & Catechol-o-methyl transferase (COMT). Breakdown enzymes Breakdown enzymes •3-methoxy-4-hydroxyphenylglycol (MHPG) & VMA – vanillyl mandelic acid. •MHPG is the major metabolite in CNS while VMA is major metabolite from peripheral nervous system/endocrine system. Breakdown product Breakdown product •noradrenaline reuptake channel (tricyclics, reboxetine inhibit this) Reuptake Reuptake •arousal, anxiety, mood regulation, autonomic mediation Function Function •2 major types; α and β. •α divided into a1 and a2 •α1 receptors phospholipase C coupled; mostly postsynaptic •α2 receptors Gi coupled ; mostly presynaptic autoreceptors •β-receptors Gs coupled; predominate locus ceruleus – may regulate a •β1-receptors – high affinity to norepinephrine and β2-receptors – high affinity to epinephrine. Receptors Receptors •Levels low in depression and abnormal in panic/anxiety disorders. Disorders Disorders # 05 - 5. Serotonin # 5. Serotonin © SPMM Course 5. Serotonin •tryptophan5 hydroxy l-tryptophan  serotonin Source Source •availability of tryptophan (hence it is possible to conduct tryptophan depletion studies and manipulate 5HT system) Rate limiting step Rate limiting step •tryptophan hydroxylase Synthetic enzymes Synthetic enzymes •MAO (preferentially MAO-A) Breakdown enzymes Breakdown enzymes •5-hydroxyindoleacetic acid (5-HIAA) Breakdown product Breakdown product •Serotonin reuptake channel (tricyclics, SSRIs inhibit this) Reuptake Reuptake •mood, perception of pain, feeding, sleep-wake cycle, motor activity, sexual behaviour, and temperature regulation. Function Function •14 known subtypes of serotonin receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7) •All except 5-HT3 are G-protein-coupled receptors; 5HT3 predominant in gut; associated with motility. •5-HT1A receptors – Gi coupled postsynaptic; antidepressant response; sexual behaviour •5-HT1B receptors – Gi coupled presynaptic; •5-HT1D receptors – Gi coupled - both presynaptic and postsynaptic. •5-HT2 receptors - phospholipase C coupled; postsynaptic; antagonism leads to antipsychotic response (atypicals) and sedation; LSD causes 5-HT2 stimulation; down regulation noted after antidepressant treatment / ECT. •5-HT6 may be involved in antidepressant action •5-HT7 - regulation of circadian rhythm Receptors Receptors •low serotonin levels  increased depression, aggression, suicide, and impulsivity; regulate dopamine system – role in psychosis Disorders Disorders © SPMM Course Receptor Action 5HT1A Antidepressant (agonist), anxiolytics (partial agonist) 5HT1B Aggression 5HT1D Antimigraine (antagonist) 5HT2A Antipsychotic (antagonist); hallucinogens (agonist / partial agonist); implicated in working memory; also seen in platelets and smooth muscles 5HT2B Stimulation may produce cardiac valvular fibrosis (dexfenfluramine) 5HT2C Anxiogenic and anorexic effect (agonists) 5HT3 Antiemetic (antagonist) 5HT6 Possible antipsychotic/antidepressant action (antagonism) 5HT7 Regulation of circadian rhythm DOPA decarboxylase (DDC) “is an enzyme implicated in 2 metabolic pathways, synthesizing two important neurotransmitters, dopamine and serotonin (Christenson et al., 1972). Following the hydroxylation of tyrosine to form L-dihydroxyphenylalanine (L-DOPA), catalyzed by tyrosine hydroxylase, DDC decarboxylates L-DOPA to form dopamine. This neurotransmitter is found in different areas of the brain and is particularly abundant in basal ganglia. Dopamine is also produced by DDC in the sympathetic nervous system and is the precursor of the catecholaminergic hormones, noradrenaline and adrenaline in the adrenal medulla”. In the nervous system, tryptophan hydroxylase produces 5-OH tryptophan, which is decarboxylated by DDC, giving rise to serotonin. DDC is a homodimeric, pyridoxal phosphate-dependent enzyme. (Excerpt from www.omim.org) # 06 - 6. Acetylcholine # 6. Acetylcholine © SPMM Course 6. Acetylcholine •choline and acetyl-coenzyme A Source Source •availability of choline Rate limiting step Rate limiting step •choline acetyltransferase Synthetic enzymes Synthetic enzymes •acetylcholinesterase – rapid metabolism Breakdown enzymes Breakdown enzymes •Choline Breakdown product Breakdown product •no reuptake. Degraded choline is re up-taken and recycled. Reuptake Reuptake •Modulate arousal, learning, memory, rapid eye movement sleep, pain perception, and thirst and parasympathetic mediation. Function Function •Muscarinic receptors - G-protein-coupled. •Five subtypes (M1, M2, M3, M4, and M5) •Nicotinic receptors - ion channels; •more in peripheral parasympathetic system; •Less common than M receptors in CNS – mediates attention. Receptors Receptors •reduced cholinergic function in Alzheimer's dementia; dopamine balance affected in Parkinson’s Disorders Disorders # 07 - 7. GABA # 7. GABA © SPMM Course 7. GABA •Glutamic acid (glutamate) Source Source •glutamic acid decarboxylase (GAD) catalysis Rate limiting step Rate limiting step •glutamic acid decarboxylase (GAD) Synthetic enzymes Synthetic enzymes •GABA transaminase Breakdown enzymes Breakdown enzymes •Broken down to glutamate, and then eventually to succinic acid Breakdown product Breakdown product •reuptake into both presynaptic nerve terminals and surrounding glial cells; uptake system is bidirectional and both temperature- and ion-dependent process; (inhibited by tiagabine) Reuptake Reuptake •Mediates anxiety, seizure cessation, and actions of benzodiazepines, barbiturates, and alcohol. Function Function •GABAA and GABAB •GABAA – opens chloride channel; inhibitory – leads to hyperpolarization; made of five subunits and at least 14 subunit subtypes •GABAB receptor is G-protein-coupled; baclofen is selective agonist Receptors Receptors •Role in anxiety disorders and alcoholism; may have a role in many other disorders including epilepsy and Huntington’s. Disorders Disorders # 08 - 8. Glutamate # 8. Glutamate © SPMM Course 8. Glutamate •1. from 2-oxoglutarate and aspartate by aspartate aminotransferase, •2. from glutamine by glutaminase, or •3. from 2-oxoglutarate by ornithine aminotransferase Source Source •accumulation of precursors such as glutamine or by end-product inhibition Regulation Regulation •glutaminase Synthetic enzymes Synthetic enzymes •Glutamate dehydrogenase, glutamine synthetase Breakdown enzymes Breakdown enzymes •Broken down to glutamine or alpha-ketoglutarate Breakdown product Breakdown product •Largely glial uptake with conversion to glutamine Reuptake Reuptake •Important metabolic role – intermediary in oxidation pathway (malate shuttle), immediate precursor of all GABA in CNS, intermediary in ammonia cycle; NMDA - memory acquisition, developmental plasticity, epilepsy, and ischemic brain injury. NMDA receptor mediates long-term potentiation Function Function •metabotropic - 8 in total; 3 groups. Group I - mGluR1& mGluR5 – linked to phospholipase C •Ionotropic: NMDA and non-NMDA •NMDA - made up of subunits with distinct binding sites for glutamate, glycine, phencyclidine (PCP), magnesium, and zinc. •Non NMDA – kainate binding or AMPA type. Receptors Receptors •excitotoxic glutamate toxicity in stroke/schizophrenia/seizures suspected. NMDA antagonists can cause hallucinations – e.g. PCP, ketamine Disorders Disorders # 09 - 9. Glycine # 9. Glycine # 10 - 10. Endocannabinoids # 10. Endocannabinoids # 11 - 11. Neurotrophins # 11. Neurotrophins © SPMM Course 9. Glycine  Glycine is the primary inhibitory neurotransmitter in the spinal cord  It has the simplest structure of all aminoacids  It is synthesized primarily from serine by serine trans-hydroxymethylase and glycerate dehydrogenase, both of which are rate-limiting steps.  Glycine acts as a ‘mandatory adjunctive neurotransmitter’ for glutamate receptors; the excitatory glycine site on the NMDA receptor is called non-strychnine-sensitive glycine receptor.  Strychnine-sensitive glycine receptor is an inhibitory receptor seen in the spinal cord where glycine acts independently.  Facilitating glycine transmission can help reduce negative symptoms of schizophrenia. An experimental agent called bitopertin is a glycine reuptake inhibitor that has shown some early promise in reducing negative symptoms. 10. Endocannabinoids  Two endogenous cannabinoid substances - Anandamide (a weak ligand) and 2arachnidonylglycerol (a strong ligand) are formed from arachidonic acid and ethanolamine.  The two types of cannabinoid receptors, central (CB1) and peripheral (CB2), both bind tetrahydrocannabinol (THC), the active ingredient of marijuana.  Anandamide lowers intraocular pressure, decreases activity level, and relieves pain. 11. Neurotrophins These are substances that act as polypeptide growth factors influencing proliferation and differentiation of neurons and glial cells. The best-characterised factors are Nerve growth factor (NGF); brain derived neurotrophic factor (BDNF), neurotrophin 3 and neurotrophin 4. According to neurotrophin hypothesis neurons compete during development for the limited resource of growth factors in the target region. Those neurons that are highly responsive, e.g. via high affinity binding sites, survive while others undergo programmed cell death. Incorrect targeting of axons may also lead to apoptosis (programmed cell death). BDNF may have a role in long-term potentiation (LTP) of memory. In animals, chronic stress leads to down regulation of BDNF. BDNF has been shown to have trophic effects on serotonergic and noradrenergic neurons. SSRIs and other antidepressants including ECT up regulate BDNF. The time course of this up regulation coincides with observed therapeutic actions of antidepressant interventions. A single nucleotide polymorphism in the BDNF gene on chromosome 11p13 results in an amino-acid substitution of valine (val) with methionine (met) at codon 66 (Val66Met) reducing BDNF activity. BDNF met/met mice demonstrate increased anxiety. Clinical studies in humans have demonstrated that subjects with the Val66Met allele have impaired hippocampal activation and performance. It is controversial if BDNF polymorphism increases the risk of clinical disorders or not. # 12 - 12. Some clinical implications # 12. Some clinical implications © SPMM Course 12. Some clinical implications β ADRENOCEPTOR Chronic antidepressant treatment induces a reduction in β adrenoreceptor density around 2 weeks after starting antidepressants; this correlates with therapeutic effects. Unmedicated suicide victims show higher density of β adrenoreceptors. β blockade can reduce peripheral features of anxiety driven by sympathetic overdrive. 5HT & DEPRESSION An increased density of 5HT2 binding sites has been shown in post mortem studies of depressed / suicidal patients. The increase in 5HT2A receptors is most prominent in dorsolateral prefrontal cortex and in platelets of medication naïve patients. A reduction in 5HT1A receptors has also been noted in cortex Long-term antidepressant treatment has been shown to reduce 5HT2 receptors and increase 5HT1A function. But these changes may not be causative of antidepressant action as they predate any clinical response to antidepressant therapy Most directly acting 5HT1A agonists have poor antidepressant activity. Ach & LEWY BODY DEMENTIA Brain acetylcholine levels are reduced in DLB similar to Alzheimer’s. Cortical choline acetyl transferase (ChAT) is reduced to a greater extent (85%) in patients with hallucinations in Lewy body dementia than in those without hallucinations (50%). This may partially explain the altered sleep-wake patterns seen in DLB and also the response of hallucinations to acetylcholinesterase inhibitors ABERRANT SALIENCE Kapur proposed that in the normal individual, the role of mesolimbic dopamine is to attach significance or ‘salience’ to an external stimulus, or an internal thought. This converts a neutral piece of information into an attention grabbing one (Kapur, 2003). In acute psychosis where hyperdopaminergic state is noted in mesolimbic system, insignificant events and perceptions receive inappropriate salience leading to delusional elaborations. Antipsychotics are claimed to "dampen the salience" of these abnormal experiences - do not erase the symptoms - but provide the platform for a process of psychological resolution. © SPMM Course Notes prepared using excerpts from:  http://omim.org/entry/107930  Kapur, S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003; 160  Angelucci et al. BDNF in schizophrenia, depression and corresponding animal models. Molecular Psychiatry (2005) 10, 345–352  Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacology & Therapeutics, 2013; 119-31 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 08 - 34_Molecular_Genetics # 01 - 1. Cell cycle # 1. Cell cycle # 02 - 2. Cell division # 2. Cell division # 03 - Meiotic division # Meiotic division © SPMM Course 1. Cell cycle Each cell undergoes a natural cycle in terms of its replication and nucleic acid synthetic activity. The cell cycle consists of four separate phases: G1 phase, S phase, G2 phase and M phase. G1 stands for growth phase 1, S for the synthetic phase, G2 for growth phase 2 and M phase for mitosis phase. Cells in the quiescent G0 phase of the cycle are stimulated by the growth factors (e.g. EGF, epithelial growth factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor) and result in activation of transcription factors and lead to the initiation of DNA synthesis, followed by mitosis and cell division. Thus from G0 the cell moves on to G1 when the chromosomes are prepared for replication. This is followed by the synthetic (S) phase, when the 46 chromosomes are duplicated into chromatids, followed by another gap phase (G2), which eventually leads to mitosis (M). Note that while certain cells pause or freeze the cycle temporarily and stay in G0, e.g. liver cells, neurons remain in G0 indefinitely. 2. Cell division Cell division is a process by which cells reproduce. During cell division, a sequence of steps enables the replicated genetic material in a parent cell to be equally distributed to two daughter cells. Before a dividing cell enters mitosis, it undergoes a period of growth called interphase. Interphase can be termed as the "holding" stage occurring between two consecutive cell divisions. Replication of cellular genetic material and organelles occurs during interphase in preparation for the next division. It is the longest phase, and all steps in the cell cycle (i.e. G0, G1, G2 and S) except stage (M) constitute interphase. Mitotic division Mitosis is composed of several stages.  Prophase: Condensation of chromatin to discrete chromosomes, accompanied by a breakdown of the nuclear envelope and the formation of spindles at opposite cellular "poles”.  Metaphase: Alignment of chromosomes at the metaphase plate (a plane that is equidistant from the two spindle poles) – equatorial alignment.  Anaphase: Separation of paired chromosomes (sister chromatids) followed by migration to opposite ends of the cell. This separation of chromatids preserves the chromosomal numbers in daughter cells.  Telophase: In this last stage, the chromosomes are packed into distinct new nuclei in the emerging daughter cells. Cytokinesis (division of cytoplasm) also starts at this time. Meiotic division  Meiosis is divided into two parts: meiosis I and meiosis II. At the end of the meiotic process, four daughter cells are produced (only two are produced at the end of the mitotic process), each with onehalf of the number of chromosomes as the parent cell, unlike mitosis where each cell has the same number of chromosomes as the parent. Meiosis 1 is a reduction division. # 04 - 3. Chromosomal Numbers # 3. Chromosomal Numbers: © SPMM Course  The main differences are the occurrence of synapsis (crossing over) in the prolonged prophase phase and non-separation of sister chromatids during anaphase 1, leading to reduced (half) chromosomal numbers in daughter cells. Meiosis 2 is same as a normal mitosis. 3. Chromosomal Numbers: Chromosomes are intranuclear structures containing one linear molecule of DNA. Human cells are called diploid as they have 46 chromosomes, 23 inherited from each parent; thus there are 23 'homologous' pairs of chromosomes (22 pairs of 'autosomes' and two 'sex chromosomes'). The sex chromosomes, called X and Y, are not homologous but are different in size and shape. Males have an X and a Y chromosome; females have two X chromosomes. During the mitotic division, each chromosome divides into two; this ensures that each daughter nucleus has the same number of chromosomes as its parent cell. During gametogenesis, the number of chromosomes is halved with meiosis so that after conception the number of chromosomes remains the 2 same and not doubled. Hence, gametes are haploid cells. Chromosomes can be classified according to their size and shape, the largest being chromosome 1. The constriction in the chromosome is the centromere, which divides the chromosome into a short arm and a long arm, which are referred to as the p arm and the q arm respectively. o A metacentric chromosome has centromere right in the middle. So p and q arms are of equal length. o If it is placed at one end, it is called as an acrocentric or submetacentric where the arms are of unequal length. o If centromere is at the tail of a chromosome, it is called telocentric. With holocentric chromosomes, the entire length of the chromosome acts as the centromere. These latter two types are not seen in humans. When cells possess chromosomal numbers different from normal diploid status, they are called aneuploid cells. Aneuploidy can occur in single numbers e.g. trisomy 21, trisomy 18, monosomy of Turner’s, etc. Very rarely, the entire chromosome set will be present in more than two copies, so the individual may be triploid rather than diploid and have a chromosome number of 69. Triploidy and tetraploidy (four sets) result in spontaneous abortion. These aberrations result from the failure of chromosome or chromatids to separate ('non-disjunction') in meiosis, with one gamete receiving two copies of that chromosome and one another with no copies of the chromosome. This can produce (i) an extra chromosome, so resulting in a fetus that is 'trisomic' and has three instead of two copies of the chromosome; or (ii) no chromosome, so the fetus is 'monosomic' and has one instead of two copies of the chromosome. Nondisjunction can occur with autosomes or sex chromosomes. However, only individuals with trisomy 13, 18 and 21 survive to birth, and most children with trisomy 13 and trisomy 18 die in early childhood. # 05 - Important trisomiesmonosomies # Important trisomies/monosomies © SPMM Course Sometimes, non-disjunction can occur during mitosis immediately after two gametes have fused. This leads to the formation of two cell lineages, each with a different chromosomal make-up. This occurs more frequently with the sex chromosomes and results in a 'mosaic' individual. Mosaics exhibit milder malformations than those who carry complete aneuploidies. Important trisomies/monosomies  Down’s syndrome: Trisomy 21 is the most common chromosomal disorder that occurs at a rate of 1:700 causing congenital mental retardation. Prominent findings are reduced maternal levels of αfetoprotein, increased β-hCG and increased nuchal fold thickness in fetal ultrasound. The child shows mental retardation, flat facial profile, prominent epicanthal folds, simian palmar crease, duodenal atresia, hypothyroidism and heart disease (most common malformation is septum primum–type ASD due to endocardial cushion defects). Alzheimer’s disease and leukaemia are common in affected adults who survive childhood difficulties. 95% of Down’s is attributed to meiotic nondisjunction of homologous chromosomes. This is associated with an advanced maternal age (rates are 1:1500 in women < 20 but 1:25 in women > 45). 4% of cases due to Robertsonian translocation and 1% of cases are attributed to Down’s mosaicism (no maternal age association is seen in these). The features of mosaic Down syndrome are milder but similar to the features of full Down syndrome. However, the clinical phenotype varies according to the level and distribution of trisomic cells. Thus, the affected individuals may range from completely normal to presenting the full expression of Down syndrome.  Edwards’ syndrome is characterised by severe mental retardation and rocker bottom feet, low-set ears, micrognathia (small jaw), congenital heart disease, clenched hands, the a prominent occiput. It is a result of trisomy 18. It occurs at a frequency of 1:8000 and often death occurs within 1 year of birth. It is three times more common in girls than boys.  Patau’s syndrome is due to trisomy 13, and it is characterised by severe mental retardation, microphthalmia, microcephaly, cleft lip/palate, coloboma eye, abnormal forebrain structures, polydactyly, and congenital heart disease. The rate of occurrence is 1:6000.  Metafemale – trisomy X  Turner’s syndrome: Low hairline, broad chest, short stature, retrognathism and webbed neck are features of Turner’s syndrome. In 80% cases the origin of the aneuploidy is from paternal X chromosome; hence the single X chromosome present in a subject with Turner’s is of maternal origin. The incidence of Turner’s syndrome is approximately 1 in 2000 live-born female infants. Random inactivation (see below) does not occur in cells with a single X chromosome. In general, girls with Turner show a disharmonic IQ profile. The full scale IQ is either comparable to general population or lower by a mean of 10 points (nearly one standard deviation) mostly due to reduced performance IQ (at least 20 points or 1 standard deviation lower) though verbal IQ is preserved. Specific subtests assessing visuospatial processing such as ‘Block Design’ and ‘Object Parental origin of meiotic error leading to aneuploidy. Aneuploidy Paternal % Maternal % Patau 13 85 Edward’s 18 90 Down’s 21 95 Turner’s 45X 20 Klinefelter’s 47 XXY 55 # 06 - 4. DNA & RNA structure # 4. DNA & RNA structure © SPMM Course Assembly’ may be affected more than others. Mathematical ability may also be lower than expected. This specific profile persists into adulthood. Females with a 45X karyotype (Turner syndrome) may have higher verbal skills if their only X chromosome is paternally derived instead of being maternal origin (most commonly it is maternal). This suggests the existence of an imprinted gene that is inactive if carried on a maternally derived X chromosome. 4. DNA & RNA structure Genetic information is stored in the form of double-stranded DNA. DNA and RNA are the most important nucleic acids in the cellular machinery. These nucleic acids are composed of many nucleotides. Nucleotides are phosphorylated versions of nucleosides. Each nucleoside consists of two components: A nitrogenous base and a pentose sugar. Each strand of DNA is made up of a deoxyribose-phosphate backbone and a series of purine (adenine (A) and guanine (G)) and pyrimidine (thymine (T) and cytosine (C)) bases of the nucleic acid. The length of DNA is generally measured in numbers of base-pairs (bp). Each nucleotide is a base joined to a sugar-phosphate unit. The two strands of DNA are held together by hydrogen bonds between the bases. There are only four possible pairs of nucleotides - TA, AT, GC and CG. The two strands twist to form a double helix structure for DNA. RNA is single stranded in human cells. A gene is a sub-portion of DNA. It contains codes for a polypeptide sequence. The length of each gene is variable depending on the size of the polypeptide coded. A set of three adjacent nucleotides is called as a codon; each codon codes for a specific amino acid. There are only 20 amino acids of which around 10 are ‘essential’ (i.e. those aminoacids not found in food and so need to be synthesized), but 64 possible codon combinations that make up the genetic code. This means that most amino acids are encoded for by more than one triplet; other codons are used as signals for 'initiating' or 'terminating' polypeptide-chain synthesis. The polypeptide coding sequences in a DNA are called exons; these are interrupted by intervening EXON INTRON # 07 - 5. Synthesis of DNA, RNA & Protein # 5. Synthesis of DNA, RNA & Protein © SPMM Course sequences that are non-coding (called introns) at various positions. The introns contain three types of sequences (satellite, mini and microsatellite: see the graph below). All introns are removed from the mRNA before it leaves the nucleus and start protein synthesis. Humans have 3 × 109 bp of total chromosomal DNA but among these the protein-coding genes constitute only 32 000 bp. 5. Synthesis of DNA, RNA & Protein Replication refers to the production of new DNA copies from template copies of DNA. Synthesis of RNA from nuclear DNA is called transcription. This takes place in the nucleus of the cell. Such transcripted RNA initially contains the ‘junk’ sequences – introns – that do not code for polypeptides. This unprepared RNA is called heterogeneous nuclear RNA or hnRNA. This hnRNA then undergoes splicing aided by nucleosomes in the nucleus to remove non-coding sequences and results in messenger RNAs (mRNA). tRNAs (transfer RNAs) are also synthesized from DNA in the nucleus in a separate process. Translation refers to the production of proteins from RNA. This takes place in the cytoplasm, aided by ribosomes. Ribosomes can be seen attached to rough endoplasmic reticulum.  As tRNAs that are synthesized in the nucleus enter the cytoplasm, they are attached to specific amino acids according to the codon sequences. This energy dependent process is called amino acid activation, catalyzed by a specific amino acid activating enzyme (aminoacyl-tRNA synthetase) in the presence of Mg2+. There is a separate aminoacyl-tRNA synthetase enzyme for each kind of amino acid. The energy stored in such activated amino acids is used in making peptide bonds during protein translation.  Translation takes place in the cytoplasm on ribosomes where specific mRNAs are involved. tRNAs with their aminoacids, sequentially bind to various sites along the mRNA in a zipper like fashion.  Translation includes three steps – initiation, elongation and termination. The ribosome contains two sites – Peptidyl P site where methionine-containing tRNA initially binds and aminoacyl A site where each new incoming tRNAs with activated amino acids can bind. In elongation step, amino acids are added one by one in a sting like fashion to produce proteins. Chain termination is signaled by one of the three codons UAA, UGA or UAG. Modification refers to posttranslational changes in a protein molecule before it becomes functionally active. Following protein synthesis (sometimes simultaneously as the protein is being synthesized) posttranslational modifications take place to transport the synthesized proteins to appropriate cellular sites. These modifications take place in endoplasmic reticulum and golgi bodies. The Golgi complex is a dynamic system acting as a temporary protein repository that gives off vesicles and vacuoles for further processing and transport. These processes include covalent modifications, protein folding and tagging with signal peptides to dispatch to appropriate cellular destinations. Glycosylation, proteolysis, phosphorylation, gamma carboxylation, prenylation, ubiquitation, polyamination and nitration are some of the recognized posttranslational chemical modifications. This process is essential in tagging wrongly # 08 - 6. Types of mutations # 6. Types of mutations © SPMM Course folded or aberrant proteins to enter lysosomes for destruction. Study of mRNAs using microchip arrays is called transcriptomics. Note that microsatellite tandem repeats give rise to trinucleotide sequences: these are linked to a group of non-Mendelian disorders called trinucleotide repeat disorders. 6. Types of mutations  A mutation is a sudden, permanent and heritable change in the DNA sequence. Such changes in DNA will be transcripted to mRNA and can get translated into proteins leading to disease expression.  Point mutation refers to single-base alteration in DNA. Point mutations are usually substitutions where one base is replaced by another. It could be termed as transition if a purine Telomeric repeats (necessary for integrity of chromosomes) Satellite (10-15% large series of simple repeats) Microsatellite (single, di or tri nucleotide repeats) Tandem Repeats INTRONS (noncoding) Minisatellite Hypervariable repeats (used in DNA fingerprinting) Interspersed Short Interspersed Nuclear Elements Long Interspersed Nuclear Elements DNA Sequences EXONS (coding) # 09 - Some deletion syndromes of psychiatric releva # Some deletion syndromes of psychiatric relevance © SPMM Course is replaced by another purine or a pyrimidine replaced by another pyrimidine (e.g. A to G). It is called transversion if a purine is replaced by a pyrimidine or vice versa (e.g. A to T).  According to the effect on triplet sequence, mutations could be frame shift or in-frame. In frame shift mutations, the deletion or insertion is not in multiples of three codons e.g. a segment of 5 bases deletion mutations. This leads to a shift in triplet reading frame with variable results. In frame, mutation refers to changes happening in multiples of 3 bases, with no disturbances in actual reading frame.  According to the effect of a mutation on protein product, mutations could be silent, mis-sense or nonsense. A silent mutation causes no change in protein product – this is possible because a single amino acid is often coded by more than one triplet sequence. In a silent mutation one triplet sequence is replaced by a different sequence but without changing amino acid product. In mis-sense mutation, the new mutant codon specifies a different amino acid with variable effects on final protein product. For example, haemophilia, sickle cell anaemia. In non-sense mutation the new codon is UUA UGA or UAG, which signals ‘stop’ to the amino acid sequence resulting in nonfunctional protein. Point substitutions do not shift the reading frame; they often occur in non-coding regions and go unnoticed. Even at coding regions they are often silent or mis-sense mutations.  Translocation refers to exchange of chunks of genetic materials from one chromosome to another. These are essentially mutations occurring at ‘larger’ dimensions.  These are mostly reciprocal so one segment is exchanged for another segment among chromosomes.  Robertsonian translocation is a non-reciprocal (i.e. unequal exchange) that results in a single fused chromosome from 2 acrocentric (non homologous) chromosomes. Following a Robertsonian translocation, the small 'p' arms are discarded, and a metacentric fusion chromosome results. Thus from 2 chromosomes a single chromosome is formed with no significant (only trivial) loss of genetic material. Hence, these are viable and ‘balanced’ within the individual in whom they occur.  But when gametes are formed, only one of the two gametes can have the whole translocated metacentric fusion chromosome, effectively resulting in monosomy (unbalanced translocation) for one gamete if fertilized and trisomy for the gamete with fused chromosome (extra load of genes now). This is one of the mechanisms for Down’s syndrome. Due to the mother being a carrier of such translocation, the recurrence rate of Down’s is extremely high in such cases compared to sporadic Down’s due to non-disjunction. Some deletion syndromes of psychiatric relevance # 10 - 7. Mendelian inheritance # 7. Mendelian inheritance © SPMM Course Disorder Location and mode of transmission Features DiGeorge (Velocardiofacial) 22q11.2 Autosomal dominant, 50% risk to offsprings, 5-10% risk of deletion in parents. If offspring has the deletion, then 25% chance of schizophrenia, if not then general population risk ~1%. Mild to moderate learning disability, facial deformities esp. cleft palate, absent or malformed parathyroids resulting in hypocalcemia, broad nasal bridge, articulatory speech and swallowing problems, >25% have psychosis Williams syndrome 7q11 microdeletion Hypercalcemia at birth, supra valvular aortic stenosis, moderate learning disability, disinhibited disposition, speech that appears superficially fluent, hyperacusis. Smith Magenis syndrome 17p11.2 microdeletion Moderate to severe learning disability, self harming behaviours e.g., pulling off nails (onychotillomania) and inserting foreign bodies into body orifices. Sleep disturbances and self hugging are also noted. Angelman syndrome Deletion of 15q11-13 maternally inherited (see genomic imprinting below) Developmental delay, low IQ, jerky movements especially hand-flapping, frequent smiling, and seizures. Prader-Willi syndrome Deletion of 15q11-13 paternally inherited (see genomic imprinting below) Obesity, short stature, small limbs, decreased IQ with hyperphagia and skin picking. Cri-du-chat syndrome Deletion of chromosome 5p (the locus 5p15.2 is responsible for the phenotype) Feeding problems due to difficulty swallowing and sucking, cat-like cry with poorly developed facial features. 7. Mendelian inheritance Johann Mendel was a Catholic priest who was interested in horticulture and botany. He studied garden peas and proposed ‘laws’ of inheritance. The first law is the law of uniformity. According to this law, if two plants that differ in just one trait (black and white) are crossed, then the resulting hybrids will be uniform in the chosen trait (either black or white, not blue). This is not entirely true as later geneticists demonstrated intermediate phenotypes resulting from co-dominant heterozygous expression. The second law is called the principle of segregation. It states that “for any particular trait, the pair of alleles of each parent separate and only one allele passes from each parent on to an offspring. Which allele in a parent's pair of alleles is inherited is a matter of pure chance”. For example if there are two alleles one determining black colour and the other determining white in mother and two alleles with one # 11 - A. Single gene inheritance (Mendelian) disord # A. Single gene inheritance (Mendelian) disorders # 12 - Autosomal dominant disorders # Autosomal dominant disorders © SPMM Course determining white colour and one determining black colour in the father, then these two alleles segregate and only one of them could be passed on to the second generation from each parent. This will produce three possible types of offsprings as shown in the table. This was later proved to be true by studying chromosomes during cell division. The third principle is the principle of independent assortment. It states that “different pairs of alleles are passed to offspring independently of each other. The result is that new combinations of genes present in neither parent are possible”. As a very simplistic example, if a man with blue eyes and brown hair mates a woman with brown eyes and black hair; their child can have blue eyes and black hair. The inheritance of blue eyes does not take brown hair ‘with it’; these traits are independently assorted. Thus Mendelian principles are applicable to human genetics as well. Note that all traits studied using Mendelian genetics refer to categorical, all or none traits i.e. black vs. brown, blue vs. brown, tall vs. short, etc. It does not apply with same simplicity to dimensional traits such as IQ or blood pressure. Mendel’s Laws (aide memoir) Explanations Law of uniformity: DD X dd  Dd Two alternative alleles at one locus Two homozygous parents (with a double dose of either one). All off springs are of uniform type (all Dds) Law of segregation Dd X Dd  DD | Dd Dd | dd Two heterozygous parents Three possible types of offsprings 1DD.2Dd.1dd Law of independent assortment DdHh (blue-eye:brown hair) X ddhh (brown eye: black hair)  DdHh | ddHh | Ddhh | ddhh Two loci with alleles D,d and H,h. Double heterozygote X Double homozygote parent Four possible types of offspring, each with equal probability (blue eye/brown hair, blue eye/black hair, brown eye/black hair, brown eye/brown hair). Adapted from McGuffin et al. (ed) Psychiatric genetics and genomics. Oxford Press: P37 A. Single gene inheritance (Mendelian) disorders Autosomal dominant disorders Each cell contains two copies of all the autosomes. An autosomal dominant disorder occurs when one of the two copies has a mutation and the protein produced by the normal form of the gene cannot compensate. So the mutant allele becomes dominant over the normal allele and results in disease expression. In this case, a heterozygous individual who has two different forms (or alleles) of the same gene will manifest the disease. The offspring of heterozygotes have a 50% chance of inheriting the chromosome carrying the disease allele, and therefore also of having the disease. If both parents are heterozygous, the recurrence risk is 75%. 'Incomplete penetrance' may occur if patients have a dominant disorder but it does not manifest itself clinically in them. This gives the appearance of the gene having 'skipped' a generation. Having incomplete # 13 - Autosomal recessive disorders # Autosomal recessive disorders # 14 - Sex linked disorders # Sex-linked disorders © SPMM Course penetrance increases the likelihood of having an unaffected child. The variable expression refers to differences in severity of the disease expressed. A mildly affected parent may have a severely affected child. Spontaneous disease-causing mutations can often present as diseases that are known to occur in autosomal dominant fashion. For example, achondroplasia and tuberous sclerosis are commonly due to spontaneous mutations, but families show AD pattern. Often the abnormal gene in autosomal dominant diseases codes for structural proteins such as receptors or cytoskeleton proteins. Sometimes such aberrant production of an autosomal dominant disorder without family history may be due to a phenotypically indistinguishable disorder without the genotype – this is called phenocopy. (Goldschedt, 1935) e.g., anti-psychotic medication causes patients to manifest the same symptoms as the genetically determined Parkinson’s disease. Another example is genotypically determined Pendred syndrome being mimicked by endemic cretinism. Autosomal recessive disorders These disorders manifest themselves only when an individual is homozygous for the disease allele; i.e. both chromosomes carry the mutated gene. In this case, the parents are generally unaffected, healthy but carriers (heterozygous for the disease allele). There is usually no family history, although the defective gene may be passed from generation to generation (skipping). The offsprings of an affected person are healthy heterozygotes unless the other parent is also a carrier. If carriers marry each other, the offspring has a 1 in 4 chance of being homozygous and affected and a 1 in 2 chance of being a carrier, and a 1 in 4 chance of being genetically normal. Consanguinity increases the risk. Often the abnormal gene in autosomal recessive diseases codes for enzymatic proteins. Sex-linked disorders Genes carried on the X chromosome are said to be 'X-linked', and can be dominant or recessive in the same way as autosomal genes. Normally males inherit an X chromosome from their mother and a Y chromosome from their father, whereas normal females inherit an X chromosome from each parent. The Y chromosome contributes very less genetic material to a man’s genetic makeup. Hence, there must be a mechanism to simulate this deficiency in females too to preserve natural equality. This phenomenon is now known to be ‘X inactivation’. This occurs very early in the development of female embryos. When an X chromosome is inactivated, it could be visualized under the microscope as a highly condensed Barr body in the nuclei of interphase cells. An inactivated X chromosome does not get transcripted to produce mRNA. X inactivation is random process. In other words, some cells of the female embryo have paternally inherited X inactivated while the other cells have maternally inherited X inactivated. It is an irreversible, fixed process and once inactivated these chromosomes do not get reactivated life long. The entire cell’s progeny will have same inactivation replicated. All X chromosomes in a cell are inactivated except one, irrespective of original number of X chromosomes in a cell. Thus females with trisomy X will have two Barr bodies. X inactivation occurs via DNA methylation. # 15 - X linked recessive disorders # X-linked recessive disorders © SPMM Course X-linked recessive disorders If a recessive disease-causing mutation occurs on the single X chromosome of a man, this is sufficient to cause disease, as another X chromosome is not existent to compensate any deficiencies. As females have two copies of the X chromosome, they need a double identical mutation for disease expression, which is extremely rare. But during random X inactivation if most X chromosomes carrying normal alleles are inactivated (called unfavourable Lyonisation), then these females can manifest the disease phenotype – termed as manifesting heterozygotes. But nevertheless the severity of expressed disease is mild and can go unnoticed too. Skipped generations are commonly seen because an affected male can transmit the disease-causing mutation to a heterozygous daughter, who remains normal phenotypically but carries and transmits the disease-causing allele to her sons. From McGuffin et al. (ed) Psychiatric genetics and genomics. Oxford Press: 2002 Male-to-male transmission is not seen in X-linked inheritance. Affected male mates with a homozygous normal female, all of the daughters will be heterozygous carriers; all of the sons will be homozygous normal. If a carrier female mates with normal male (which is often the case in this transmission), then half Disorder Location and mode of transmission Features Tuberous sclerosis  9q34 / 16p13  Auto.dominant (but most are spontaneous)  1 in 30 000 Adenoma sebaceum, normal to sever MR, ash leaf macules, brain hamartomas, heart and kidney cysts Treacher Collins syndrome  5q31  Auto.dominant  1 in 40 000 Maxilla-mandibular hypoplasia, malformed pinna, down slanting palpebrae, mild to moderate MR Apert syndrome  10q  Auto dominant Variable MR, cranio synostosis, shallow orbits, trapezoid mouth, ‘mitten’ hands and feet. Noonan syndrome  Chr 12  Auto.dominant  1 in 1 500 Mild MR, short stature, nuchal edema/webbed neck, pulmonary stenosis, cryptorchidism Hurler syndrome  4p16  Auto. recessive  1 in 100 000 Deteriorating IQ after age 2, coarse facies, clouded cornea, joint stiffness. Lesch-Nyhan syndrome  Xq 26-27  X linked recessive  Deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) Poor muscle control, and moderate mental retardation – year 1. Self-mutilating behaviors, characterized by lip and finger biting – by year 2. Hyperuricemia and hyperuricosuria -severe gout and kidney problems – can present anytime. # 16 - X linked dominant disorders # X-linked dominant disorders # 17 - B. Non Mendelian inheritance # B. Non Mendelian inheritance # 18 - Mitochondrial inheritance # Mitochondrial inheritance © SPMM Course of the sons will be affected, and half of the daughters will be carriers. e.g. haemophilia A/B, Duchene muscular dystrophy, and androgen insensitivity syndrome. X-linked dominant disorders These are rare. Similar to X-linked recessive pattern, male-male transmission of the disease-causing mutation is not seen. Because females have higher gene frequency for X chromosomes compared to males, females have twice as much chance than males to inherit an X-linked disease-causing mutation. Vitamin D-resistant rickets is the best-known example. Females who are heterozygous for the mutant gene and males who have one copy of the mutant gene on their single X chromosome will manifest the disease. As in autosomal dominant inheritance, the disease phenotype is seen in multiple generations making ‘skipped generations’ relatively unusual. If the affected male mates with homozygous normal female, none of the sons will be affected but all of the daughters will be affected. Heterozygous female mating a normal male will result in 50% of sons being affected and 50% of daughters being affected. An atypical pervasive developmental disorder called Rett’s syndrome is inherited in X-linked dominant fashion. B. Non Mendelian inheritance Mitochondrial inheritance, mosaicism, trinucleotide expansions and genomic imprinting do not follow normal Mendelian principles and so are called non-Mendelian inheritance. Polygenic and multifactorial disorders too, do not obey Mendelian principles in strict sense. Mitochondrial inheritance Mitochondrial DNA is wholly inherited from the ovum. The sperm has no mitochondria in its ‘head’; ‘head’ is made of nuclear material and acrosomal cap. The ‘body’ of sperm has many mitochondria that provide energy in propelling the ‘tail’. The ‘body’ and ‘tail’ are shed on entry of sperm into the ovum. Hence the mitochondria of an embryo are completely maternal-derived. The mitochondrial chromosome has no introns in the genes. Therefore any mutation has a high chance of having an effect. Most mitochondrial diseases are myopathies and neuropathies. This is important in clinical genetics as mitochondrial DNA abnormalities result in various diseases such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and recurrent stroke syndrome) and Leber hereditary optic neuropathy. X-LINKED MENTAL RETARDATION (XLMR) Learning disability is significantly more common in males than in females. So X linked genes are a suspect in their aetiology. XLMR is a heterogenous condition - subdivided into syndromic (1/3rd) and nonsyndromic (2/3rd) forms, depending on the presence of further abnormalities. The most common form of XLMR is the Fragile X syndrome. Mutations in MECP2 gene in X chromosome give rise to a wide range of disorders, including female-specific Rett syndrome. MECP2 mutations also lead to other phenotypes such as severe encephalopathy, progressive spasticity, Angelman and PraderWilli like phenotypes and nonsyndromic XLMR in males # 19 - Trinucleotide expansions # Trinucleotide expansions © SPMM Course Leber's hereditary optic neuropathy (LHON) is the commonest cause of blindness in young men, with bilateral loss of central vision and cardiac arrhythmias. These diseases are purely maternally inherited. Mitochondrial DNA codes for 13 proteins involved in the respiratory chain in addition to 22 tRNAs and 2 ribosomal RNAs. Many other syndromes have been described. Myopathies include chronic progressive external ophthalmoplegia (CPEO); encephalomyopathies include myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Kearus-Sayre syndrome includes ophthalmoplegia, heart block, cerebellar ataxia, deafness and mental deficiency due to long deletions and rearrangements. Trinucleotide expansions Trinucleotides repeat disorders are a set of genetic disorders caused by trinucleotide repeats (codons – e.g. CGG, CTG, CAG, etc.) in certain genes exceeding the normal number of repeats. The mutation results in an unstable site, which is often fragile. Anticipation refers to a pattern of inheritance in which individuals in the most recent generations of an affected family develop a disease at an earlier age and with greater severity than those in previous generations. This is mostly due to the gradual expansion of trinucleotide repeat polymorphisms (this instability is called a dynamic mutation). Fragile X genetics: This X-linked condition accounts for more cases of mental retardation in males than any condition except Down syndrome with the frequency of 1 in 4000. It can affect females but 50% less frequently than in males. A fragile site near the tip of the long arm of the X chromosome was initially suspected. Now it is known that fragile X results from the an expansion of a trinucleotide repeat (CGG) proximal to FMR1 gene. If the number of CGG repeats in this location increases beyond 52, this destabilizes this sequence allowing further expansion during spermatogenesis or oogenesis. Being born with one FMR1 allele with 200 or more repeats results in lower IQ in most men and ~ 60% of women. The phenomenon of anticipation is seen. Unlike men, heterozygous women usually have the other X chromosome that can compensate to some extent; thus they show no physical signs other than early menopause, mild learning difficulties and rarely frank retardation. Affected males suffer from enlarged testes, prominent ear lobes and a protracting jaw, a high-pitched voice, and mental retardation. Some men carry an increased number of CGG repeats in the FMR1 locus but do not show a full-blown clinical phenotype; these individuals are called premutation carriers. Though premutant carriers were long thought to be free from clinical features, it is now known that they are at increased risk for developing intention tremor and ataxia especially after middle age. Women who are premutation carriers (55–200 CGG repeats) are at increased risk of premature ovarian failure and/or mild cognitive or behavioral abnormalities. The fragile site at first exon of FMR1 is called FRAXA, a second site at Xq28 called FRAXE Frag(g)ile X syndrome Frag(g)ile X syndrome •cGG Friedreich AtaxiA Friedreich AtaxiA •gAA Huntington ChoreA Huntington ChoreA •CAg MyoTonic dysTrophy MyoTonic dysTrophy •cTg © SPMM Course is also linked to mental retardation. FRAXF is the third fragile site sensitive to folate, but not linked to MR. Similar to Myotonic Dystrophy (but in contrast to Huntington’s), anticipation rates are higher in maternal than paternal inheritance. This is because further trinucleotide expansion occurs during oogenesis rather than spermatogenesis. Huntington’s genetics: Huntington's disease is inherited in an autosomal dominant manner with full penetrance and a prevalence rate of about 5 per 100,000. The gene responsible is an expanded and unstable CAG trinucleotide repeat on the short arm of chromosome 4 - 4p16.3. This results in translation of an extended glutamine sequence in huntingtin, the protein product of the gene. Huntingtin is expressed throughout the body. Its function is unclear. Though slightly unusual for a genetic disease; the onset is usually between 30 and 50 years of age. Most adult-onset HD cases have CAG expansions of 40-55 repeats while greater expansions (>70 repeats) are seen in childhood-onset HD. The phenomenon of anticipation is seen here too. But unlike other X-linked disorders (see myotonic dystrophy below), inheritance of HD from the father is associated with the greater repeat expansion and earlier age of onset. Nearly one-third of father-to-offspring cases show an expansion resulting in juvenile-onset HD. Characteristic protein deposits form nuclear inclusions in neurons of HD patients. Myotonic dystrophy is another neurological disease with trinucleotide repeat expansion. Here CTG repeats are expanded. The anticipation resulting from trinucleotide instability is higher if the inherited expansion comes from the mother than the father in MD. This is because oogenesis, due to its inherently long dormancy compared to spermatogenesis, results in much higher instability. As a result anticipation is more prominent in maternal transmissions. Genomic imprinting Though no structural differences exist between maternal and paternally inherited chromosomes in humans, there are some subtle functional differences, which are increasingly being appreciated. For example, a deletion of part of the long arm of chromosome 15 (15q11-q13) will give rise to the Prader-Willi syndrome (PWS) if it is paternally inherited. A deletion of a similar region of the chromosome gives rise to Angelman's syndrome (AS) if it is maternally inherited. This may be due to differential regional expression of the chromosomes. Maternal chromosome 15q11-13 is expressed in the brain and hypothalamus, leading to neuronal damage in its absence. This phenomenon is called genomic imprinting. It is thought to be due to DNA methylation effects. In genomic imprinting, the disease phenotype expressed depends on whether the allele is of maternal or paternal lineage. This parent-of-origin phenomenon is an important exception to the Mendelian inheritance patterns. Approximately 70% of patients with Prader Willi syndrome have a deletion in their paternally derived 15q11-q13. Maternal uniparental disomy (inheriting both copies from mother when embryo is formed) occurs in most of the remaining patients (25%). Most patients with Angelman’s syndrome have a deletion in their maternally derived 15q11-q13. Paternal uniparental disomy occurs in about 4% of Angelman’s syndrome. # 20 - Multifactorial inheritance # Multifactorial inheritance # 21 - Polygenic inheritance # Polygenic inheritance # 22 - 8. Polymorphisms # 8. Polymorphisms © SPMM Course Multifactorial inheritance It is a complex inheritance in which multiple genes are involved jointly with environmental influences. Most common psychiatric disorders such as schizophrenia do not show a Mendelian pattern of inheritance. But these disorders are categorically defined as present or absent hence cannot be regarded as continuous variables too. But these conditions could be regarded as quasi-continuous in that those who are affected can be graded along a continuum of severity. So we can also assume that there is an underlying liability to develop the disorder, which is continuously distributed in the population. Those who pass a certain threshold manifest the condition. This is known as the liability/threshold model. If the underlying liability to develop the disorder is inherited in a multifactorial fashion, one can assume that the distribution will be approximately distributed along a normal distribution curve. But compared to the normal population, the genetic liability of relatives of affected individuals will be increased, and their liability distribution will be shifted to the right. Thus, the proportion of relatives above the disease threshold will be greater compared with the general population. If we know the proportion of affected relatives of probands and the proportion of those affected in the general population, it is possible to calculate the correlation in liability between pairs of relatives using this model. Recurrence risks to relatives for multifactorial disorders are influenced by the disease severity, the degree of relationship to the index case, the number of affected close relatives and, if there is a higher incidence in one particular sex, the sex of the index case. Polygenic inheritance Polygenic inheritance is again a complex inheritance in which multiple genes but no environmental factors are involved. Both polygenic and multifactorial inheritances defy normal Mendelian principles. The additive effects of many genes, i.e. polygenic inheritance, probably cause characteristics such as height and intelligence, which show a normally distributed continuous distribution in the general population. 8. Polymorphisms Polymorphism refers to variations in genetic make-up at a particular locus noted in general, apparently healthy population. To be defined as polymorphism the variant must occur in at least 1% of the total population and must be associated with normal but varied (not disease causing) expression of final phenotype. This excludes spontaneous mutations that are random and so cannot simultaneously occur in such significant (1%) proportion of total population. ABO blood groups are good examples of polymorphism expressed in protein products of genes.  Restriction fragment length polymorphisms are variations that change the sites at which restriction enzymes can act on a DNA molecule, rendering differences in the final ‘restricted’ or cleaved DNA when these enzymes are applied in vitro (Southern Blotting).  If polymorphisms are due to changes in single nucleotide in a sequence, then these are called SNPs or single nucleotide polymorphisms. These single-base polymorphisms can be assayed by DNA sequencing or through the use of DNA chips.  If the variations are due to changes in length of the genetic sequence, these are termed length polymorphisms. # 23 - 9. Cytogenetic techniques # 9. Cytogenetic techniques © SPMM Course  VNTRs (variable number of tandem repeats). These polymorphisms are the result of varying numbers of repeats in a specific region of a chromosome. These Polymorphisms can be classified according to the length of polymorphic fragments; Short tandem repeat polymorphisms (STRPs) or microsatellites range in size from 2 to 6 bases. The minisatellites vary between 20 to 70 bases each. Microsatellites are currently preferred as genetic markers in disease mapping because they can be detected using the polymerase chain reaction.  Polymorphisms arise out of mutations originally but are maintained in population due to number of factors such as founder effect, genetic drift and natural selection.  Note that most polymorphisms occur in non-coding areas (introns) – as coding sequences or exons on mutation often produce disease phenotypes.  Serotonin transporter polymorphisms are noted in promoter region, which is a non-coding part of DNA (5HTTLPR – 5HT transporter linked promoter region). 5HTTLPR can be of a short variant or long variant (length polymorphism). 55% of Europeans carry the long allele. In those with short variant, the serotonin transporter expression is low; short variant is speculated to be associated with higher incidence of affective disorders, neuroticism, anxiety and PTSD. But the evidence is inconclusive as most studies are case control design with significant heterogeneity. In an interesting study of environment-gene interaction, Caspi et al (2003) noted that individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. 9. Cytogenetic techniques  Blotting techniques  Southern blotting is a widely used method for the detection of a specific sequence in DNA. This method was named after Dr. E. M. Southern who introduced this method in 1975.  Western blotting is another widely used method for the detection of specific protein after electrophoresis. The sample is electrophoresed on a polyacrylamide gel, then, blotted to a membrane. The membrane is incubated with the antibody to the specific protein.  Northern blotting is a detection method for a specific RNA after electrophoresis.  Polymerase chain reaction (PCR) Minute amounts of DNA can be amplified over a million times using an in vitro technique called polymerase chain reaction. Using this technique, minute amount of DNA such as those from buccal cell scrapings, blood spots, or single embryonic cells can be analysed. The DNA is amplified between two short single-stranded DNA fragments called oligonucleotide primers, which are complementary to the sequences at each end of the DNA of interest. Hence the exact DNA sequence to be amplified needs to be # 24 - 10. Heritability & concordance # 10. Heritability & concordance © SPMM Course known to carry out PCR. It is not error free as laboratory contaminants can have DNA which gets amplified erroneously. The technique has three steps. (1) Double-stranded genomic DNA is denatured by heat into singlestranded DNA. The reaction is then cooled to favour DNA annealing, and the primers bind to their target DNA. (2) DNA polymerase is used to extend the primers in opposite directions using the target DNA as a template. After one cycle there are two copies of double-stranded DNA, after two cycles there are four copies, and this number rises exponentially with the number of cycles. (3) The cycling is set to produce necessary number of amplifications.  FISH – Fluorescent in situ hybridisation FISH is a cytogenetic technique to detect and localize specific DNA sequences on chromosomes. It uses fluorescent probes that bind to only those parts of the chromosome with which the probes have high degree of sequence similarity. Fluorescence microscopy is employed to detect the location where the fluorescent probe binds to the chromosome. FISH is often employed to detect specific features in DNA.  DNA Cloning Plasmid is a bacterial DNA, which is extra chromosomal, and independently replicating (similar to mitochondrial DNA in humans). Any particular DNA fragment of interest can be isolated and inserted (using a DNA ligase enzyme) into the genome of such self-replicating plasmids. When used for such a purpose the plasmids are called vectors (vehicles for DNA replication). Bacteriophages and other viruses can also be used as vectors. Replication by the millions of the vectors results in multiple copies or clones of the inserted sequence. Removal of inserted gene sequences from the host vector results in large quantities of the required genes. 10. Heritability & concordance Concordance: A twin pair is said to be concordant when both co twins have the same disease expression (or both are disease free). The pair can be discordant if one of them harbours a disease while the other does not. Due to higher degree of genetic sharing among homozygous individuals, one would expect higher concordance among monozygotes compared to dizygotes if the disease being studied has a significant genetic component. In contrast, a trait that has no genetic basis should have equivalent concordance rates for MZ and DZ twins. Heritability is the main measure of genetic variation in polygenic (quantitative) traits. The total variation of a trait in a population can depend on genetic variation or environmental variation, so heritability is the proportion that is genetic, not environmental, out of that total. The relative influence of genetic factors in defining the variance in a trait is expressed as heritability. If this is defined as the proportion of the total phenotypic variance attributable to additive genetic variance, then it is known as narrow-sense heritability. Heritability is also sometimes used to describe the proportion of variance explained by the total genetic variance (additive and non-additive genetic variance). Here it is called broad-sense # 25 - Specific heritability factors # Specific heritability factors © SPMM Course heritability. Non-additive genetic influences include phenomena such as epistasis – gene-gene interaction, and dominance effects where presence of one gene mitigates the expression of other gene. Heritability can be calculated from concordance rates using the mathematical formulae. Interpretation of heritability: (from Visscher et al., 2008) STATEMENT ACCURACY A high heritability means that most of the variation that is observed in the present population is caused by variation in genotypes. CORRECT. So, in the current population, the phenotype of an individual is a good predictor of the genotype A heritability of 80% means that 80% of the variability in whether an individual becomes affected is inherited, while 20% is not. CORRECT. It does not mean that genes account for 80% of the causative factors – as inheritance is not same as genetic causation. High heritability implies genetic determination FALSE. It does not mean that the phenotype is determined once we know the genotype, because the environment can change or can be manipulated to alter the phenotype Heritability is the proportion of a phenotype that is passed on to the next generation FALSE: Phenotype is not passed on – only the genotype. There are many modifiers in the environment and cellular machinery between a genotype and phenotype. Heritability is informative about the nature of between-group differences FALSE. Heritability is measured within a specified population – differences among groups may not be due to genetic differences but due to nature of studied population A large heritability implies genes of large effect FALSE. Not true for polygenic disorders. There is no strong relationship between heritability and the number or size of genes affecting the trait. An exception is Mendelian single gene disorders – they all have heritability of 100%. Specific heritability factors Some common and highly regarded as environmental disorders such as obesity have been demonstrated to have high familial loading. 80% of offspring with both parents obese, 40% of offspring with one parent obese are obese themselves compared to 10% obesity in children with both lean parents. Reported estimates of heritability for IQ from twin studies are remarkably consistent in the range of 0.5–0.8, with differing estimates for the various components of cognitive abilities. Disorder Heritability estimate* Schizophrenia # 26 - 11. Hardy Weinberg equilibrium # 11. Hardy Weinberg equilibrium © SPMM Course Bipolar disorder >80 Major depression Generalized anxiety Panic disorder Phobia Alcohol dependence *Based on DSM-IIR diagnosis. The estimates must be treated as approximations only. Autism and Tourette’s may have around 90% heritability. (From Owen, MJ., Cardno, AG. &O’Donovan, MC. Psychiatric genetics: Back to the future Molecular Psychiatry (2000) 5, 22–31) The Big Five personality traits have following heritability: Openness: 57%; Extraversion: 54%; Conscientiousness: 49%; Neuroticism: 48%; Agreeableness: 42% 11. Hardy Weinberg equilibrium In the absence of mutation, non-random mating, selection and genetic drift, the genetic constitution of the population remains the same from one generation to the next. This principle can be used mathematically to determine frequency of an abnormal gene or genotype in the population. If p is the frequency of the normal gene in the population, q is the frequency of the abnormal gene, p2 is the frequency of the normal homozygote, q2 is the frequency of the affected abnormal homozygote, 2pq is the carrier frequency, and p + q = 1. The equation can be used, for example, to find the frequency of heterozygous carriers in an autosomal recessive disease XYZ. If the incidence of disease XYZ is 1 in 3600 live births, then q2 = 1/3600, and therefore q = 1/60. Since p = 1 - q, then p = 59/60. The carrier frequency is represented by 2pq, which in this case is 1/30. Thus 1 in 30 individuals in the whole population is a heterozygous carrier for disease XYZ. Hardy Weinberg equilibrium does not always hold true. Consider the following circumstances;  Natural Selection: Genes which hinder survival and fertility are not maintained in the genetic pool of a population. This is because the abnormal genes are not passed on to next generation when reproductivity is low or if the patient dies at very young age. Similarly some mutations that offer survival benefits are maintained in higher than expected rates in the population. For example, GENOTYPE FREQUENCY For a given locus, the genotype frequency measures the proportion of each genotype in a population. In a population of 100 individuals assume 33 have AA, 45 have AB and 22 have BB genotypes. The genotype frequency is obtained by dividing the count for each genotype by the total number of individuals. i.e genotype frequency for AA = 0.33, AB = 0.45 and BB = 0.22. The term gene frequency refers to the proportion of chromosomes in a population that contain a specific single allele. In the above example, frequency of allele A = 2x33 (where A occurs twice) + 45 expressed as percentage = 111% or 1.11. Similarly the gene frequency of B is 2X22 + 45 = 89% or 0.89. © SPMM Course sickle cell carriers are protected against sever falciparum malaria, cystic fibrosis carriers may have an advantage against typhoid, etc.  Genetic Drift: Genetic drift refers to gene frequency change caused by limitations in population size. Genetic drift explains why some genetic diseases are unusually common in small, isolated populations. In a small population, the chances of random distribution is limited as probabilities of the combination are restricted. This is very close to what is termed as ‘founder effect’.  Gene Flow: Gene flow refers to the exchange of genes between populations. Due to migration or other social reasons, the populations studied are not ‘closed’ populations anymore.  Consanguinity: Non-random mating occurs, and mutations are preserved within a closed pedigree due to consanguinity. Autosomal recessive diseases are more often seen in consanguineous families.  High frequency of mutations: Environmental exposure can provoke mutations at a higher frequency than expected in a stable population e.g. living near a nuclear reactor leak. EPISTASIS, HETEROGENEITY & PLEIOTROPY Gene- gene interaction particularly between different alleles at different genes is called epistasis. This can occur at the same step or at different stages of the same biochemical pathway. Locus heterogeneity exists when the same disease phenotype can be caused by mutations in different loci. It becomes especially important when genetic testing is performed by testing for mutations at specific loci. For example early onset Alzheimer’s could be caused by mutations in chromosome 1, 14 or 21. Allelic heterogeneity refers to the same disease phenotype resulting from different types of mutations at the same loci. Consider cystic fibrosis, here nearly 600 different mutations at the same site of chromosome 7 results in same disease. Pleiotropy exists when a single disease-causing mutation affects multiple organ systems. Pleiotropy is a common feature of genetic diseases. For example, consider Marfan’s syndrome. Cardiovascular system, connective tissue, skeletal system etc. are affected by a single genetic aberration. # 27 - 12. Types of genetic studies # 12. Types of genetic studies # 28 - A. Classical genetic studies # A. Classical genetic studies: # 29 - Twin Studies # Twin Studies © SPMM Course 12. Types of genetic studies Genetic methods can be classified into four paradigms 1. Basic genetic epidemiology: to quantify degree of familial aggregation and heritability estimates 2. Advanced genetic epidemiology: to explore the mechanism of action of genetic risk factors 3. Gene finding: to determine the genomic location and identity of offending genes 4. Molecular genetics: to trace biological pathways from DNA to disorder. Gene mapping refers to any strategy that permits finding the chromosomal location of one or more genes, often related to a disease. Genetic mapping of disease genes is a very useful method because it does not require any knowledge of a gene's function to find the chromosomal location initially. Once located then the identity of the disease gene could be dissected. Not all genetic studies are aimed at gene mapping; certain simpler designs are primarily aimed at demonstrating the presence or absence of a genetic influence in the aetiology of a disease or trait. These include family studies, twin studies, and adoption studies. Gene mapping studies involve linkage analysis, sib-pair analysis and to some extent allelic association studies. A. Classical genetic studies: Twin Studies Monozygotic (MZ, or "identical") twins are formed when an embryo is cleaved during early development. The result is two genetically identical embryos wherein 70% sharing even the same chorion. Dizygotic (DZ, or "fraternal") twins are the result of the fertilization of two different ova by two different sperm cells. DZ twins are genetically the same as siblings, sharing 50% of their genes. A pairwise concordance rate is estimated as the number of twin pairs who both have the disorder divided by the total number of pairs. However, where there has been systematic ascertainment, one can report a probandwise concordance rate, which is calculated as the number of affected twins divided by the total number of co-twins. This is possible if a twin register is maintained; it is also more useful method as this allows comparison of general population risk with the rate in co-twins of probands. Challenges in interpreting twin studies  Monozygotes are often treated more closely than dizygotes as they look identical; so they share more environment than dizygotes. So a higher concordance may be due to higher environmental effect.  Zygosity assignment done via anatomical similarity is far from perfect. Somatic mutations may occur in MZ twins after the cleavage event that forms them, causing "identical" twins to be at least somewhat different genetically.  Chorionicity i.e. how many amnions and chorions are present for both foetuses determines shared uterine environment.  Twin studies assume that the risk of disorder is same in monozygotic and dizygotic pairs, and in singletons at the outset. This assumption holds good for most major psychiatric disorders, while it may not be the case for some physical disorders. # 30 - Family studies # Family studies © SPMM Course Family studies There are two types of family studies. The family history method is simple but unreliable; here psychiatric history is taken from the probands himself/herself. A comparison can be then made as to how many relatives are affected in one group compared to another. A more thorough but more timeconsuming approach is the family study method. Here all available relatives are directly interviewed. See below for other major disorders. From McGue M & Bouchard TJ Jr. Genetic and environmental influences on human behavioral differences. Annu Rev Neurosci. 1998;21:1-24. Complete case ascertainment refers to the identification of all affected individuals in a given population. This is rarely possible. In multiple incomplete ascertainments consecutive referrals are identified; there is a chance that more than one probands may come from same family. Most genetic studies are concerned with in the proportion of individuals who have ever had the disorder (lifetime prevalence). But not all family members may have reached the age of risk for the disorder, and some may have died prematurely before the age of risk. Hence, age correction is important while ascertaining cases. There are many methods of age correction; Weinberg's shorter method is the often used as it is simpler. (note that such standard age correction methods do not exist for twin studies; it is a problem in MZ twins with psychiatric disorders as there is a high correlation between age of onset; sometimes survival analysis can be used for non-psychiatric phenotypes in twins) Relative risk of common psychiatric conditions derived from family studies Adapted from Johnstone, EC. Et al (Ed)Companion to Psychiatric studies Page 158 Disorder MZ Concordance DZ concordance Male alcoholism 41% 22% Female alcoholism 34% 31% Panic disorder 24% 11% Bulimia 23% 9% ADHD 58% 31% Autism 64% 9% Tourette’s 53% 8% Advantages Disadvantages Family History Method Practical Many false negatives Few false positive Family Study Few false positives or negatives Expensive Disorder Relative risk ADHD 55 times Autism 45 times Schizophrenia 10 times Bipolar disorder 7- 11 times Alcoholism 4 to 6 times Anorexia 2-4 Somatisation 3 times Unipolar depression 1.5-3 Generalised anxiety disorder 2-5 Alzheimer’s (late onset) 2 times Panic disorder 3 -8 (summarized as 5 by Hettema, 2001) # 31 - B. Molecular genetic studies # B. Molecular genetic studies # 32 - Linkage analysis # Linkage analysis © SPMM Course Adoption studies Adoption studies are useful to differentiate the effects of genes and environment. The basic method of the adoption study lies in comparing the rates of disorder in biological relatives and adoptive relatives. There are many types of adoption studies. Types Compared groups Group1 Group2 Parent as proband (1 and 2) Adopted away children of ill parents (biological or adoptive) Adopted away children of well parents (biological or adoptive) Adoptee as proband (3) Biological relatives of (ill and well) adoptees Adoptive relatives of (ill and well) adoptees Crossfostering (4) Children with ill biological parents but raised by well adoptive parents Children with well biological parents but raised by ill adoptive parents Adoption studies have certain potential problems. (1) There is a tendency for higher rates of some psychiatric difficulties amongst adopted children as adoption itself occurs due to various difficult social circumstances. (2) Adoptive parents are more likely than not to resemble biological parents as social agencies attempt to match the families of origin to families of adoption. B. Molecular genetic studies Linkage analysis During prophase I of meiosis, homologous chromosomes line up and occasionally exchange portions of their DNA. This process is termed crossover or synapsis. When a crossover event occurs between two loci, x and y, the resulting chromosomes may contain a new combination of alleles at loci x and y. This new combination is called a recombination. Because crossover events occur more or less randomly across chromosomes, loci that are located farther apart are more likely to experience an intervening crossover and thus a recombination of alleles. This offers a means of assessing the distance between loci on chromosomes. Alleles of loci that are close together on the same chromosome are likely to be inherited together; these loci are said to be linked. To be linked, these alleles must be syntenic i.e. on the same chromosome. If two loci are on different chromosomes, or if they are far apart on the same chromosome, their alleles will be transmitted independently. As crossing over is an independent event for each locus, if an allele at one locus is transmitted, there is a 50% chance (as in coin tossing) that a given allele at the # 33 - LOD Scores # LOD Scores © SPMM Course other locus will also be transmitted to the daughter cell. But linked loci are close enough together so that the chance of a recombination is less than 50%. Thus, their inheritance is not independent. The distance between two loci can be inferred by estimating the frequency with which cross-overs occur among them. The lesser the cross-over, the closer the loci. Because this is done by looking at recombination in families, this is called as recombination frequency. The recombination frequency provides a measure of the genetic distance between any pair of linked loci. Genetic distances are often expressed in centiMorgans (cM). One centiMorgan is equal to a 1% recombination frequency between two loci. 1 cM is approximately equal to 1 million base pairs of DNA (1 Mb). But crossovers occur more commonly at telomeres and less common near centromeres. LOD Scores To estimate the likelihood that two loci are truly linked with a specific recombination frequency, an LOD score is used. The LOD ("log of the odds") is estimated using the following expression LOD = log 10 (probability that recombination frequency is the observed value Ø) (probability that the recombination frequency is 50% i.e. chance) A logarithm is used because it allows LOD scores from different individual families studied to be added together later to obtain an overall LOD score. An LOD score greater than 3 is usually interpreted as statistical evidence of linkage (i.e., the numerator is 1,000 times greater than the denominator, indicating that linkage is 1,000 times more likely than nonlinkage). Conventionally an LOD score of -2 or less is taken as evidence that two loci are not linked (i.e., nonlinkage is 100 times more likely than linkage). Two loci are said to be in linkage disequilibrium if specific combinations of alleles at the loci are seen together on chromosomes more often than expected by chance. Because recombination is rare for very closely linked loci, such loci are more likely to exhibit linkage disequilibrium. Such linkage disequilibrium can be analysed in association studies too. Two different approaches can be adopted in linkage studies: 1. Candidate gene approach: A protein is suspected to be involved, then the gene is traced from this pathogenetic knowledge. 2. Positional cloning approach: Genes are identified through their positions in the genome rather than functions. Supported by human genome project. A prerequisite for successful linkage analysis (see below) is the availability of a large number of highly polymorphic markers dispersed throughout the genome. Sib pair analysis In this method several hundred DNA markers roughly evenly spaced along the 23 pairs of human chromosomes are taken and genotyping is carried out in a series of concordant sibling pairs. ‘The probability that siblings share 0, 1, or 2 alleles at any marker locus is respectively, 0.25, 0.5, and 0.25. However, if a marker locus is close to (and therefore linked with) a locus conferring susceptibility to # 34 - Whole genome scan # Whole genome scan # 35 - Association studies # Association studies © SPMM Course the disease this will be detectable as increased allele sharing at the marker. This approach has been successful in identifying susceptibility loci for disorders such as type 1 diabetes. The main drawback is that susceptibility loci of very small effect (such as conferring a relative risk of less than 2) may require large numbers of sib pairs in the region of 600 to 800 to be detected. In a disorder such as schizophrenia the relative risk in a sibling of an affected individual is about 10; thus, if several additive genes are involved, none may individually have a relative risk of more than 2’. (Excerpts from McGuffin & Martin, BMJ. 1999 Jul 3; 319(7201): 37–40) Whole genome scan It is a type of linkage analysis in which markers placed at regular intervals covering the whole genome are typed. It is tedious but often the first approach when no genetic information is available about a particular phenotype. A good example is that of neuregulin. Stefansson et al. typed 950 microsatellite markers covering the whole genome in 110 Icelandic patients with reconstructed genealogical relationships, and found that neuregulin-1 is a candidate gene for schizophrenia (Malats & Calafell, 2003). Association studies Association studies are more straightforward to carry out than linkage studies. Here a case control design is often adapted, and a sample of cases affected by a disorder is compared with controls. The frequency of alleles at the marker locus is then compared in the two groups. This method, though increasingly used, cannot make strong causal inferences. The locus chosen for study must predispose to illness. Thus, loci chosen for association studies are often known as candidate genes. If the locus does not predispose to illness, then the results of an association study should be negative. However, false positive results can occur if the two populations are not carefully matched for ethnic background. One alternative control group is the parents or relatives of affected individuals (the alleles not transmitted to the affected child compose the "control group"—this is known as the Transmission Disequilibrium Test or TDT). In Genome Wide Association Studies (GWAS), ‘candidate gene’ approach is not used. Instead, several thousands of single nucleotide polymorphisms are assayed in thousands of individuals. This is the new ‘hot’ study technique in psychiatric genetics. Questions Most appropriate method Is the phenotype familial? Family study What is the relative contribution of genetic and environmental factors? (Heritability) Twin studies, adoption studies What is the mode of transmission? Segregation analysis Where might be the ‘culprit’ genes? Linkage analysis (known ancestries) What are the actual genes responsible? Association analysis (population level) # 36 - Linkage vs. association # Linkage vs. association # 37 - C. Alternative approaches in genetic studies # C. Alternative approaches in genetic studies © SPMM Course Linkage vs. association Linkage studies Association studies Uses families Uses cases and controls or families with ‘internal controls’ Detectable over large distances >10cM Detectable only over small distances <1cM Can usually only detect large effects i.e. RR>2 Capable of detecting small effects e.g. OR<2 From McGuffin et al. (ed) Psychiatric genetics and genomics. Oxford Press: 2002 C. Alternative approaches in genetic studies  Transgenic studies: Transgenesis is a term that describes the transfer of a gene from one species to another. In practice, this term often refers to the insertion of a modified mouse gene into the mouse genome to study gene function. Transgenesis is a direct and powerful approach for analysing gene function.  Epigenetics: A discrepancy exists between the information provided by the DNA sequence (i.e. number of genes) and what is translated and produced by cellular machinery (messenger RNA and proteins). Though the DNA sequence provides a blueprint for synthetic activities of the cell, a number of ‘epigenetic’ modifications occur resulting in a second, equally complex layer of information. Waddington coined the term epigenetics to explain such mechanisms. DNA methylation and histone modification explain most of the epigenetic variations discovered to date. Crow has argued for long that epigenetic defects explain most of the concordance seen in schizophrenia; according to Crow, the hemispheric laterality and language specialisation unique to human brains is the source of schizophrenic defect and it can be ascertained only by an epigenetic enquiry.  Position effects: gene activity can be dependent upon the precise chromosomal location of the gene and its ‘neighbourhood’. Such genes will show altered activity during translocation, even if the gene itself is not disrupted by chromosomal breakage.  Endophenotypes: This term was coined by Gottesman and Shields in 1975. An endophenotype is an unseen but measurable phenomenon that is present in the distal genotype to disease pathway. It can be a biochemical, neuroimaging, electrophysiological, pathological, neuropsychological or sociofunctional marker. To be termed as an endophenotype, Gottesman suggested certain criteria to be satisfied by an identified disease marker. These are as follows: 1. Must be associated with a candidate gene or region 2. Must be present with a high relative risk in relatives, thus cosegregating with actual illness 3. Must be a parameter associated with disease with biological plausibility 4. Must be independently expressed in clinical state (i.e. must not be a state but a trait marker) 5. Must be heritable 6. Must be present in relatives more often than general population It is anticipated that the genetics of a complex construct such as schizophrenia can be studied easily in more or less Mendelian fashion if the constructs are broken down to constituent endophenotypes. The simpler a construct under study, the less number of genes will be on the causal pathway. Working # 38 - 13. Psychiatric genetics # 13. Psychiatric genetics # 39 - A. Causal models # A. Causal models © SPMM Course memory defects, information processing defects such as prepulse inhibition, smooth pursuit defects, glial cell changes and certain other putative neurocognitive markers are termed as probable endophenotypes for schizophrenia. To be an endophenotype, a character must be observable independent of clinical state and must be measurable in relatives at a higher degree than the general population. In spite of their simplicity, there are some important problems that need to be overcome while studying endophenotypes.  The endophenotypic expression could be well under the influence of the developmental environment.  An endophenotype can be differentially expressed in different brain regions.  Often patients have multiple endophenotypic deficits with significant interaction among these.  In spite of hard toil, researchers are unable to narrow down genetic linkages of suspected endophenotypes to achieve better than modest LOD (log of odds) scores. 13. Psychiatric genetics A. Causal models Several notable features regarding psychiatric genetics are listed here (excerpted from Craddock et al., BJPsych, 2007:190;3) 1. Families with clear Mendelian inheritance patterns are rare: There are no clear demonstrations of Mendelian pattern of inheritance of schizophrenia or other psychiatric disorders in families. 2. Single genes of major effect have not been found: Even in extended pedigrees with multiple cases of psychiatric illnesses, intensive molecular genetic studies have not demonstrated mutations of major effect (LOD scores are meager). The odds ratio in most psychiatric genetic association studies are in the order of 1 to 2; median being 1.3. This is insufficient to prove a genetic cause for most disorders. These findings are suggestive of multiple risk alleles of modest effect. 3. Mathematical modelling of familial risk is inconsistent with single genes of large effect: According to Craddock et al., “for both schizophrenia and bipolar disorder there is a very rapid, non-linear decrease of risk when moving from a genetically identical individual (i.e. monozygotic co-twin where the risk is 50– 60%), to an individual who shares half the genes (e.g. sibling, parent, dizygotic co-twin where risk is around 10%)”. This rapid, non-linear decrease of risk is compatible with multiple interacting risk factors, albeit of unknown frequency, that individually have modest effects. 4. The causal pathway from an identified genetic abnormality to actual disease expression is too complex and not fully explored in any known genetic markers of psychiatric diseases. For example it is unclear how mutant dysbindin gene that is implicated in schizophrenia can lead to a belief that aliens are invading earth. The association between genes and diseases are very non-specific and weak with respect to psychiatric diseases. © SPMM Course 5. Contingent models of association: Non-contingent gene–disorder association refers to the fact that the relationship is not influenced by other factors such as environment or presence of other genes i.e. not polygenic or multifactorial. But most psychiatric disorders do not follow non-contingent association models. 6. Practical difficulties in conducting genetic enquiries in psychiatry: a. Wide ethnic, geographical variations are seen in psychiatric disorders. b. Ascertainment method. The spectrum of clinical features (symptoms, severity, functioning, illness course, etc.) of individuals recruited depends upon the mode of ascertainment. These variations can reduce or increase the modest effect sizes noted. c. Unknown phenotypic model. Reliance on DSM–IV or ICD–10 categories is a huge challenge for psychiatric genetics. These are arbitrary classifications, and it is possible that we have been missing many etiological factors due to these empirical categories. For example, the distinct DSM-based categories of affective disorders may not breed true as strong overlap exists between the genetic risk of unipolar and bipolar disorders. Two views exist concerning the causal modeling of genetic factors in psychiatric disorders (Craddock et al., 2007): 1. Common disease–rare variant model: Rarely occurring mutations cause diseases such as schizophrenia. There are various different mutations that can explain the disease (locus and allelic heterogeneity). But each mutation is sufficient but not necessary to cause the disease. Each family inherits one such mutation explaining higher risk in the relatives. These mutations are rare, but when present they commonly cause the disease. 2. Common disease–common variant model: Here a disease such as schizophrenia is thought to be a result of the co-action of multiple (ranging in principle from a few to many thousand) common variants (`polymorphisms'), each of which has a small effect on illness susceptibility – see table below. When an individual inherits several, or many, susceptibility variants together, they have a sizable influence on disease risk. Hence, the mutations or polymorphisms are not sufficient by themselves to cause disease, but they occur very commonly so they can interact in combinations and produce the disease. This model is more popular currently and forms the basis of association and linkage studies being carried out widely. Characteristics Mendelian disorders Most psychiatric disorders Diagnostic boundaries Clear Vague Phenocopies Absent Multiple Penetrance Usually complete/ predictable Incomplete / unpredictable Association Non-contingent models Contingent models Modelling familial risk Linear change in risk Non-linear changes in risk MZ concordance Nearly 100% 30-70% only Locus heterogeneity Never within families; often absent across families too Likely # 40 - B. Genetics of Schizophrenia # B. Genetics of Schizophrenia © SPMM Course B. Genetics of Schizophrenia How important is the genetic contribution to schizophrenia? The relative risks for first-degree relatives / twins of probands are higher than relative risks due to any individual environmental factors. Without genetic contribution, schizophrenia cannot be explained. Risk to family members: In the attached chart ‘parents’ refer to one parent having schizophrenia, where the risk to the child is 13%. If both parents have schizophrenia, then the risk is 46% - close to monozygotic twin risk. The risk to a half sibling is 4%. Note that for the children and siblings of individuals with schizophrenia, the increase in risk is around 10-fold, but it is somewhat less than this in parents. This is probably ‘explained by a reduction in the reproductive opportunities, drive, and possibly fertility of affected individuals’ (Craddock et al. 2005).  Monozygotic (MZ) concordances = 41–65%  Dizygotic (DZ) concordances = 0–28%  Broad heritability = 80%  The most frequent personality disorder in relatives of schizophrenia patients is schizotypal personality disorder (DSM)-nearly 15% can be diagnosed with it.  Twin studies had shown significantly higher MZ concordance rates for schizophrenia when probands had hebephrenic or nonparanoid subtypes than paranoid subtypes.  Psychotic symptom dimensions consistently show only modest familial aggregation in affected sibling pairs, and rather weak and inconsistent relationships with the familial risk of psychoses. So the severity of schizophrenia is not directly associated with a family history or genetic loading. Gene suspected in schizophrenia Locus NRG1 Neuregulin 8p12-p21 DTNBP1 dysbindin 6p22 G72 13q34 DAAO (interacts with G72) D amino acid oxidase 12q24 RGS4 Regulator of G protein signalling 4 1q21-22 COMT Catechol-o-methyl transferase 22q11 DISC1 Disrupted in Schizophrenia 1q42 # 41 - C. Genetics of Mood disorders # C. Genetics of Mood disorders # 42 - Bipolar disorder # Bipolar disorder © SPMM Course  Murray et al. (2002) point out a number of studies that have shown a higher familial risk to be associated with earlier age of onset. Sham et al. (1994) showed that the morbid risk of schizophrenia is greater among the relatives of those probands who had an onset before rather than after age 21 years.  Most case-control studies have not provided evidence in support of COMT associations, but association studies with family design provide greater evidence for COMT in schizophrenia.  In Down’s syndrome, the risk of schizophrenia is same as or lower than the general population. The exact figure is unknown, but an estimate of less than 0.6% is quoted. C. Genetics of Mood disorders If one parent has a mood disorder, a child will have a risk of between 10 and 25 percent for mood disorder. If both parents are affected, this risk roughly doubles. The presence of more severe mood disorder in the family conveys a greater risk. Bipolar disorder  A family history of bipolar disorder conveys a greater risk for mood disorders in general and bipolar disorder in particular. This may be due to common genetic underpinnings between these two forms of mood disorder. Estimates of broad heritability are high: nearly 85-90%. The lifetime risk in relatives does not vary according to the sex of relative or sex of proband.  Because of its higher prevalence, the unipolar disorder is typically the most common mood disorder in families of bipolar probands.  According to Craddock et al. (2005), lifetime risk of narrowly defined bipolar disorder in relatives of a bipolar proband are: o unrelated member of the general population: 0.5–1.5%; o first degree relative 5–10% (relative risk = 8); o monozygotic co-twin 40–70% (relative risk = 60);  Lifetime risk of unipolar disorder in relatives of a bipolar proband are: o unrelated member of the general population: 5-10%; o first degree relative 10-20% (relative risk = 2-3times); o monozygotic co-twin 15-25% (relative risk = 3-5 times); o Note: You can get the risk of major mood disorder by adding the absolute risk of unipolar and bipolar from the above data. Genes suspected in Bipolar Disorder Locus BDNF (Brain-derived neurotrophic factor) 11p13 DAO G72/G30 D aminoacid oxidase 13q33 COMT Catechol-o-methyl transferase Breakpoint cluster region (BCR) gene 22q11 # 43 - Unipolar depression (MDD) # Unipolar depression (MDD) # 44 - Schizoaffective disorder # Schizoaffective disorder # 45 - Molecular associations (Schizophrenia and Bip # Molecular associations (Schizophrenia and Bipolar disorder) © SPMM Course Other implicated chromosomes –  Chr 18 - nearly 4 loci, affective disorders in general;? parent of origin effect)  Chr 21q - both in scz and BPAD.  An X-chromosomal locus to BPAD has been suggested on the basis of the cosegregation of BPAD in some families with color blindness, the glucose-6-phosphate dehydrogenase deficiency, and the coagulation factor IX deficiency. In an extended Finnish pedigree, Xq24-q27.1 was demonstrated to segregate with bipolar disorder.  Low activity allele in COMT gene may be associated with rapid cycling.  Serotonin transporter gene (hSERT) and 5HT2A gene may be associated with modest statistical significance in Seasonal Affective Disorder. Unipolar depression (MDD)  Age-adjusted risk of MDD to first-degree relatives: 5-30%, relative risk 1.1-4.0. MZ Twin concordance for MDD: 40%. DZ Twin concordance for MDD: 11%. Heritability: Unclear (~20-80%); meta-analysis reports 31-42%. (Data from NCHPEG Empric Risk Data: Retrieved from www.nchpeg.org )  Early onset and recurrent episodes likely increase risks to first-degree relatives. Recurrence risks for unipolar depression could be 50 percent or higher for probands with early-onset and recurrent episodes. While the definition of “early onset” is not entirely clear, research suggests that family members of probands who had onset before age 25-30 years have the highest risk; relatives of probands with onset between ages 25-40 years have an intermediate risk; and relatives of probands with onset after age 40 years have a risk that is only slightly increased over the population risk Schizoaffective disorder  The risk to first-degree relatives for ANY psychiatric disorder is higher in SA disorder than any other psychiatric disorder. The extent of heritability is unclear, although likely in the range of schizophrenia.  Relatives have a higher rate of schizoaffective illness, schizophrenia and bipolar disorder.  The rate of bipolar disorder is high if proband has a schizoaffective-manic presentation. The rate of schizophrenia is high if proband has schizoaffective-depressive presentation. In depressive subtype no elevation in bipolar risk has been noted in a large cohort (Andreasen 1987). Molecular associations (Schizophrenia and Bipolar disorder)  G72: The function of G72 (also sometimes referred to as DAOA) may be to, oxidize serine, a potent activator of glutamate transmission via a modulatory site on the NMDA (n-methyl-d-aspartate) receptor. Inadequate DAOA function might be hypothesized to lead to problems in modulating the glutamate signal in areas of the brain such as the prefrontal cortex. A new suggestion is that the major role of G72 may be in maintaining neuronal structure.  Brain-Derived Neurotrophic Factor (BDNF): Several studies have shown that antidepressant administration is associated with increased central BDNF levels in experimental animals, and administration of BDNF itself has been associated with the antidepressant-like activity. Depression has Shared genes – BPAD and Schizophrenia DAO & BDNF – seen more in mood disorders than schizophrenia DISC 1 & NRG – shared with schizophrenia; seen in schizoaffective disorder Dysbindin – seen more in schizophrenia than mood disorders CREB1 (chr2) – unipolar depression # 46 - D. Genetics of dementias # D. Genetics of dementias © SPMM Course been postulated to be associated with decreased neurogenesis in the hippocampus, which is dependent on neurotrophic factors, including BDNF.  Disrupted in Schizophrenia 1 (DISC1): This gene on chromosome 1q was identified in a Scottish family with a genetic translocation and with multiple cases of psychiatric disorders, primarily schizophrenia. This gene is expressed in multiple brain regions, including the hippocampus, where it is differentially expressed in neurons. It is associated with microtubules; in mice, disruption of DISC1 leads to abnormal neuronal migration and dendritic organization in the developing cerebral cortex. DISC1 appears to interact with phosphodiesterase 4B, which may play a role in mood regulation.  5HTT, MAOA, COMT: These three genes have been shown in meta-analyses to be associated with BP disorder. The effect size for each appears to be in the range of 10–20% increase in risk. Each of these genes is associated with other behavioral phenotypes, and each has been reported to interact with the environment to increase the risk of specific disorders (major depression, antisocial personality disorder, and schizophrenia respectively). Recent data in BP illness are more positive for 5HTT than for MAOA or COMT.  Dysbindin: Also known as dystrobrevin binding protein 1 - involved in the formation of synaptic structures  Neuregulin: Involved in neuronal migration and in the genesis of glial cells and subsequent myelination of neurons by these cells  GRK3: This is the only candidate identified using animal model studies (a mouse model employing methamphetamine). This gene participates in the down-regulation of G-protein coupled receptors and is associated with Bipolar disorder. D. Genetics of dementias Alzheimer’s disease (AD)  Mutations in the amyloid precursor protein (chr 21 ) and presenilin 1 (chr 14) and 2 (Chr 1) genes may be responsible for as much as 50% of familial (ie, autosomal dominant) AD beginning before 60 years of age (presenile). But this accounts for less than 1% of patients worldwide.  The genetic factor with the highest attributable risk for AD is apolipoprotein E (APOE). The APOE gene on chromosome 19q has 3 codominant alleles, 2, 3, and 4, differing by single-base substitutions in the coding region of the gene. The ancestral allele, 4, is overrepresented, and 2 is underrepresented in AD (from Graff-Radford et al.: Arch Neurol. 2002;59(4):594-600). In Caucasian subjects, the odds of AD for those homozygous for 4 and for 3/ 4 heterozygotes are 14.9 and 3.2 times, respectively, greater than the odds associated with 3 homozygosity. The mean age of onset of AD is 2 decades earlier in 4 homozygotes. The APOE 4 allele has also been found to increase AD risk in nonwhite populations, including Afro-Caribbean, Chinese and Japanese. The increased risk associated with the 4 allele is greater in women than in men though this is not replicated in African Americans.  Chr 21 harbours mutant APP (Amyloid Precursor Protein) – this is related to Down’s syndrome and explains the higher prevalence of AD in patients with Down’s syndrome Male Abs. risk% Female Abs. Risk % Relative risk (both sexes) # 47 - Frontotemporal dementia # Frontotemporal dementia © SPMM Course ApoE status unknown (general population) 6.3% 12% - No Apo 4 4.6% 9.3% 0.75 times (less) Apo 4 heterozygote 12% 23% 3.2 times (up to 5 times in some studies) Apo 4 homozygote 35% 53% 14.9 times Modified from McGuffin et al. (ed) Psychiatric genetics and genomics. Oxford press: 2002  An actually predicted risk of developing Alzheimer's disease in the first-degree relatives of probands with Alzheimer's disease is 15-19%, compared with 5% in controls. Thus, the risk to the first-degree relatives of patients with Alzheimer's disease who developed the disorder at any time up to the age of 85 years is increased some 3 – 4 times relative to the risk in controls. This translates to a risk of developing Alzheimer's disease of between one in five and one in six (from Liddell et al., 2001).  In the case of patients with Alzheimer's disease who became demented late in old age, say by their 80s, relatives probably run the same 30-50% risk of developing dementia as anyone else who live to the age of 90 years and beyond (from Liddell et al., 2001).  Like other disorders that reflect the combined action of several genes, the risk to relatives drops rapidly as the degree of genetic relatedness falls. Data are limited, but the risk to second-degree relatives, such as grandchildren, is probably less than twice the population levels (from Liddell et al., 2001)  Probandwise concordance rates of about 40% for DZ and 84% for MZ twins are seen. Frontotemporal dementia  Frontotemporal lobar degeneration (FTLD) refers to the 3 different syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia and semantic dementia.  Some patients with FTLD show tau protein based pathological changes. In familial cases, mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21.  Many cases are tau-negative but show ubiquitin-immunoreactive neuronal cytoplasmic inclusions. In some of these tau negative cases mutations have been identified in progranulin (PGRN) gene, also on chromosome 17q21.  Progranulin is a widely expressed growth factor that plays a role in wound repair and inflammation by activating signalling cascades in cell cycle. Progranulin has also been linked to tumorigenesis CADASIL CADASIL is a form of amyloid angiopathy that can present with Alzheimer’s like features. NOTCH3 is the only gene currently known to be associated with CADASIL. Most mutations in the NOTCH3 gene in individuals with CADASIL are located in exon 4. The mutation detection rate is up to 96% in individuals with well-defined or biopsy-proven CADASIL. The defective gene is identified as NOTCH3 in 19p13.1-13.2 # 48 - Lewy Body dementia # Lewy Body dementia # 49 - E. Other disorders # E. Other disorders # 50 - Autism # Autism © SPMM Course Lewy Body dementia No specific genetic associations have been established for Lewy Body Dementia. Certain mutations have been reported inconsistently at alpha-synuclein locus. DLB is considered as a part of ‘synucleinopathies’ where synuclein molecules aggregate in presynaptic terminals producing Lewy bodies. Other diseases included are Parkinson’s and Multisystem atrophy. Parkinson’s disease LOCUS POSITION/Protein Clinical features/inheritance PARK1, PARK4 4q21 Alpha-synuclein gene Dominant inheritance; not seen in sporadic cases. Onset in 40s. nigral degeneration with Lewy-bodies. PARK2 6q25 Parkin gene Recessive inheritance; nigral degeneration without Lewy-bodies. Onset 40 – 60. (most early onset cases, l-dopa responsive) PARK8 cen (pericentromeric) LRRK2 gene Dominant. Onset around 60. Variable -synuclein and tau pathology. PARK6 1p35-37 PTEN-INduced Kinase (PINK1) in mitochondria Autosomal recessive; onset 30-40 (12% of early-onset cases, l-dopa responsive) PARK7 1p38 DJ-1 Autosomal recessive; onset 30-40 α-synuclein is a protein that is expressed throughout the brain and has potential roles in learning, synaptic plasticity, vesicle dynamics and dopamine synthesis. E. Other disorders Autism  The recurrence rate in siblings of autistic children is 2% to 8% (higher than the rate in the general population but lower than in single-gene disorders). This translates to 50 times (range: 30 – 120) relative risk in siblings.  Risk of autistic disorder in a sibling of 2 autistic children: 25-30% (nearly 300 times higher)  Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins. If a broader autistic phenotype that included communication, and social disorders is considered, the concordance increased remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This translates to 90% heritability.  The identity and number of genes involved remain unknown. Chromosomes 2, 7 and 15 are implicated. A segregation analysis in a series of multiplex families was consistent with autosomal recessive inheritance with sex-specific modifications  The striking feature is the association of the genetics of autism with multiple single-gene disorders. The most clearly documented of these disorders is the fragile X syndrome. Perhaps 8% of autistic subjects have the cytogenetic fragile X; 16% of fragile X males are autistic. There are also probable associations between autism and tuberous sclerosis, neurofibromatosis, and phenylketonuria # 51 - ADHD # ADHD # 52 - Personality disorders # Personality disorders # 53 - Panic disorder # Panic disorder # 54 - Social phobia # Social phobia # 55 - Alcoholism # Alcoholism © SPMM Course  There appears to be as much variability in the phenotypic symptom expression within monozygotic twins as between MZ pairs. This suggests non-genetic influences play an important role in determining the pattern of phenotype in autism (LeCouteur, 1996).  Risk for broader phenotype (delayed speech, reading/spelling difficulties, social reticence/awkwardness, poor social language abilities) in first-degree relatives and dizygotic twins: 30%. In monozygotic twins, the spectrum phenotype has 82% concordance. (All data excerpted from http://pediatrics.aappublications.org/content/113/5/e472)  ADHD  Risk to first-degree relatives: 15-60%, 2-6 relative risk  Risk to second-degree relatives: 3-9%, 0.5-0.8 relative risk  Heritability: ~70-80%  Risks are higher for male relatives and lower for female. It is unclear if recurrence risks are higher when the proband is female. Continuation of illness into adulthood may indicate increased risk to relatives. Personality disorders  The largest factor accounting for nearly 50% or more of the variation in most personality traits is nonshared, person-specific environmental variation.  Among personality disorders, antisocial PD has the highest heritability (60-70%).  Emotional dysregulation has high heritability among various features of borderline PD.  A variant of the tryptophan hydroxylase gene (which codes for the synthetic enzyme for serotonin) is associated with low 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid and suicide attempts in violent criminal offenders. Panic disorder  Lifetime prevalence of panic disorder (+/-agoraphobia) is around 4.7%.  In a metaanalysis of family studies, Hettema et al. (2001) found OR of 5 for panic disorder in firstdegree relatives (absolute risk 8-31%). Early onset panic disorder confers increased risk than lateronset disease. Nearly 17 fold increase in risk is seen if the onset is before 20 years compared to the only 6-fold increase in relatives of probands with onset after 20 years. The heritability is estimated to be around 0.43. Social phobia  The 10-fold increase in risk is seen in first-degree relatives of probands with generalized social phobia. Non-generalised discrete social phobia does not show familial transmission.  Specific phobias are 3-4 times more common in 1st degree relatives of probands (OR 4). Nevertheless, twin data suggest that individual-specific environmental influences are more important in the development of simple phobias. Alcoholism  Genetic influences play an important role in alcoholism: the risk in families may be 4 to 6 times higher than in the general population. # 56 - OCD # OCD © SPMM Course  Majority of adoption studies show that the risk of alcoholism in adopted children is strongly correlated with their biological parents rather than adoptive parents ( 3- 4 times higher); no protective effect was noted in being raised away from drinking biological parents (Goodwin 1973). The genetic risk is clearly higher in males and weak in females.  Variants in GABRA2 on chromosome 4p have been shown to be associated with alcohol dependence - particularly strongly related to problems with impulse control; the risk allele is also seen in adolescents with conduct disorder and in alcohol dependent persons who are drug dependent.  ADH (alcohol dehydrogenase) is the major metabolic enzyme for alcohol, catalyzing its breakdown into acetaldehyde, which is then further metabolized by aldehyde dehydrogenase (ALDH). Both ADH and ALDH have variants associated with the "flushing" reaction to alcohol. The strongest finding with regard to alcoholism is in ADH4, which appears to be associated with the early onset of regular drinking.  A meta-analysis of 21 studies shows an increased risk of alcoholism of 50–100% of persons carrying the A1 allele of DRD2. However, recent work has questioned whether this polymorphism may actually be reflecting variation in a gene next to DRD2. OCD  Early onset suggests higher genetic risk for family members; some studies suggest increased risk only in the case of early age at onset (generally defined as before 18 years) [www.nchpeg.org].  Fathers were three times as likely as mothers to receive a diagnosis of OCD for probands with severe childhood OCD.  Increased severity and chronicity appear to increase risk  Risk to 1st degree relatives:  Onset before age 18: range of ~10-35%  Onset after age 18: no increased risk to ~15%  MZ Twin concordance: 53-87%  DZ Twin concordance: 22-47% Family History Increased Risk for Offspring General Population Risk Unipolar depression Unipolar 2-fold (16%); Bipolar 4-fold (4%) 6% Bipolar depression Unipolar 2-3 fold (16%); Bipolar 8 to 9-fold (9%) 1% Schizophrenia (SZ) Unipolar - 2-fold (16%); Bipolar -4-fold (4%) 1% Alcoholism 5-fold (27% for males, 5% for females) 5% males, 1% females Panic disorder 12-fold (6%) 0.5% Tourette's syndrome 100-fold (25%) 0.25% Alzheimer's disease 5-fold (15%) at age 75 3% Attentiondeficit/hyperactivity disorder 5-fold (15%) 3% Anorexia nervosa 10-fold (5%) 0.5% Adapted from Tsuang D, Faraone SV, Tsuang MT. Psychiatric genetic counseling. In: Floyd EB, David JK (eds). Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, 1995. # 57 - 14. Clinical genetics # 14. Clinical genetics © SPMM Course 14. Clinical genetics When an individual approaches a genetic clinic for genetic testing, 2 approaches can be employed.  Direct testing: This is very much like any other lab test. A sample is tested for the presence of a certain genotype. Only one individual is tested, and the abnormality that is being sought is already known to have an association with the illness studied.  Gene tracking: Many family members are tested to discover whether or not the suspected patient seeking the test has inherited the high-risk chromosome from a heterozygous parent. The test is based on Mendelian principles and seeks information about the segregation of a chromosome within a family. It can be used even if the exact genetic locus associated with a disease is unknown. . Prenatal identification: Prenatal test is the test of a fetus to identify a suspected genotype. It is often initiated on the basis of family history or maternal factors (e.g. older mothers at risk of Down’s). Maternal serum screening to identify neural tube defects and Down’s is offered routinely in many countries. In general, adult-onset genetic conditions are not usually tested prenatally. . Genetic counseling is routinely offered to individuals seeking genetic tests. The counseling service provides information about risks and probabilities before the test and also provides support (but not psychological) services after the testing. Within the NHS Regional Genetic Centres that incorporate cytogenetic, molecular and clinical genetic services operate and offer familial (carrier) testing, diagnostic and prenatal (presymptomatic) testing. . DNA banks provide secure, long-term storage for an individual’s genetic material. While this is seen as beneficial for biomedical research the possibility of misuses has raised several ethical issues. . . . . . . . . . DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. © SPMM Course Notes prepared using excerpts from  Bouchard & McGue, 2003. "Genetic and environmental influences on human psychological differences." Journal of Neurobiology, 54, 4-45.  Braff DL, et al. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull 2007; 33:21–32  Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389.  Collins, K et al. The cell cycle and cancer. Proceedings of the National Academy of Sciences 94: 2776-2778.  Craddock & Jones The British Journal of Psychiatry (2001) 178: s128-s133  Craddock N, et al (2005) The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet, 42, 193–204.  Craddock, N et al. British Journal of Psychiatry 2007 190: 200-203  Devlin and Morrison. Mosaic Down's syndrome prevalence in a complete population study. Arch Dis Child 89,12 (2004): 1177-1178.  DNA figure source: Boundless. “Chromosomes in Human Cells.” Boundless Anatomy and Physiology. Boundless, 05 Dec. 2014. Retrieved 14 Dec. 2014 https://www.boundless.com/physiology/textbooks/boundless-anatomyand-physiology-textbook/  European Journal of Human Genetics (2003) 11, 2, S8–S10.  Farrer MJ. Nat Rev Genet. 2006 Apr;7(4):306-18.  Gottesman, II. & Gould, TD. The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions. Am J Psychiatry 2003 160: 636-645  Graff-Radford NR et al. Association between apolipoprotein E genotype and Alzheimer disease in African American subjects. Arch Neurol. 2002;59:594-600.  Hayes, P.C., et al. Blotting techniques for the study of DNA, RNA, and proteins. BMJ. 1989, 299(6705): 965–968.  Kato, T. Molecular genetics of bipolar disorder and depression. Psychiatry and Clinical Neurosciences 2007 61:3-19.  Kendler, K. Psychiatric Genetics: A Methodologic Critique. Am J Psychiatry 2005; 162:3–11  Kendler, KS (2005) “A Gene for...”: The Nature of Gene Action in Psychiatric Disorders. American Journal of Psychiatry; 162: 1243 - 1252.  Leonard, JV & Shapira, AHV. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. The Lancet, 2000. 355: 299-304.  Liddell et al. The British Journal of Psychiatry, 2001:178, 7-11.  McGuffin P & Martin N. Behaviour and genes. BMJ 1999; 319, 37- 40.  Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004; 113(5):472-486.  Murphy, K. Schizophrenia and velo-cardio-facial syndrome . The Lancet , 359, 426 - 430  Murray et al (ed). The epidemiology of Schizophrenia. Cambridge University Press, 2003. p212  Peter M. Visscher, William G. Hill, and Naomi R. Wray, “Heritability in the genomics era - concepts and misconceptions,” Nat Rev Genet 9, no. 4 (April 2008): 255-266.  Psychiatric genetics data from National Society of Genetic Counselors (www.nsgc.org) and American Association of Family Physicians ACF Genomics data.  Qiu J (2006) Epigenetics: unfinished symphony. Nature, 441, 143–145.  Ranke, M & Saenger, P. Turner's syndrome. The Lancet, 358, 309-314.  Ropers, H. H. & Hamel, B. C. J. (2005) X-linked mental retardation. Nat Rev Genet, 6, 46-57.  Snowden JS et al. (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129:3091–102.  Strachan & Read. Human Molecular Genetics, 2nd ed. New York: Wiley-Liss; 1999  Therman, E. Susman, B. & Denniston, C. The nonrandom participation of human acrocentric chromosomes in Robertsonian translocations. Annals of Human Genetics 1989;53:49-65  Williams et al. Is COMT a Susceptibility Gene for Schizophrenia? Schizophr Bull. 2007; 33: 635-641 # 09 - 35_Neuropathology # 01 - A. Senile plaques # A. Senile plaques # 02 - B. Neurofibrillary tangles (NFT) # B. Neurofibrillary tangles (NFT) © SPMM Course 1. Alzheimer’s Dementia (AD) Gross changes include diffuse atrophy, flattened cortical sulci and enlarged cerebral ventricles. Histological changes include neuronal loss (particularly in the cortex and the hippocampus), synaptic loss, granulovascular degeneration (small vacuoles with central granules, in the cytoplasm of neurons especially in the temporal lobes), senile plaques, neurofibrillary tangles and Hirano bodies. Astrocytic gliosis and microglial activation are also noted in some cases. A. Senile plaques  Plaques are insoluble amyloid peptide deposits. The peptide involved is called Aß (beta A4) peptide.  Amyloids are fibrils of multimeric chains of peptides deposited extracellularly. They have a beta pleated sheet confirmation.  Aß is cleaved from a larger transmembrane protein—amyloid-ß precursor protein—by the action of ßand -secretases and its formation is prevented by the action of -secretase.  Plaques vary in appearance, and two main subtypes are recognised.  Neuritic plaques: o They contain Aß in the form of amyloid fibrils, among which are irregularly swollen dystrophic neurites (degenerated neuronal processes). o The neurites are well visualised with silver stains; they may be seen as an eosinophilic mass on haematoxylin & eosin stains. o Neuritic plaques may contain a dense central core of amyloid. o Microglia and astrocyte processes are present towards the periphery of neuritic plaques. o Seen in Down syndrome and, to some extent, in normal aging as well. o Amyloid sensitive stain Congo red, under polarized light, demonstrates the "apple green" birefringence of the stained tissue with neuritic plaques, due to the presence of beta-pleated sheets.  Diffuse plaques: o They consist largely of non-fibrillar extracellular Aß. o They are not related to the degree of cognitive decline o Diffuse plaques contain the same peptides as those responsible for amyloid formation in the neuritic plaques. However, these peptides are not polymerized to form fibrils and lack beta-sheet configuration o Only neuritic plaques are counted in neuropathological tests. B. Neurofibrillary tangles (NFT)  NFT are composed of cytoskeletal elements, primarily abnormally phosphorylated tau protein. AD is one of the several degenerative tauopathies.  Tau is a peptide required for microtubule assembly. Microtubules are essential to transport of materials down the axons. # 03 - C. Hirano bodies # C. Hirano bodies # 04 - Neuropathological correlate of cognitive decl # Neuropathological correlate of cognitive decline © SPMM Course  Beta A4 peptide interacts with cholinergic receptors and this interaction stimulates the abnormal phosphorylation of tau. The hyperphosphorylated tau is a major constituent of the tangle. It is also present in the degenerated neurites. Hence both tangles and neuritic plaques can be identified by staining with antibody to the abnormal tau.  Apart from Alzheimer’s, NFT occur in several disorders including Down syndrome, dementia pugilistica (punch-drunk syndrome), Parkinson-dementia complex of Guam, Hallervorden-Spatz disease, and the normal elderly.  Most tangles are faintly basophilic. Tau immunostaining and silver impregnation can be used to improve the chances of light microscopic detection.  Tangles are mostly intraneuronal, though upon neuronal degenration, they may appear extracellularly, thus losing their basophilia.  According to Love (2005), “the earliest pattern of involvement is usually not associated with clinical symptoms: tangles and neuropil threads are restricted to parts of the entorhinal cortex and the CA1 field of the hippocampus. As dementia develops, tangles and neuropil threads accumulate in increasing density in other parts of the hippocampus and medial temporal neocortex, and then in other cortical regions and in subcortical grey matter structures such as the hypothalamus and thalamus”.  A staging scheme devised by Braak and Braak (1995) is often employed to describe the extent of tangle related abnormalities (distribution from entorhinal cortex to isocortex) in AD and correlates well with the severity of dementia. Stages V-VI operationally define AD. C. Hirano bodies  These are rod-shaped eosinophilic bodies in the cytoplasm of neurons. Hirano bodies are seen in the extracellular space when the neuron dies.  Hirano bodies are intracellular aggregates of actin and actin-associated proteins  They are frequently seen in hippocampal pyramidal cells Neuropathological correlate of cognitive decline The number and distribution of tangles increases as cognitive decline increases. When both neuritic plaques and tangles are present, the presence of even a few tangles in a single field in the neocortex suggests a significant cognitive decline. There is also an association between the numbers of neuritic plaques and the degree of cognitive decline. However, this is less apparent than the relationship between CEREBRAL AMYLOID ANGIOPATHY (CAA) CAA is the accumulation of Aß in the walls of blood vessels (particularly arteries and arterioles) in the cerebral cortex and overlying leptomeninges. This affects about 30% of normal elderly people but over 90% of patients with AD, in whom the angiopathy tends also to be much more severe. CAA is an important cause of strokes in the elderly. Most of these are haemorrhagic; CAA is confined to superficial cerebral blood vessels, rupture of the amyloid laden blood vessels usually causes relatively superficial, lobar haemorrhages that may extend into the subarachnoid space. # 05 - Hippocampal pathology # Hippocampal pathology © SPMM Course tangles and cognitive decline. The best neuropathological correlate of decline is the number of synapses. The marker for synapses has been antibody to synaptophysin, a protein found in the presynaptic endings. Hippocampal pathology The specific cellular pattern of neuronal loss is noted in the subiculum of the hippocampal formation and layers II and IV of the entorhinal cortex. The affected cells connect hippocampal formation with the association cortices, basal forebrain, thalamus, and hypothalamus, structures crucial to memory. This pattern of neuronal loss isolates the hippocampal formation from its input and output, contributing to the memory disorder in Alzheimer patients Binswanger's disease This is also known as subcortical vascular dementia or subcortical arteriosclerotic encephalopathy Characterized by the presence of many small infarctions of the white matter that spares the cortical regions Often coexists with AD-type changes # 06 - 2. Lewy Body Dementia (DLB) # 2. Lewy Body Dementia (DLB) © SPMM Course 2. Lewy Body Dementia (DLB)  Lewy bodies are weakly eosinophilic, spherical, cytoplasmic inclusions.  In Parkinson’s disease they are confined to substantia nigra; in DLB they are also present in many areas of the cerebrum including the temporal lobe, the cingulate gyrus and the frontal lobes. They may also be found in the dorsal motor nucleus of the vagus.  Cortical Lewy bodies are less conspicuous, less eosinophilic and lack clear halo compared to those in the substantia nigra. Cortical Lewy bodies take up a homogeneous eosinophilic staining in the cytoplasm, along with a peripheral displacement of the nucleus.  There is no simple correlation between number of Lewy bodies and cognitive decline.  Antibody to protease ubiquitin can be used to identify Lewy bodies.  Lewy bodies--in Parkinson's disease and DLB contain accumulations of alpha-synuclein. Staining with alpha-synuclein antibodies is an excellent tool for detecting both Lewy bodies. DLB is one of the various degenerative synucleopathies.  Alpha-synuclein accelerates reuptake of dopamine in neurons, and this dopamine overload might be toxic.  A high proportion of patients with DLB/PDD (about 75%) also have AD-type neuropathological abnormalities. Here the plaque/tangle burden associated with dementia is less than that seen in Alzheimer's disease.  Lewy neurites—these are nerve cell processes that contain aggregates of -synuclein. These abnormal structures can occur in both DLB/dementia of Parkinson’s disease and idiopathic Parkinson’s disease and are most numerous in the CA2/3 region of the hippocampus and in the substantia nigra.  Some patients with DLB show microvacuolation of the cerebral cortex, predominantly in the medial temporal regions. This can mimic a prion disease. Tauopathies (tau deposits) Tauopathies (tau deposits) •Alzheimer’s dementia •Pick’s disease •Progressive supranuclear palsy •Corticobasal degenerations •Frontotemporal dementia with parkinsonism (FTDP17) Synucleopathies (alpha synuclein deposits) Synucleopathies (alpha synuclein deposits) •Parkinson’s •DLB •Multisystem atrophy # 07 - 3. Frontotemporal Dementia (FTD) # 3. Frontotemporal Dementia (FTD) # 08 - Frontal lobe degeneration type # Frontal lobe degeneration type # 09 - Motor neurone disease (MND) type # Motor neurone disease (MND) type © SPMM Course 3. Frontotemporal Dementia (FTD) FTD is associated with three types of underlying pathology: Frontal lobe degeneration type  Most common type  Spongiform degeneration or microvacuolation of the superficial neuropil is seen chiefly in layers III and V of the cortex.  Loss of large cortical nerve cells with minimal gliosis Pick’s type  Pick's disease is characterized by a preponderance of atrophy in the frontotemporal regions.  These regions also have a loss of large cortical nerve cells, abundant gliosis, and neuronal Pick's bodies, which are masses of cytoskeletal elements.  Abnormal swollen oval-shaped neuronal cells with loss of Nissl’s substance and peripherally displaced nucleus are called Pick cells  Pick's bodies are seen in some postmortem specimens but are not necessary for the diagnosis. These are argentophilic, tau and ubiquitin reactive filamentous inclusions.  Hirano bodies may also be seen albeit with a lesser frequency than in Alzheimer’s. Motor neurone disease (MND) type  Cerebral atrophy is less marked; limbic areas are largely preserved  Loss of large cortical nerve cells, microvacuolation, and mild gliosis.  Ubiquitinated but not tau-immunoreactive inclusions are present within the frontal cortex and hippocampus  MND pathology is also seen in anterior horn cells. HUNTINGTON’S DEMENTIA Pathologically there is severe loss of small neurons in the caudate and putamen with subsequent astrocytosis. Characteristic protein deposits form nuclear inclusions in neurons of HD patients. With the loss of cells, the head of the caudate becomes shrunken and there is "ex vacuo" dilatation of the anterior horns of the lateral ventricles. # 10 - 4. Creutzfeldt Jakob Disease (CJD) # 4. Creutzfeldt-Jakob Disease (CJD) © SPMM Course 4. Creutzfeldt-Jakob Disease (CJD)  Three forms exist: sporadic (most common), familial and variant CJD (vCJD - related to bovine spongiform encephalopathy).  There are no characteristic gross pathologic features of CJD because of the typical short course of the disease. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy.  Microscopically CJD shows a spongiform encephalopathy secondary to neuropil vacuolisation. Many round to oval vacuoles are seen in the neuropil of cortical gray matter - vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis.  Prion protein (PrPc) is a normal neuronal cell surface protein encoded by a gene on chromosome 20. In CJD, this is converted via a conformational change to an abnormal form designated as PrPSc. This abnormal form is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation triggers further conversion of normal PrPc to PrPSc and accounts for the degenerative changes in the cerebral cortex.  The PrP can be identified in tissues with immunoperoxidase staining.  These abnormal PrPSc can be transmitted from one person with spongiform encephalopathy to another person via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes from neurosurgical procedures.  In variant CJD, there is a marked accumulation of the prion protein, and the plaques are florid.  An abnormal protein called 14-3-3 can be found in the CSF by immunoassay, but this protein is nonspecific and may be found in association with viral encephalitis and stroke. It is less frequent in variant CJD.  In familial cases of CJD, the typical EEG changes are often lacking, and the 14-3-3 proteins are absent in CSF in more than 50% of cases.  The presence of particular polymorphisms at codon 129 of PrP may have an influence on susceptibility to disease. The amino acids methionine (M) or valine (V) may be present at this locus. In 37% of healthy persons, both inherited PrP genes code for methionine (M/M), and 50% have M/V. In contrast, 73% of persons with sporadic CJD have the M/M phenotype, and 100% of persons with variant CJD have this phenotype.  MRI is the most useful supportive diagnostic test in variant CJD. A characteristic abnormality seen in the posterior thalamic region (pulvinar sign) is highly sensitive and specific for variant CJD. The pulvinar sign has been found in more than 90% of pathologically proven vCJD cases. FLAIR sequences of MRI are most likely to show the abnormality. © SPMM Course Feature Classic CJD Variant CJD Age Elderly 7th or 8th decade of life Adults in 3rd/4th decade of life Course Shorter course (5 months) More prolonged (1 year) Symptoms Early neurological signs and dementia Early psychiatric/behavioural signs with delayed neurological features EEG Triphasic sharp waves often seen Triphasic waves are rare, and changes are often nonspecific MRI Pulvinar sign is not seen Pulvinar sign is present Biopsy Only a few plaques noted Large number of plaques Tonsils Prion protein cannot be isolated from lymphoid tissue Tonsillar tissue carries prion agent # 11 - 5. HIV associated pathology # 5. HIV associated pathology # 12 - CNS entry # CNS entry # 13 - Mechanism of neuropathogenesis # Mechanism of neuropathogenesis © SPMM Course 5. HIV associated pathology CNS entry  The major HIV-1 receptors are CD4 and CD8; various chemokine receptors e.g. CXCR4 and CCR5 are considered as HIV-1 co-receptors.  CD4+ helper T lymphocytes are the major routes of multiplication and entry, apart from monocytes. Infected CD4+ T cells and monocytes, which circulate in the blood, are the potential source of CNS infection.  The strains of HIV, which are isolated from the brain, have the characteristic of infecting macrophages rather than lymphocytes. Macrophage-tropism is related to a mutation in a specific region of gp120, the external glycoprotein of the virus. In the late stages of the infection, active replication of the virus generates more of these mutants and the compromised immune system permits the escape of these mutants, leading to predominance of macrophage-trophic strains.  In order to enter the brain, HIV-1 must cross the BBB using mechanisms that remain unclear. The generally accepted model is the "Trojan Horse hypothesis". HIV enters the CNS as a passenger in cells trafficking to the brain via CD4 T cells or monocytes. Virus accumulation in perivascular regions has been demonstrated as a proof for the above model.  An alternative hypothesis of HIV-1 neuro-invasion proposes the entry of free HIV-1 by migration between or, transcytosis of endothelial cells. The mechanism of endothelial infection remains a controversial issue – as CD4 expression in endothelial cells is unclear.  Theoretically all the main cell types of the CNS, astrocytes, oligodendrocytes, neurons, perivascular macrophage and microglia, can be infected by HIV-1 since they possess the receptors and/or coreceptors for HIV-1 entry, but only the latter two are the most commonly infected cells by HIV-1. Most studies have indicated an absence of in vivo infection in neurons - It is unclear whether detection of infected neurons is complicated by the loss of the infected neuronal populations. Mechanism of neuropathogenesis  Two components of this mechanism are: 1. The direct effect of the HIV-1 infection 2. The indirect consequence of infection comprising the secretion of cytokines and neurotoxins.  The infected macrophages and microglia participate actively in the neurodegeneration by: 1) shedding viral proteins and 2) releasing significant amount of cytokines and neurotoxins into the CNS. 3) Tat and TNF-α contribute to the disruption of the blood-brain barrier, which in turn become more permeable to infected monocytes and cytokines present in the periphery.  The secreted pro-inflammatory cytokines activate microglia and astrocytes, which in turn secrete neurotoxins. In addition, the alteration of astrocyte function results in an increase in the level of neurotoxicity in the brain.  Neuronal injury via apoptosis is currently believed to be produced by toxic products released directly by HIV-infected macrophages and microglia or by activated astrocytes. Some of these factors have been identified: they include the platelet activating factor, quinolinic acid, nitric oxide, and some # 14 - Biopsy findings # Biopsy findings © SPMM Course metabolites of arachidonic acid, which are neurotoxic, and tumour necrosis factor, which is toxic for oligodendrocytes and can cause demyelination. Biopsy findings The following can be seen in the biopsy of an HIV infected brain tissue 1. Infiltration of macrophages into the CNS 2. Formation of microglial nodules 3. Multinucleated giant cells from virus-induced fusion of microglia and/or macrophages in central white and deep gray matter; 4. Astrocyte activation and damage; 5. Neuronal loss particularly in hippocampus, basal ganglia and caudate nucleus. 6. A variable degree of white matter pathology with myelin damage 7. Accumulation of lipid macrophages in extreme cases Most common psychiatric presentation in AIDS is HIVrelated dementia, followed by depression. Psychosis is seen only in 10% of HIV-infected individuals. VIRAL LOAD The current method used to predict stage of disease, to monitor disease progression, and to formulate treatment strategies is to determine viral load (actual number of viral particles found in a cubic millimeter of blood). HIV-1 can also be detected in the cerebral spinal fluid (CSF). But CSF viral load is not established as an accurate indicator of CNS disease related to HIV. # 15 - 6. Schizophrenia # 6. Schizophrenia # 16 - Gross changes # Gross changes # 17 - Histological changes # Histological changes © SPMM Course 6. Schizophrenia Gross changes  A decrease in brain weight, brain length and volume of the cerebral hemispheres enlargement of the lateral ventricles (especially temporal horns)  Reduced tissue volume in the thalamus, in temporolimbic structures including hippocampus, amygdala, parahippocampal gyrus.  White-matter reductions in parahippocampal gyrus or hippocampus  An increased incidence of a cavum septi pellucidi is noted.  Basal ganglia volume reduction was noted especially in preneuroleptic era, in the catatonic subgroup. Enlargement of basal ganglia is now more common in schizophrenia as a consequence of treatment with classical neuroleptics, which can be reversed by the use of atypical substances.  Schizophrenia-like psychosis is commoner in temporal lobe epilepsy when the focus is in the left hemisphere.  The planum temporale, the posterior superior surface of the superior temporal gyrus, is a highly lateralized brain structure involved with language. In schizophrenic patients, a consistent reversal of the normal left-larger-than- right asymmetry of planum temporale surface area is noted. Heschl's gyrus (primary auditory cortex) showed no differences between the left and right sides. Histological changes  No evidence for astrogliosis in schizophrenia  Reduced cell numbers or cell size has been described especially affecting neurons in the hippocampus and DLPFC.  Increase in neuronal density, which may relate to the observed decrease in neuronal size (with decreased dendritic arborization and a decreased neuropil compartment) has been reported.  Subtle cytoarchitectural anomalies were described in the hippocampal formation, frontal cortex, e.g. a significant cellular disarray in the CA3–CA4 interface  Synaptic studies in the hippocampus and DLPFC in schizophrenia show decrements in presynaptic markers. These changes may reflect a reduction in the number of synaptic contacts formed and received in these areas and supports the hypothesis of excessive synaptic pruning in schizophrenia.  Glutamatergic synapses may be especially vulnerable in the hippocampus and perhaps the DLPFC, with predominantly GABAergic involvement in the cingulate gyrus.  Antipsychotics alter synaptic and neuronal morphology, particularly in the caudate–putamen and may increase glial density in the prefrontal cortex. # 18 - 7. Mood disorders # 7. Mood disorders # 19 - 8. Alcoholic brain damage # 8. Alcoholic brain damage # 20 - 9. Autism # 9. Autism © SPMM Course 7. Mood disorders  A strong association between mood disorder and the number and severity of focal signal hyperintensities on T2-weighted images has been established. These white matter hyperintensities (WMH) occur particularly in the deep subcortical white matter and to a lesser extent in the basal ganglia and periventricular tissue. They are seen in excess in both bipolar and unipolar mood disorder, with an odds ratio of 3 to 7 when compared to healthy controls.  In major depression, WMH are particularly common in elderly subjects, where they are linked to risk factors for, and the presence of, vascular disease. This finding is consistent with a robust epidemiological association between the two conditions.  WMH confer a poor prognosis in major depression and bipolar disorder.  Lithium treatment increases cortical grey matter volume suggesting that lithium is neurotrophic. Lithium may also enhance neurogenesis and inhibit apoptosis  Antidepressants may affect neuronal morphology. These agents help regenerate monoaminergic axons, promote hippocampal neurogenesis and prevent the loss of dendritic spines in animal models. 8. Alcoholic brain damage  Wernicke's encephalopathy is characterized by degenerative changes including gliosis and small hemorrhages in structures surrounding the third ventricle and aqueduct (i.e. the mamillary bodies, hypothalamus, mediodorsal thalamic nucleus, colliculi, and midbrain tegmentum), as well as cerebellar atrophy.  Brain shrinkage can be found in uncomplicated alcoholism, which can largely be accounted for by the loss of white matter. Some of this damage appears to be reversible.  Alcohol-related neuronal loss has been documented in specific regions of the cerebral cortex (superior frontal association cortex), the hypothalamus (supraoptic and paraventricular nuclei), and cerebellum. 9. Autism  Hypoplasia of cerebellar vermis and to some extent the cerebellar hemispheres is documented.  Purkinje cell count in the cerebellum is significantly lower.  Inconsistent changes noted in the neocortex. Some suggest increased cortical volume, probably related to reduced pruning. © SPMM Course Notes prepared using excerpts from:  Belay & Schonberger. Variant Creutzfeldt Jakob disease and BSE. Clin Lab Med 2002;22:849-62  Harrison PJ. The neuropathology of primary mood disorder. Brain 2002;125:1428–49.  Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122: 593–624  Neary, D & Snowden, J. Fronto-temporal Dementia: Nosology, Neuropsychology, and Neuropathology. Brain & Cognition 1996;31:176-87  Love, S. Neuropathological investigation of dementia: a guide for neurologists Journal of Neurology, Neurosurgery, and Psychiatry 2005;76(Supplement 5 ):v8-v14.  Ghafouri, M., Amini, S., Khalili, K., & Sawaya, B. E. (2006). HIV-1 associated dementia: symptoms and causes. Retrovirology, 3(1), 28. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 10 - 36_Applied_Neuroscience # 01 - 1. Lobar functions # 1. Lobar functions # 02 - A. Tests for frontal and parietal lobes # A. Tests for frontal and parietal lobes © SPMM Course 1. Lobar functions A. Tests for frontal and parietal lobes Frontal tests Comments Similarities Comparing two objects to test the ability of ‘categorisation’ and not a description of common ‘parts’. This is a test for abstract ability. Lexical fluency Naming items bought in a supermarket or animals (category fluency) or generation of words starting with alphabets FAS (word fluency). Tests not only the speed and accuracy but also the ability to shift from one set of objects to the next. e.g., supermarket list must include not only fruits, but also baked goods, drinks, cleaning items, etc. Luria motor test Fist palm edge – must not be verbally facilitated. Test for motor planning, execution and error correction. Go/on go test Tests response inhibition, the absence of perseveration and resistance to interference. Cognitive estimates test E.g. ‘How tall is an average English woman?’ Use questions that need abstract not mere factual thinking. Trail making test Consists of two parts. In part, A simple number sequence is used to join the dots. Test B uses alternating numbers and letters and is thought to be more sensitive to frontal lobe dysfunction. Not specific for frontal lobe; tests visuomotor tracing, attention, conceptualisation and set shifting. Other tests Include alternate pyramids and squares drawing, proverb interpretation, and to some extent frontal release signs and digit span (normal: 7±2 forwards, 5±1 backwards) reflect frontal functions. Parietal test Comments Copying shapes Ability to draw shapes and constructing geometrical patterns is a parietal (esp. nondominant) function. Identifying fingers Dominant parietal damage can cause finger agnosia as a part of Gerstmann syndrome. Test for the ability to recognise the touched finger when eyes are closed. Also test for the ability to correctly show one’s index, middle and ring fingers. Interlocking fingers test (ability to copy examiner’s interlocked fingers) is also a parietal test. Calculation ability Dominant parietal damage can cause acalculia as a part of Gerstmann syndrome. Test for simple mathematical functions. Mere recognition and use of numbers constitute arithmetic ability; this is often intact. Graphesthesia Ability to recognise what number or alphabet is scratched on one’s skin without seeing. Bilateral parietal function (somatosensory cortices) Right Left orientation Dominant parietal damage can cause right-left disorientation as a part of Gerstmann syndrome. Test for the ability to touch right ear lobe with the left index finger when eyes are closed. Stereognosis Ability to recognise objects by palpation, and without visual inspection. Bilateral parietal function (somatosensory cortices) Two point discrimination Cortical sensation; bilateral somatosensory cortical function Visual inattention Hemineglect is a feature of parietal lesions. Letter or star cancellation task, line bisection task, draw-a-person or draw-a-tree tasks are useful to identify hemineglect. # 03 - B. Lobar lesions # B. Lobar lesions # 04 - Frontal lobe lesions # Frontal lobe lesions # 05 - Parietal lobe lesions # Parietal lobe lesions © SPMM Course B. Lobar lesions Frontal lobe lesions Parietal lobe lesions Unilateral lesions Bilateral lesions Contralateral spastic hemiplegia Bilateral hemiplegia Slight elevation of mood, increased talkativeness, tendency to joke inappropriately (Witzelsucht) Spastic bulbar (pseudo bulbar) palsy Frontal release signs (grasp and suck reflexes) Abulia (indecisiveness, lack of drive) Anosmia Decomposition of gait and sphincter incontinence Motor speech disorder with agraphia, with or without oro-buccal apraxia (left) Varying combinations of grasping, sucking, obligate imitative movements, utilization behavior. Loss of verbal fluency with perseveration (left) Specific frontal syndromes (pseudo depressive, dysexecutive and pseudo psychopathic) Unilateral lesions Bilateral lesions Corticosensory syndrome and sensory extinction Spatial disorientation & visual spatial defects Mild hemiparesis Bilateral ideomotor and ideational apraxia (more prominent with left-sided lesions) Homonymous hemianopia or inferior quadrantanopia (incongruent or congruent) Tactile agnosia (bimanual astereognosis) (more prominent with left sided lesions) Neglect of the opposite side of external space (right parietal lesions) Anosognosia, dressing and constructional apraxias (may occur with lesions of either hemisphere are more frequent and severe with nondominant right lesions) Gerstmann syndrome (dysgraphia, dyscalculia, finger agnosia, right-left confusion) (left) Balint syndrome GELASTIC SEIZURE An epileptic fit of incessant ‘laughter’, not necessarily euphoria, is called gelastic seizure. This occurs with left prefrontal seizures. # 06 - Temporal lobe lesions # Temporal lobe lesions © SPMM Course Temporal lobe lesions Unilateral lesions Bilateral lesions Homonymous upper quadrantanopia Auditory, visual, olfactory, and gustatory hallucinations Wernicke’s aphasia Dreamy states with uncinate seizures Varying degrees of amusia and/or visual agnosia Emotional and behavioural changes Impairment auditory verbal learning Disturbances of time perception Dysnomia Korsakoff amnesic defect (hippocampal formations) Apathy and placidity Hypermetamorphopsia (compulsion to attend to all visual stimuli), hyperorality, hypersexuality, blunted emotional reactivity (KluverBucy syndrome; the full syndrome is rarely seen) •most common of auras, causing epigastric aura, salivation, sometimes vertigo etc. Autonomic sensations Autonomic sensations •The individual has a compulsion to think on a certain restricted topic. Forced thinking Forced thinking • Intrusion of stereotyped words or thoughts. Evocation of thought Evocation of thought •Similar to schizophrenic thought block is also reported. Sudden obstruction to thought flow Sudden obstruction to thought flow •Recall of expansive memories in incredible detail, as if running a video show of past. Panoramic memory Panoramic memory •Isolated auras with hallucinations, depersonalisations, micropsia or macropsia, déjà vu or jamais vu (especially if right sided origin) Psychic seizures Psychic seizures •Hallucinations of taste and smell associated with dream like reminiscence and altered consciousness. Uncinate crises Uncinate crises • Points to left hemisphere origin. Transient dysphasia Transient dysphasia •Fear and anxiety very common. Strong affective experiences Strong affective experiences •Ecstatic content in epileptic aura. Dostoevsky’s epilepsy Dostoevsky’s epilepsy GESCHWIND SYNDROME This is an uncommon type of personality change reported in epilepsy patients (esp. TLE). Symptoms include hypergraphia, circumstantiality, interpersonal viscosity, hyperreligiosity, and hyposexuality. It is thought to be result of lost connectivity among cerebral areas. This may also explain the personality features Psychopathology of the auras of Temporal lobe epilepsy # 07 - Occipital lobe lesions # Occipital lobe lesions # 08 - C. Neuropsychological tests # C. Neuropsychological tests # 09 - The Wechsler Adult Intelligence Scale (WAIS) # The Wechsler Adult Intelligence Scale (WAIS) © SPMM Course Occipital lobe lesions C. Neuropsychological tests The Wechsler Adult Intelligence Scale (WAIS)  Most widely used intelligence test in clinical practice.  The latest revision, the WAIS-III, is designed for persons 16 to 89 years of age. Wechsler Intelligence Scale for Children-III [WISC-III] is used for <16. For ages, 4 to 61/2 years Wechsler Preschool and Primary Scale of Intelligence-Revised [WPPSI-R] is used.  The WAIS is composed of 11 subtests made up of six verbal subtests and five performance subtests, which yield a verbal IQ, a performance IQ, and a combined or full-scale IQ.  Verbal tests = similarities, arithmetic, digit span, vocabulary, information and comprehension  Performance tests = picture arrangement, block design, picture completion, digit symbol, matrix reasoning (replaces object assembly)  Certain tests are called ‘hold tests’ as they are supposed to be resistant to age-related decline; these tests may be sensitive for organic brain damage such as dementia. In WAIS, hold tests are vocabulary, information, object assembly and picture completion. Non-hold tests are block design, digit span, similarities and digit symbol. A deterioration quotient is derived from the difference between ‘don’t hold’ and ‘hold’ test scores. Unilateral lesions Bilateral lesions Contralateral (congruent) homonymous hemianopia which may be central (splitting the macula) or peripheral; also homonymous hemiachromatopsia Cortical blindness (pupils reactive) Elementary (unformed) hallucinations—usually due to irritative lesions Anton syndrome (visual anosognosia, denial of cortical blindness) If deep white matter or splenium of corpus callosum is involved, alexia and color-naming defect Loss of perception of color (achromatopsia) Visual object agnosia Prosopagnosia (temporo-occipital), simultanagnosia (parieto-occipital) Visual illusions (metamorphopsias) and hallucinations (more frequent with right sided lesions) Balint syndrome (parieto-occipital) # 10 - Other cognitive instruments # Other cognitive instruments © SPMM Course Other cognitive instruments Raven’s progressive matrix is a test for IQ that is independent of education and cultural influences. It taps on general intelligence with visuospatial problem-solving tasks (performance IQ). Reading is an ability that is seemingly resistant to organic brain damage. NART – National adult reading test taps on previous word knowledge before becoming ill. Hence, it is used to estimate premorbid IQ. Stroop test measures set shifting abilities and response inhibition. It is a test of frontal function and the ability to pay selective attention. The Wisconsin Card Sorting Test (WCST) contains stimulus cards of different colour, form, and number. These are presented to patients to sort into groups according to a single principle (e.g., to sort by colour, ignoring form and number). Persons with damage to the frontal lobes or to the caudate and some persons with schizophrenia give abnormal responses. Trail Making Test (TMT - B), Wisconsin Card Sort Test (WCST), Hayling test (Sentence completion), Brixton task, all test set-shifting ability, which is a part of executive functioning. The Wechsler Memory Scale-Revised (WMS-R) is the most widely used memory test battery for adults. The scale yields a memory quotient (MQ), which is corrected for age and generally approximates the WAIS IQ. In amnesic conditions, a disproportionately low MQ but a relatively preserved IQ is seen. WMS consists of the following tests:  verbal paired associate  paragraph retention,  visual memory for designs,  orientation,  digit span,  rote recall of the alphabet, and  counting backward. Benton Visual Retention Test involves the presentation of a geometric figure for 10 seconds, after which the patient attempts to draw the figure from memory. (Short-term visual memory test) The Bender Visual Motor Gestalt Test is a test of visuomotor coordination that is useful for both children and adults. Halstead & Reitan developed a battery of tests that helps to determine the location of specific brain lesions. It consists of Category test, Tactual performance test, Rhythm test, Finger-oscillation test, Speechsounds perception test, Trail making test A and B, Critical flicker frequency, Time sense test, Aphasia screening test, Sensory-perceptual tests. NEUROCOGNITIVE DEFICITS IN SCHIZOPHRENIA Overall deterioration in IQ. Short-term memory disturbances. Deficits in higher order reasoning and perceptual difficulties. Frontal test deficits: Patients perform far more poorly than controls on category test, Wisconsin card sort test, paired associates verbal learning test, Trail B of the Halstead-Reitan battery. # 11 - 2. Consciousness # 2. Consciousness © SPMM Course 2. Consciousness  Consciousness is a state characterised by an awareness of self and environment and an ability to respond to environmental factors; it is made up of two components – arousal (wakefulness) and awareness (attentional processing).  Arousal depends on intact functioning of ARAS – Ascending Reticular activating System. Thalamocortical connections generate rhythmical bursts of neuronal activity (20 – 40 Hz) which are in desynchrony by default. ARAS acting via the thalamic intralaminar nuclei synchronises these oscillations. Arousal is directly proportional to the degree of such synchrony achieved. The absence of arousal produces stupor and coma.  The maintenance of attention appears to require an intact right frontal lobe  Small lesions of ARAS are enough to produce a stuporous state, but large bilateral lesions are required at the cortical level to cause the same depression in alertness.  Stupor: In this state the individual appears to be asleep and yet, when vigorously stimulated, may become alert as manifest by eye opening and ocular movement (Cartlidge 2001). Most patients in stupor have diffuse organic cerebral dysfunction. Caloric testing in organic stupor will usually reveal tonic deviation whereas in a psychiatric stupor (catatonia/depression) ocular nystagmus will be seen (Cartlidge 2001). This is because the following tonic deviation in a conscious subject, a fast phase of correction appears resulting in nystagmus.  Akinetic mutism: It is seen in patients with diencephalic or bilateral anterior cingulate damage. The syndrome is characterised by immobility and eye closure with little or no vocalisation. Sleep/wake cycles can be seen, as indicated by eye opening. There is little in the way of movement to painful stimuli, and the hallmark is the absence of spasticity and rigidity (Cartlidge 2001). Akinetic mutism can arise as a result of lesions that interfere with reticular/cortical integration but spare the corticospinal pathways. There is some debate about whether or not the syndrome should be clearly differentiated from the vegetative state. CJD can also present with akinetic mutism before death.  Vegetative state: This results from the isolated actions of the ARAS and the thalamus in the absence of higher cortical influence due to extensive cortical damage. A patient in the fully established vegetative state will almost invariably show spasticity and rigidity of the limbs, which are absent in patients with the syndrome of akinetic mutism. In the early stages of the vegetative state, the two clinical syndromes are indistinguishable.  Locked in syndrome: Acording to Cartlidge (2001), the ventral pontine or locked in syndrome describes a condition of total paralysis below the level of the third nerve nuclei. Such patients can open their eyes and elevate and depress their eyes to command. Horizontal eye movements are usually lost, and no other voluntary movement is possible. The diagnosis of this state depends on the recognition that the patient can open his eyes voluntarily rather than spontaneously in the vegetative state. This generally results from infarction of the ventral pons, pontine tumours, pontine haemorrhage, central pontine myelinolysis, head injury or brain stem encephalitis. # 12 - 3. Attention and orientation # 3. Attention and orientation © SPMM Course 3. Attention and orientation  Attention can be clinically tested using serial 7s, digit span, spelling ‘‘world’’ backwards, or asking to recite the months of the year or days of the week in reverse order.  Although serial 7s is commonly used, it is frequently performed incorrectly by the elderly, as well as by patients with impaired attention.  A reverse-order month of the year is a highly over-learned sequence and is a preferred measure of sustained attention.  Digit span is a relatively pure test of attention that depends on working memory. Digit span is impaired in delirium, focal left frontal damage, aphasia, and moderate to severe dementia, but preserved in the amnesic syndrome (for example, Korsakoff’s syndrome or medial temporal lobe damage). Normal digit span of 7 +/- 2 varies with age and general intellectual ability. In the elderly, or intellectually impaired, 5 can be considered normal. Reverse digit span is usually one less than forward span.  Orientation is usually assessed in time, place and person; it is worth noting that an intact orientation does not exclude a memory disorder.  Time orientation is the most helpful test and should include the time of day. Many apparently healthy people do not know the exact date, and being inaccurate by two days or less is considered normal.  Time intervals are often poorly monitored by patients with delirium, moderate to severe dementia, and in the amnesic syndrome, and are easily tested by asking about the length of time spent in hospital.  Person orientation includes name, age, and date of birth. Disorientation to one’s own name is usually only seen in psychogenic amnesia.  Orientation to place is affected in reduplicative paramnesia, seen in delirium. # 13 - 4. Executive function # 4. Executive function © SPMM Course 4. Executive function  This includes planning, initiation, sequencing, coordinating, error detection, error correction, set shifting, and termination. It is closely allied to other frontal functions such as judgement, problem solving, impulse control, and abstract reasoning.  Executive function is generally believed to be a dorsolateral frontal lobe function and depends on intact frontal-subcortical circuits.  Impulsivity is thought to reflect failure of response inhibition, and is seen in inferior frontal pathology. It can be assessed using the Go-No-Go task. The examiner instructs the patient to tap once in response to a single tap, and to withhold a response for two taps. This test can be made more difficult by changing the initial rule after several trials (for example, ‘‘tap once when I tap twice, and not at all when I tap once’’).  The ability to switch task, and the inhibition of inappropriate, or perseverative, responses can also be assessed by asking the patient to copy a short sequence of alternating squares and triangles, and then to continue across the page. Perseveration in drawing one or other of the shapes may be seen in frontal lobe deficits, but the test is relatively insensitive.  The cognitive estimates test may prompt bizarre or improbable responses in patients with frontal or executive dysfunction. Although it is a formal test performed at the bedside by asking, for example, the height of the Post Office Tower, the population of London, or the speed of a typical racehorse.  Questions about the similarity between two conceptually similar objects can be used to assess inferential reasoning, which may be impaired in the same way. Simple pairs such as ‘‘apples and oranges’’ or ‘‘desk and chair’’ are tested first, followed by more abstract pairs such as ‘‘love and hate’’ or ‘‘sculpture and symphony’’. Patients typically answer, quite concretely, that two objects are ‘‘different’’ or that they are ‘‘not similar’’ instead of forming an abstract concept to link the pair. This often persists despite encouragement to consider other ways in which the items are alike.  Testing of proverb meanings probably measures a similar skill, but it is highly dependent on educational and cultural background. # 14 - 5. Visuospatial ability # 5. Visuospatial ability # 15 - Neglect # Neglect # 16 - Dressing and constructional apraxia # Dressing and constructional apraxia © SPMM Course 5. Visuospatial ability  Information from the visual cortex is directed towards the temporal or parietal cortex via one of the two streams. The dorsal (‘‘where’’) stream links visual information with spatial position and orientation in the parietal lobe, whereas the ventral (‘‘what’’) stream links this information to the store of semantic knowledge in the temporal lobes.  The frontal eye fields are important in directing attention towards targets in the visual field.  Neglect and constructional apraxia are disorders of visuospatial function. Neglect o Neglect of personal and extrapersonal space is usually due lesions to the right hemisphere— usually the inferior parietal or prefrontal regions. o Left side of personal and extrapersonal space is represented only on right parietal lobe, but right personal and extrapersonal space gets bilateral representation. Hence, a left-sided lesion rarely results in neglect, but right-sided lesion can result in left-sided neglect. o Deficits can be uncovered by simultaneous bilateral sensory or visual stimulation, or having the patient bisect lines of variable length. Letter and star cancellation tasks are similar, more formal tasks. o Visual neglect may produce a failure to groom one-half of body, or eat what is placed on one side of a plate. In extreme cases, patients may have anosognosia and deny they are hemiplegic or even that the affected limb belongs to them. Dressing and constructional apraxia o Although deficits in dressing and constructional ability are termed apraxias, they are best considered as visuospatial, rather than motor impairments. o Copying three-dimensional shapes such as a wire cube, interlocking pentagons (as in MMSE), or constructing a clock-face with numbers are good tests of constructional ability and may also highlight neglect if present. o Dressing apraxia is easily tested by having the patient put on clothing that has been turned inside out. # 17 - 6. Memory # 6. Memory # 18 - Classification of memory # Classification of memory # 19 - Brain structures involved in memory # Brain structures involved in memory © SPMM Course 6. Memory Classification of memory  According to duration:  Immediate memory functions over a period of seconds; closely related to concept of working memory  Recent memory applies on the scale of minutes to days; and  Remote memory encompasses months to years.  According to the type of encoding memory, can be classified into explicit or declarative memory and implicit or procedural memory.  Explicit memory can be either semantic (meanings) or episodic (events). Episodic memory depends on the hippocampal–diencephalic system. It is the time-locked memory for personal events (‘when and where’ memory); it includes both anterograde and retrograde memory. Semantic memory involves memory for word meaning and general knowledge.  The implicit memory includes skills and procedures e.g. car driving.  Working memory refers to the very limited capacity that allows us to retain information for a few seconds.). It is made of a central executive system (attentional system, dorsolateral prefrontal) and at least 2 important buffer systems – the visuospatial sketchpad (right hemisphere) and phonological loop (left hemisphere).  The term ‘‘short term’’ memory is applied, confusingly, to a number of different memory problems, but has no convincing anatomical or psychological correlate Brain structures involved in memory  Hippocampus  Left hippocampus for encoding declarative verbal and right hippocampus for encoding nonverbal memories.  Navigational memory and memory of object location in space are also served by the hippocampus.  Animal studies have defined a hippocampal place code, a pattern of cellular activation in the hippocampus that corresponds to the animal's location in space.  Unilateral hippocampal lesions are compensated well, and clinically significant amnesia does not occur.  Amygdala has been suggested to rate the emotional importance of experience and to regulate the level of hippocampal activity accordingly. It is involved in emotional memory and emotional face processing. It helps in memory consolidation, depending on emotional input for the content of the memory. Amygdalar damage leads to loss of fear conditioning and in monkeys, loss of maternal behaviour has also been noted. Despite the amygdalar damage, learning and consolidation of memory can occur, especially in the absence of emotional valence and arousal.  Diencephalic structures such as the dorsal medial nucleus of the thalamus and the mamillary bodies are associated with new learning; their damage leads to diencephalic amnesia seen in Korsakoff syndrome. # 20 - Disorders of memory # Disorders of memory © SPMM Course  Other regions: In most cases of memory loss procedural memory is intact. A deficit in procedural memory with preservation of declarative memory may be seen in persons with Parkinson's disease, in whom dopaminergic neurons of the nigrostriatal tract degenerate. Though speculative, cerebellum, striatum, amygdala and certain parts of the neocortex (including motor area) are thought to be involved in non-declarative procedural memory storage. The anterior temporal lobe is the key area for semantic memory.  Long-term potentiation: Strengthening of the connection between two neurons on repeated communication is called long-term potentiation - LTP. This may be the neuronal basis of memory. It is mediated by NMDA mediated Ca2+ entry in glutamate neurons. Learning increases branching and synapse formation and may also influence neurogenesis. Disorders of memory  Amnesia is a term used either for pure memory deficits (mostly episodic) or cognitive deficits where memory loss is predominant and not congruent with the level of loss in other domains.  Generally both anterograde and retrograde memory loss occur in parallel, such as in Alzheimer’s disease or head injury.  Relatively pure anterograde amnesia may be seen when there is hippocampal damage, e.g. herpes simplex encephalitis, focal temporal lobe tumours, or infarction.  Confabulation—for example, in Korsakoff’s syndrome—might be grandiose or delusional, but more often involves the misordering and fusion of real memories which end up being retrieved out of context.  A transient amnesic syndrome with pronounced anterograde, and variable retrograde, amnesia is seen in transient global amnesia (TGA), while ‘‘memory lacunes’’, and repeated brief episodes of memory loss suggest transient epileptic amnesia (TEA).  Ribot's Law of retrograde amnesia: ‘The dissolution of memory is inversely related to the recency of the event’. Recent memories are more likely to be lost than the more remote memories in organic amnesia (not always the case though).  Semantic dementia: It is a variant of frontotemporal dementia. Patients with semantic breakdown typically complain of loss of words. Vocabulary diminishes, and patients use substitute words such as ‘‘thing’’. There is a parallel impairment in appreciating the meaning of individual words, which first involves infrequent or unusual words.  A word finding difficulty is common in both anxiety and aging, but variable and not associated with impaired comprehension. This is in stark contrast to the anomia in semantic dementia which Anterograde amnesia Forgetting newly encountered information from the time of a lesion. Presents as forgetfulness regarding appointments, losing items around the home, inability to remember conversation leading to repeated questions etc. Retrograde amnesia Loss of memory of past events that happened before the lesion was sustained. Presents as loss of memory of past events such as jobs, holidays, not able to remember the topography of a route and getting lost. © SPMM Course is relentlessly progressive and associated with atrophy of the anterior temporal lobe, usually on the left.  Working memory deficits can present as lapses in concentration and attention e.g. losing one’s train of thought, inability to process a complex task as the components are not retained long enough in memory to be processed. Basal ganglia and white matter diseases may present with predominantly working memory deficits.  Dissociative amnesia is not an organic syndrome, but centred on the loss of memory of important recent events that is partial, patchy and selective. It can occur as a part of dissociative fugue. The characters of dissociative amnesia are episodic memory loss (retrograde only with no anterograde deficits) for events that happened in a discrete period of time from minutes to years. In dissociative amnesia, the problem is not inefficient retrieval but the strikingly complete unavailability of memories which were formed normally and were previously accessible. The forgotten events are generally traumatic or stressful. # 21 - 7. Language # 7. Language © SPMM Course 7. Language  Aphasia refers to a higher-level language defect despite intact hearing, sound production, articulation mechanisms.  Aphasia is almost always organic. Naming defects (anomia) accompanies any aphasia in various degrees.  To understand aphasia, consider the following facts  Sound received by ears is transmitted to Wernicke’s area and auditory association cortex that processes the language component.  Arcuate fasciculus connects Wernicke’s area to Broca’s area. (NOTE: this is different from the uncinate fasciculus that interconnects the anterior temporal and inferior frontal gyrus)  Broca’s area is the higher motor area of language production. Signals from Broca’s area are relied on onto the motor area to coordinate the delivery of language via the tongue, lips and vocal cords.  Three important components of language are  Fluency depends on intact Broca’s area and its forward connections.  Comprehension depends on intact Wernicke’s area and its connection with association cortex and sensory input  Repetition requires no high-level processing. Repetition can occur if Broca’s, Wernicke’s and arcuate fasciculus are intact. Repetition does not need relay of signals from either Broca’s or Wernicke’s areas to higher association areas. Adapted from Harrison’s Textbook of internal medicine; 15 e  In Broca's aphasia the speech is nonfluent; it often appears laboured with any interruptions and pauses. Function words (propositions, conjunctions) are most affected though the good degree of meaning-appropriate nouns and verbs are still produced. Abnormal word order and a characteristic agrammatism are noted. Speech is telegraphic. Harrison’s Textbook of Medicine quotes the following example: "I see...the dotor, dotor sent me...Bosson. Go to hospital. Dotor...kept me beside. Two, tee days, doctor send me home”.  In Wernicke's aphasia, the comprehension is impaired for both spoken and written language. Language output is fluent but is highly paraphasic, sometimes with string of neologisms and circumlocutions. Hence, it is also termed as "jargon aphasia." The speech contains large numbers of function words (e.g., prepositions, conjunctions) but few substantive nouns or verbs that refer to specific actions. The output is, therefore, voluminous but uninformative, mimicking schizophrenic speech disturbance at times. Type of aphasia Fluency Repetition Comprehension Naming Wernicke’s sensory aphasia Intact Lost Lost Lost Broca’s motor aphasia Lost Lost Intact Lost Conduction aphasia Intact Lost Intact Lost Transcortical sensory aphasia Intact Intact Lost Lost Transcortical motor aphasia Lost Intact Intact Lost © SPMM Course  Pure word deafness: Patient can speak read & write fluently, but comprehension is impaired only for spoken language. Bilateral (or left sided with disrupted connections to non-dominant circuit) damage to the superior temporal pole is suspected.  Pure word blindness (alexia no agraphia): Here the patient can speak normally and comprehend what is spoken; he can also write spontaneously and to dictation, but reading comprehension is impaired. It almost always involves an infarct to the left posterior cerebral artery affecting splenium of the corpus callosum and left visual cortex. So the affected person, who is still able to see with the right visual cortex, cannot undertake lexical word processing making him unable to read.  Pure word dumbness: Spoken language cannot be produced clearly, but the patient can comprehend language well, can read and write.  Pure agraphia: This is an isolated inability to write while other faculties of language are preserved. # 22 - 8. Apraxia # 8. Apraxia # 23 - Types of apraxia # Types of apraxia © SPMM Course 8. Apraxia  Damasio and Geschwind (1985) defined apraxia as a condition with varying combinations of the following disturbances in order of progressive dysfunction: o A failure to produce the correct movement in response to a verbal command, o A failure to correctly imitate a movement performed by the examiner, o A failure to perform a movement correctly in response to a seen object and o A failure to handle an object correctly  Although a number of categories, such as limb kinetic, ideomotor, and ideational, exist, these labels are seldom useful in clinical practice. It is more helpful to describe the apraxia by region (orobuccal or limb), and to provide a description of impaired performance, recording both spatial and sequencing errors on several different types of task.  Apraxia is of limited localizing ability, but the left parietal and frontal lobes appear to be of greatest importance.  Progressive, isolated limb apraxia is virtually diagnostic of corticobasal degeneration. Types of apraxia Functional classification: Apraxia type Definition Localization Constructional apraxia Inability to construct elements into a meaningful whole. e.g., inability to draw or copy simple diagrams or figures. Right cerebral hemisphere, often parietal lobe. Ideational/concept ual Impairment in carrying out sequences of actions (multiple-step task) requiring the use of various objects in the correct order to achieve an intended purpose. The patient does not know ‘what’ to do. Left parieto-occipital and parietotemporal regions Ideomotor (most common type among all apraxias) The disorder of goal-directed movement. The patient knows what to do but not how to do it. Impairment of pantomiming ability to use tool. Abnormalities include the use of body-part-as-object substitution, e.g. the patient uses his own finger to represent a toothbrush when asked to brush his teeth and abnormal orientation of body part performing the action. Improves on imitation and with the use of the actual tool. Tool use is more affected than gestures. Mainly in the left hemisphere; frontal and parietal association areas. Unilateral lesions of the left hemisphere in right-handed patients produce bilateral deficits, usually less severe in the left than in the right limb Regional classification: Buccofacial apraxia (aka facial-oral apraxia) Inability to coordinate and carry out facial and lip movements such as whistling, winking, coughing, etc. on command. The most frequent type of all focal brain lesion related apraxia syndromes. Associated with left inferior frontal lobe and the insula, and commonly accompanies the aphasia caused by lesions of Broca’s area. Limb-kinetic Loss of hand and finger dexterity resulting Dominant frontoparietal or primary motor © SPMM Course from the inability to connect or isolate individual movements. Affects use of tools, gestures, especially distal fingers movements. Can be either ideomotor or ideational type. cortex Other variants Apraxia of speech, apraxia of eyelid opening and apraxia of gait. # 24 - 9. Agnosias # 9. Agnosias # 25 - Visual agnosia # Visual agnosia # 26 - Prosopagnosia # Prosopagnosia # 27 - Colour deficits # Colour deficits © SPMM Course 9. Agnosias Visual agnosia o Visual object agnosia refers to a failure of object recognition despite adequate perception. o Patients with apperceptive visual agnosia have normal vision, but cannot identify and name objects. But these subjects have preserved semantic representation of the object, as evidenced by their ability to name objects in description or touch. This is seen in patients with bilateral occipitotemporal infarction. o In associative visual agnosia, the stored semantic knowledge is affected. Lesions of the anterior left temporal lobe are often seen. o To test for visual agnosia, it is important to assess visual object naming/description and tactile naming, naming described objects, and providing semantic information about unnamed items. Prosopagnosia  The ability to recognise familiar faces is affected in prosopagnosia. But clues such as voice, gait, etc. can aid identification.  The deficit is often not just restricted to faces; fine-grained identification within categories may also be impaired (e.g. types of fruits and flowers).  The underlying semantic knowledge associated with a particular person is not disrupted; so when asked to describe the facial features of a named person, the patient can usually describe this well.  Face processing is a bilateral function; more key areas may be present on the right hemisphere.  Acquired prosopagnosia is usually associated with bilateral or right-sided lesions of the occipital - temporal junction (FUSIFORM GYRUS). In rare cases of prosopagnosia after left-sided lesions in left-handed subjects, it is attributed to a reversed hemispheric specialization for face processing. Colour deficits Achromatopsia Colour agnosia Colour anomia Loss of ability to discriminate colours. (Often associated with pure alexia) Loss of the ability to retrieve colour information stored in semantic knowledge base (E.g. ‘‘What colour is a banana?’’) Disorder of colour naming despite intact perception and colour knowledge (‘‘What colour is this?’’) Medial occipitotemporal damage due to left posterior cerebral artery infarction Left occipito-temporal damage Disconnection of the language structures in the temporal lobe from the visual cortex # 28 - 10. Other neurological deficits # 10. Other neurological deficits © SPMM Course 10. Other neurological deficits Acalculia refers to the inability to read, write, and comprehend numbers. It is NOT the same as anarithmetrica, which is the inability to perform arithmetical calculations. Acalculia can be tested using the simple calculation, writing numbers to dictation, copy numbers and read them aloud, and give reasons for calculated answers. Balint’s syndrome results from bilateral superior-parietooccipital damage (disruption to the dorsal ‘‘where” stream linking visual and parietal association areas). The triad of symptoms is shown in the attached figure. Possible causes include carbon monoxide poisoning, infarction, and Alzheimer’s disease. Gerstmann syndrome is characterized by four primary symptoms: dysgraphia/agraphia, dyscalculia/acalculia, finger agnosia and left-right disorientation. The full presentation of tetrad is rare but occurs with lesions in the dominant angular and supramarginal gyri (parietal lobe). Anton’s syndrome occurs in bilateral occipital damage. The patient denies any deficit and may even attempt to walk and navigate without success. Marchiafava-Bignami disease is due to symmetrical demyelination and necrosis of corpus callosum and adjacent anterior commissure. It is mostly seen in alcoholics using red wine excessively (not clear whether some impurities are implicated). Patients present with sudden onset of stupor or coma and seizures. A chronic onset of dementia and/or gait problems with spasticity is also reported. •inability to attend to more than one item of a complex scene at a time simultanagnosia simultanagnosia •inability to guide reaching or pointing despite adequate vision optic ataxia optic ataxia •inability to voluntarily direct saccades to a visual target oculomotor apraxia oculomotor apraxia # 29 - 11. Cranial nerves # 11. Cranial nerves # 30 - Olfactory nerve CN I # Olfactory nerve CN I # 31 - Optic nerve CN II # Optic nerve CN II © SPMM Course 11. Cranial nerves Olfactory nerve CN I  Only sensory nerve to have no thalamic relay  Unilateral anosmia should raise the suspicion of a lesion affecting the olfactory nerve filaments, bulb, tract, or stria.  Because the cortical representation for the smell in the piriform cortex is bilateral, a unilateral lesion distal to the decussation of the olfactory fibers (i.e. temporal/ uncinate) causes no olfactory impairment.  Frontal meningiomas can cause unilateral anosmia.  Head injury is probably the most common cause of disruption of the olfactory fibers Hyposmia is an early feature of Parkinson’s disease and Alzheimer’s dementia and may precede motor and cognitive signs respectively.  Impaired sense of smell is seen in some patients at 50% risk of Parkinsonism. Optic nerve CN II Syndrome Lesion Unilateral one eye blindness Lesion anterior to optic chiasm e.g. optic nerve itself or retina Bitemporal hemianopia Optic chiasmatic lesion e.g. cranipharyngioma, pineal tumors Homonymous hemianopia – left Lesions of the right sided optic tract, lateral geniculate body, optic radiations and striate cortex (any retro chiasmatic structure) Homonymous hemianopia – right Lesions of the left retro chiasmatic structures Enlargement of the blind spot Any process causing disc swelling Superior quadrantanopia Optic irradiation lesion at temporal lobes of contralateral side Inferior quadrantanopia Optic irradiation lesion at parietal lobes of contralateral side Cortical blindness Occipital cortex lesions  Hemianopia is a field defect covering roughly half of the field. Vertical hemianopia can be nasal or temporal. Horizontal or altitudinal hemianopia can be superior or inferior. If only one-fourth of the field is affected, this is called quadrantanopia.  Bilateral field defects are homonymous when they affect the identical portion of vision in both visual fields  Funnel vision: In patients with organic visual system defect, the visual field projected at 2 metre distance is larger than the field at 1 m. This is seen in glaucoma, retinitis pigmentosa, post papilledema optic atrophy, bilateral occipital infarcts with macular sparing.  Tunnel vision refers to the absence of disparity between 2m and 1m fields on confrontation test. The presence of patchy spirals of field loss is seen in hysteria or malingering.  Cortical blindness often results from simultaneous bilateral posterior cerebral artery occlusion. Patients often have a bilateral homonymous hemianopia with the small central field around the point of fixation (macular sparing or keyhole vision) or complete blindness. Occasionally, patients with cortical blindness deny their visual defect (Anton's syndrome).  The following testing is appropriate for optic nerve: # 32 - Pupillary light reflex # Pupillary light reflex # 33 - The convergence accommodation reflex # The convergence / accommodation reflex # 34 - Oculomotor nerve CN III # Oculomotor nerve - CN III # 35 - Trochlear nerve CN IV # Trochlear nerve - CN IV © SPMM Course 1. Acuity using the Snellen chart (near and distant vision) 2. Visual fields using confrontation test or perimetry 3. Colour vision using Ishihara chart 4. Fundoscopy Pupillary light reflex Afferent fibres in each optic nerve (some crossing in the chiasm) pass to both lateral geniculate bodies and relay to the Edinger-Westphal nuclei (midbrain) via the pretectal nucleus. Efferent (parasympathetic) fibres from each Edinger-Westphal nucleus pass via the third nerve to the ciliary ganglion and thence to the pupil. Light constricts the pupil being illuminated (direct reflex) and, by the consensual reflex, the contralateral pupil. The convergence / accommodation reflex Fixation on a near object requires convergence and is accompanied by pupillary constriction. Afferent fibres in each optic nerve, which pass through both lateral geniculate bodies, also relay to the convergence centre. This centre receives muscle spindle afferent fibres from the extraocular muscles - principally medial recti - which are innervated by the third nerve. The efferent route is from the convergence centre to the Edinger-Westphal nucleus, ciliary ganglion and pupils. Pupils that accommodate but do not react are said to show light-near dissociation. Two important types are Argyll Robertson pupil, seen in neurosyphilis and diabetes (more common these days), and Adie pupil due to peripheral pupillary defect producing a tonic pupil. ARP (note: Accommodation Reflex Present – light reflex absent) is due to an afferent defect in pupillary reflex pathway – possibly pretectal. Oculomotor nerve - CN III  The oculomotor nucleus of the nerve is located in the midbrain  Supplies the levator palpebrae superioris; the superior, inferior, and medial recti; and the inferior oblique muscles.  Lesions of CN III result in paralysis of the ipsilateral upper eyelid and pupil, leaving the patient unable to adduct and look up or down. The eye is frequently turned out (exotropia).  Lesions of the nucleus of the third nerve cause bilateral ptosis, in addition to the findings mentioned above.  Paralysis of CN III is the only ocular motor nerve lesion that results in diplopia in more than 1 direction.  Pupillary involvement is an additional clue to the involvement of CN III.  Pupil-sparing CN III paralysis occurs in diabetes mellitus, vasculitides of various etiologies, and certain brainstem lesions such as due to multiple sclerosis. Trochlear nerve - CN IV The nucleus of the nerve is located in the midbrain. It innervates the superior oblique muscle. Trochlear nerve typically allows a person to view the tip of his or her nose. # 36 - Trigeminal nerve CN V # Trigeminal nerve - CN V # 37 - Abducens nerve CN VI # Abducens nerve - CN VI # 38 - Facial nerve CN VII # Facial nerve - CN VII # 39 - Vestibulocochlear nerve CN VIII # Vestibulocochlear nerve - CN VIII © SPMM Course Trigeminal nerve - CN V  The nucleus of the nerve stretches from the midbrain (i.e. mesencephalic nerve) through the pons (main sensory nucleus and motor nucleus) to the cervical region ( a spinal tract of the trigeminal nerve).  It provides sensory innervation for the face and supplies the muscles of mastication.  Divisions: ophthalmic; V1, maxillary; V2, mandibular; V3.  Corneal reflex:  Afferent – V nerve  Efferent – facial nerve  Complete paralysis of CN V results in sensory loss over the ipsilateral face and weakness of the muscles of mastication. Attempted opening of the mouth results in deviation of the jaw to the paralyzed side.  Acoustic neuroma can press on 5th nerve leading to loss of the corneal reflex. Abducens nerve - CN VI The nucleus of the nerve is located in the paramedian pontine region on the floor of the fourth ventricle. It innervates the lateral rectus, which abducts the eye. Patients complain of double vision on horizontal gaze only. This finding is referred to as horizontal homonymous diplopia. Paralysis of CN VI is a false localising sign as it may result from increased intra cranial pressure. Facial nerve - CN VII  Motor supply to facial muscles from the motor nucleus.  Though it is considered a predominantly motor nerve, it also innervates a small strip of the skin of the posteromedial aspect of the pinna and around the external auditory canal. It serves to conduct taste sensation from the anterior two-thirds of the tongue and relay to sensory nucleus tractus solitarius.  Secrotomotor functions include parasympathetic relay to lacrimal, lingual and submandibular glands.  A lower-motor-neuron lesion of the nerve, results in complete ipsilateral facial paralysis; the face draws to the opposite side as the patient smiles. Eye closure is impaired, and the ipsilateral palpebral fissure is wider. This is called Bell ’s palsy where the cause is idiopathic.  In an upper motor neuron lesion, only the lower half of the face is paralyzed. Eye closure is usually preserved. Vestibulocochlear nerve - CN VIII  2 components – vestibular for balance; cochlear for hearing.  Auditory part tested using 512 Hz – Weber’s test and Rinne’s test.  The Weber test involves holding a vibrating tuning fork against the forehead in the midline. The vibrations are normally perceived equally in both ears because bone conduction is equal. In conductive hearing loss, the sound is louder in the abnormal ear than in the normal ear. In sensorineural hearing loss, lateralization occurs to the normal ear.  In the Rinne test, the vibrating tuning fork is placed over the mastoid region until the sound is no longer heard. It is then held at the opening of the ear canal on the same side. A patient with normal # 40 - Glossopharyngeal nerve CN IX # Glossopharyngeal nerve - CN IX # 41 - Vagus nerve CN X # Vagus nerve - CN X © SPMM Course hearing should continue to hear the sound. In conductive hearing loss, the patient does not continue to hear the sound since bone conduction, in that case, is better than air conduction. In sensorineural hearing loss, both air conduction and bone conduction are decreased to a similar extent.  The vestibular portion transmits information about linear and angular accelerations of the head from the utricle, saccule, and semicircular canals of the membranous labyrinth to the vestibular nucleus.  The Romberg test is performed to evaluate vestibular control of balance and movement. When standing with feet placed together, and eyes closed, the patient tends to fall toward the side of vestibular hypofunction. Results of the Romberg test may also be positive in patients with polyneuropathies, and diseases of the dorsal columns, but these individuals do not fall consistently to one side as do patients with vestibular dysfunction.  Provocative tests include caloric testing. Normally on cold water testing, nystagmus is noted to the opposite side; warm water elicits nystagmus towards the same side. (Remember the mnemonic COWS) Glossopharyngeal nerve - CN IX  The nucleus of the CN IX is anatomically indistinguishable from the CN X, therefore, known as nucleus ambiguous. Its main function is the sensory innervation of the posterior third of the tongue and the pharynx. It also innervates the pharyngeal musculature, particularly the stylopharyngeus, in concert with the vagus nerve.  Vascular stretch afferents from the aortic arch and carotid sinus travel via glossopharyngeal nerve to the nucleus solitarius – important for neural control of blood pressure.  Lesions are affecting the glossopharyngeal nerve result in loss of taste in the posterior third of the tongue and loss of pain and touch sensations in the same area, soft palate and pharyngeal walls.  CN IX and CN X travel together, and their clinical testing is not entirely separable. Vagus nerve - CN X  Starting in the nucleus ambiguous, the vagus nerve has the longest peripheral course of all cranial nerves – it stretches up to splenic flexure of the colon.  Provides motor supply to the pharyngeal muscles (except the stylopharyngeus and the tensor veli palati), palatoglossus, and larynx.  It innervates the smooth muscles of the tracheobronchial tree, esophagus, and GI tract up to the junction between the middle and distal third of the transverse colon.  The somatic sensation is carried on the back of the ear, the external auditory canal, and parts of the tympanic membrane, pharynx, larynx, and the dura of the posterior fossa.  The pharyngeal gag reflex (ie, tongue retraction and elevation and constriction of the pharyngeal musculature in response to touching the posterior wall of the pharynx, tonsillar area, or base of the tongue) and the palatal reflex (ie, elevation of the soft palate and ipsilateral deviation of the uvula on stimulation of the soft palate) are decreased in paralysis of CN IX and CN X.  In unilateral CN IX and CN X paralysis, touching these areas results in deviation of the uvula to the normal side. # 42 - Spinal accessory nerve CN XI # Spinal accessory nerve - CN XI # 43 - Hypoglossal nerve CN XII # Hypoglossal nerve - CN XII # 44 - 12. Traumatic brain injury # 12. Traumatic brain injury © SPMM Course Spinal accessory nerve - CN XI  Spinal root supplies trapezius and sternocleidomastoid. Hypoglossal nerve - CN XII  It provides motor innervation for all the extrinsic and intrinsic muscles of the tongue. To test the hypoglossal nerve, have the patient protrude the tongue; when paralyzed on 1 side, the tongue deviates to the side of paralysis on protrusion. 12. Traumatic brain injury  Traumatic brain injury is the result of mechanical forces applied to the skull and transmitted to the brain. This may lead to focal and/or diffuse brain damage.  Focal lesions often result from a direct blow to the head and include brain laceration, contusion, intracerebral hemorrhage, subarachnoid or subdural hemorrhage, and ischemic infarct.  Concussion causes transient coma for hours followed by apparent complete clinical recovery. Brain contusion leads to prolonged coma, focal signs and lasting brain damage. Pathological support for the distinction between concussion vs. contusion is poor.  Contusion occurs directly beneath (coup injury) or contralateral (contrecoup injury) to the site of impact. Contre-coup is most common in the orbital–frontal area and the temporal tips, where acceleration/deceleration forces cause the brain to impact on the bony protuberances of the skull. A frontal behavioural dyscontrol syndrome occurs in cases of bilateral orbitofrontal injury.  Mechanisms of TBI include axonal and neuronal damage from direct trauma, shearing and rotational stresses on decelerating brain, brain oedema and raised intracranial pressure, brain hypoxia and ischaemia.  The differential motion of the brain within the skull can cause shearing and stretching of the axons resulting in diffuse axonal injury (DAI). DAI related damage occurs over a more widespread area with extensive lesions in white matter tracts than in focal brain injury. DAI is more often associated with persistent vegetative state and coma.  Two types of amnesia can occur after head injury:  Post-traumatic amnesia (PTA) includes anterograde amnesia for the period of injury and the period following injury until normal memory resumes.  Retrograde amnesia includes dense amnesia for the period between the last clearly recalled memory prior to the injury and the injury itself. The duration of PTA is mostly in minutes, and with increasing time after the injury, the duration of PTA reduces gradually.  GCS (Glasgow coma scale) at 24 hours after injury is widely used to assess severity. Apart from GCS other indices of TBI severity include the length of coma (LOC), duration of post-traumatic amnesia (PTA), and the Abbreviated Injury Scale (AIS) scores. LOC and PTA have been used exclusively to predict the functional outcome, but the AIS has been used to predict survival. Most investigations have found LOC or PTA to be more predictive of functional status than GCS.  Poor prognostic factors with respect to psychiatric morbidity following head injury includes long duration of loss of consciousness, long PTA, elderly, chronic alcohol use, diffuse brain damage, new onset seizures and focal damage to dominant lobe. © SPMM Course Duration of PTA Classification Functional outcome PTA less than 60 minutes Mild injury May return to work in <1 month PTA between 1-24 hours Moderate injury May return to work in 2 months PTA between 1-7 days Severe injury May return to work in 4months PTA greater than 7 days Very severe injury May require > 1 year for return to work  Late sequelae o Cognitive impairment is common especially after closed head injuries with PTA lasting >24 hours. o Personality changes are most likely after a head injury to the orbitofrontal lobe or anterior temporal lobe. o Depression (most common sequelae) and anxiety occur in roughly 1/4 of head injury survivors. Suicide risk is also higher post head injury. o Post-concussional syndrome is characterized by headache; dizziness; insomnia; irritability; emotional lability; increased sensitivity to noise, light, etc.; fatigue; poor concentration; anxiety; and depression. o A schizophrenia-like psychosis with prominent paranoia is associated with left temporal injury while affective psychoses (esp. mania in 9% patients) are associated with right temporal or orbitofrontal injury. There is also an increased prevalence of schizophrenia post head injury (-2.5% develop the disorder). o Post-traumatic epilepsy is seen in 5% closed and 30% open head injuries (usually during the first year) and worsens the prognosis. o Less psychopathology in children after head injury due to increased brain plasticity. © SPMM Course Notes prepared using excerpts from:  Barton, JJS. Prosopagnosia associated with a left occipitotemporal lesion. Neuropsychologia. 2008 46(8):221424  Cartlidge, N. States related to or confused with coma. Neurol Neurosurg Psychiatry 2001; 71(Suppl 1):i18-i19  Higgins, E S.& George, MS. Neuroscience of Clinical Psychiatry, The: The Pathophysiology of Behavior and Mental Illness, 1st Edition. Lippincott Williams & Wilkins 2007. Page 16  http://www.emedicine.com/neuro/TOPIC632.HTM  http://emedicine.medscape.com/article/1147993-overview  Katz DI, Alexander MP. Traumatic brain injury: predicting course of recovery and outcome for patients admitted to rehabilitation. Arch Neurol 1994; 51: 661–70  Kipps & Hodges. J. Neurol. Neurosurg. Psychiatry 2005;76;22-30  Koyama T, Tamai K, Togashi K (2006) Current status of body MR imaging : fast MR imaging and diffusionweighted imaging. Int J Clin Oncol 11:278-285.  Lewis DA. Structure of the human prefrontal cortex. Am J Psychiatry. 2004; 161[8]: 1366  Moo et al. J Neurol Neurosurg Psychiatry 2003;74:530-532  Semple et al (Ed). The Oxford Handbook of Psychiatry 1st edition. Oxford University Press 2005.  Zadikoff C and Lang AE. (2005) Apraxia in movement disorders. Brain 128:1480–97 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 11 - 41_Basic_Pharmacology # 01 - 1. Historical overview # 1. Historical overview © SPMM Course 1. Historical overview  In 1915, Macht and Mora coined the term "psychopharmacology" when studying opioid alkaloids on rat behavior in a circular maze.  In 1931 Sen & Bose, Indian physicians from Calcutta, reported on the antipsychotic properties of the plant Rauwolfia serpentine. Reserpine was rediscovered by Kline in 1954.  In 1949, Cade in Australia discovered the use of lithium compounds in mania, initially on the basis of a presumed relationship between urate metabolism and mania. Lithium urate was prescribed to promote the solubility of uric acid. Later he noted that lithium ion itself had calming properties even in healthy controls.  Between 1950 & 1952 presurgical antihistamine chlorpromazine was shown to have antipsychotic effects independently by Delay and Deniker’s team, and Charpentier from Rhône-Poulenc in France. In 1955 Delay coined the term neuroleptic.  The first true antidepressant was discovered in 1952. Mood lifting properties of Iproniazid, an anti-tuberculosis treatment, led to the discovery of the antidepressant class. But hypertensive reactions precluded the large-scale use of iproniazid. Imipramine, which was manufactured as chlorpromazine derivative, came to market soon after.  The first benzodiazepine, chlordiazepoxide (Librium) was discovered serendipitously by the Austrian scientist Leo Sternbach in 1954.  Kuhn (1958) discovered that among the various different psychiatric disturbances ‘endogenous’ depression responded best to imipramine. In 1961, second TCA amitriptyline was introduced.  In 1958, Janssen synthesised butyrophenone haloperidol from pethidine. Wide scale use of antipsychotics started from this time. Antipsychotics came to be known as major tranquilizers while barbiturates and benzodiazepines were called minor tranquilizers. Large scale hospital discharges and deinstitutionalization started.  1963 Cheese reaction was proposed to be the mechanism for MAOI associated hypertension by Blackwell. © SPMM Course  Janssen synthesized an atypical agent risperidone in 1989.  Carlssen synthesized purpose made SSRI Zimeldine – but this was withdrawn due to the incidence of hypersensitivity syndrome and demyelinating disease that followed its use.  In 1970s, Fluoxetine was tested as a noradrenaline reuptake inhibitor but was discarded as it had a poor activity in this regard. Later it was rediscovered as serotonin reuptake inhibitor, reaching the market in 1987.  Kane et al. 1988 rediscovered clozapine via a multicentre randomized design comparing chlorpromazine vs. clozapine in ‘treatment resistant’ schizophrenia. 4% showed response to chlorpromazine while 30% showed response to clozapine.  1990s ‘Prozac era’ – widescale antidepressant prescription started  Reappraisal of suicides associated with antidepressant treatment – ‘black box warning’ issued for prescribing antidepressants to adolescents and children.  CATIE study results published in 2005 – reappraisal of the usefulness of atypical and typical antipsychotics. CuTLASS study from UK follows with a demonstration of no apparent economic gain from atypicals. # 02 - 2. Classification of psychotropics # 2. Classification of psychotropics © SPMM Course 2. Classification of psychotropics Chemical structure Psychotropics ANTIPSYCHOTICS Aliphatic phenothiazines Chlorpromazine, Promazine, Triflupromazine Piperidine derivatives Thioridazine Piperazine derivatives Trifluoperazine, Fluphenazine, Perphenazine, Thioridazine Butyrophenones Haloperidol, Droperidol Thioxanthenes Thiothixene, Flupenthixol, Zuclopenthixol Dihydroindoles Molindone Diphenylbutylpiperidine Pimozide (long t1/2) Dibenzoxapine Loxapine Benzisoxazole derivative Risperidone Substituted benzamides Amisulpride, Sulpiride Dibenzodiazepine Clozapine Dibenzothiazepine Quetiapine Thienobenzodiazepine Olanzapine Benzisothiazole Ziprasidone Arylpiperidylindole (quinolone) Aripiprazole ANTIDEPRESSANTS Tertiary amines Imipramine, Amitriptyline, Clomipramine, Dosulepin, Trimipramine (also Venlafaxine) Secondary amines [more potent; less sedating; more noradrenergic, less antihistaminic or anticholinergic than tertiary] Desipramine, Amoxapine, Nortriptyline and Protriptyline (also Duloxetine) Hydrazine derivatives Phenelzine, Isocarboxazid (greater hepatotoxicity than Tranylcypromine, a non hydrazine compound) Aminoketone Bupropion (amphetamine-like) OTHER PSYCHOTROPICS Azaspironedecanedione Buspirone Triazolopyridine Trazodone, Nefazodone. Imidazopyridine Zolpidem Pyrazolopyrimidine Zaleplon Cyclopyrrolone Zopiclone Benzothiazolyl piperazine Ziprasidone # 03 - Novel agents in the making # Novel agents in the making © SPMM Course Classification by mechanisms of action SSRIs Citalopram, Paroxetine, Fluoxetine, Sertraline and Fluvoxamine, S enantiomer of citalopram - Escitalopram SNRIs – serotonin and noradrenaline reuptake inhibitor Venlafaxine, Milnacipran, Duloxetine, Sibutramine NARI – Noradrenaline reuptake inhibitor – Reboxetine NDDI – Noradrenaline Dopamine DisInhibitor - Agomelatine NaSSA – Noradrenergic and specific serotonergic antagonist – Mirtazapine and Mianserin DARI – Dopamine reuptake inhibitor - Bupropion RIMA – reversible inhibitor of Monoamine A oxidase - Moclobemide SARI – serotonin antagonist and reuptake inhibitors – Nefazodone, Trazodone. Novel agents in the making Xanomeline underwent phase 3 trials as a treatment option for schizophrenia. It acts via M1/M4 agonism Xanomeline showed a trend toward improving cognitive function in Alzheimer’s, and produced robust and dose-dependent reductions in psychotic symptoms in AD. In schizophrenia, early trials showed efficacy in both the positive and the negative symptoms along with improvements in verbal learning and short-term memory but, a high degree of gastrointestinal side effects were observed. Ketamine is a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist that has shown rapid antidepressant effects in treatment-resistant depression. Large scale trials are being undertaken currently. Pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate receptor 2/3 agonist, appeared to be a promising agent for sometime as initial phase 2 studies showed promising efficacy against positive and negative symptoms when used as an add-on therapy in schizophrenia. But this result was not replicated in a later study, mostly due to high placebo response. It is devoid of affinity for dopamine receptors. # 04 - 3. The principles of rational prescribing of # 3. The principles of rational prescribing of psychotropics © SPMM Course 3. The principles of rational prescribing of psychotropics Watchful waiting: When treating conditions such as depression and anxiety, NICE recommends watchful waiting before pharmacological interventions. Start-low go slow: Psychotropic medications should be prescribed at the lowest possible dose and for the minimum duration possible. If the expected improvement does not occur, the formulation and the management plan must be revised. Therapeutic monitoring: Many psychotropics have dose-dependent therapeutic and side effects. Plasma monitoring can be useful in some circumstances (see therapeutic window phenomenon discussed later) Metabolic monitoring: Metabolic side-effects arguably contribute to more days of life lost than any other adverse effects when taking psychotropics. Various classes of psychotropics have specific recommendations as to the frequency and extent of metabolic monitoring. Response assessment: A good follow-up schedule is essential to monitor the effect of prescribed psychotropics. Without this, the purpose of pharmacological treatment will fail. Avoiding polypharmacy: Most national guidelines explicitly recommend avoiding the combination of psychotropic agents, especially antipsychotics. Informed consent: When prescribing, it is imperative that pros and cons of a treatment are discussed in advance to enable the patient to make an informed decision regarding the treatments offered. Patient choice: Guidelines such as NICE recommends that patients must be supported to make the final choice of a specific psychotropic drug for an indication (e.g. antipsychotics for psychosis) from various options provided by the psychiatrist. Off-label use: While off-label use of psychotropics for uncommon, non-specific indications is not recommended; this practice is not illegal per se in most countries. Such practices often have only flimsy or no evidence-based support. The prescriber must explain to the patient if the medication is being used outside its licensed indications and provide the available evidence to demonstrate its effectiveness. CHEMISTRY & STORAGE Drugs exposed to moisture and light can gain moisture quickly – reducing the availability of active excipients. This is termed as hygrophilicity. Some drugs are extremely sensitive to environmental moisture to such an extent that they will turn from crystalline states into pastes or liquids if left in contact with moist air even for a short period of time. A good example of this type of deliquescent material is Sodium Valproate. This property is called as deliquescence. © SPMM Course Long-term prescriptions: When treating chronic illnesses, relevant local & national guidelines should be followed. Information about which medications worked before and which did not should be noted, in addition to noting the adverse effects produced by each of them. # 05 - 4. Placebo effect # 4. Placebo effect © SPMM Course 4. Placebo effect  Placebo is any intervention deliberately used for non-specific psychological or psychophysiological treatment effect. Placebo effect, as defined in research trials, includes any difference in outcome between a placebo-treated group and an untreated control group in an unbiased experiment (Ernst 2001).  Placebos could be pharmacologically active or inert substances, most commonly the latter.  An ‘active placebo’ has some activity inherently, but not against the treated condition.  The term placebo literally translates in Latin meaning ‘to please’. It was coined by an anaesthetist Beecher in 1955.  When a substance administered for placebo effects produces prominent side-effects, it is known as a ‘nocebo’. The term ‘nocebo effect’ (Latin: ‘I shall harm’) refers to the negative consequences, adverse reactions and intolerance resulting from the administration of a placebo. Nocebo effects are usually non-specific e.g. headache and nausea.  Placebo sag is a term used to refer to decrease in placebo effect with repeated or chronic administration of placebo drugs.  The placebo effect may be disproportionately large for non-blinded therapies potentially resulting in what has been called the efficacy paradox.  Placebos work best for pain, disorders of autonomic sensation, and disorders of factors under neurohumoral control e.g. nausea, blood pressure, and bronchial asthma.  Psychiatric disorders such as depression, anxiety and phobias show good placebo response. In depressive illness, the response rate varies from 25 to 60%, in mania it is as high as 25% and in schizophrenia it may vary from 25 to 50%, depending upon the criterion of improvement that is used and other factors. In panic disorder, placebo response rates of up to 70% are seen. More chronically ill patients show lower placebo response rates.  Placebos fail in hereditary degenerative disorders, toxic and metabolic syndromes or vascular events.  Placebo effects are not unique to placebo preparations; they are seen with active drugs too. e.g. a substantial proportion of patients responding to analgesics or antidepressants do so due to the placebo effect. Hence, the net effect of a given drug is thus the sum of the drug's pharmacological effects and the placebo effect.  Physiological changes in opioids and GABA have been proposed to explain some aspects of placebo action; this neuropeptide hypothesis holds good for placebo analgesia, but not proven to operate in other conditions e.g. depression.  Three factors are necessary for placebo action: the nature of the disease treated and the nature of the dynamic relationship between patient and doctor, patients’ expectations and experience with treatment in the past. Gender, suggestibility scores, and IQ do not affect placebo effect consistently. © SPMM Course  Placebos are more effective for clinical than experimentally induced conditions.  Placebos work better for severe than mild pain, but mildly depressed patients respond well than severely depressed ones.  In studies of depression and schizophrenia the difference in improvement in the group of patients on active treatment compared with the group on placebo increases gradually, with little difference until about 2 weeks of treatment and the full difference developing by 6 weeks and it increases progressively for several months.  Those who respond to a placebo for one condition, when treated by one doctor, will not show same placebo response for another condition or another doctor. Hence, there are no homogeneous placebo reactors in the population. This view is furthered by the demonstration that the use of placebo ‘run-in’ approach in antidepressant trials, wherein ‘placebo reactors’ are eliminated before the trial commences, does not actually lower the placebo response rate or increase the drug–placebo difference to a great extent. But such procedures reduce generalisability and pragmatic nature of these trials as placebo responders may be most likely to benefit from a biologically active treatment, and their exclusion makes any estimate too conservative.  A placebo can be a procedure and not a medication e.g. sham ECT, and sham surgeries with the only skin incision.  The placebo response is higher in trials with more than 2 arms compared to those with two arms only (placebo vs. active arms). In a three-armed trial, participants are aware that they have 2 /3 chance of receiving active treatment compared to ½ chance in 2 armed study – hence there is a higher placebo response.  People have individual traits that predispose them to be more or less responsive to certain stimuli; the interaction between the learned associations of the clinical situation and the person’s particular biology produces a response.  Placebo analgesia may be associated with decreased beta-adrenergic activity of the heart as measured by decreased heart rate and low-frequency heart rate variability  Capsules are perceived to be stronger than tablets, producing more placebo effects. Larger pills have stronger placebo effect than smaller pills. The number of pills also influences the perception of pill strength. Multiple pills have stronger placebo effect than single pills.  Anxiety symptoms responded better to green tablets and depressive symptoms responded better to yellow tablets. These are examples of the relative potency of medication varying with pill colour (Schapira et al. 1970).  Injections elicit a stronger placebo effect than oral medications. Surgery is likely better than the others in terms of eliciting placebo effects. Why does a placebo work? © SPMM Course 1. Natural remission theory states that the disorders for which placebo works are inherently episodic (i.e. natural cycles show periods of remission and relapse). Hence even without treatment an improvement would have occurred, and placebo use is merely coincident. 2. Measurement regression: When a continuous variable is measured repeatedly in a sample, with each subsequent measurement the mean of the sample will move from extreme values and become closer to the population mean, the central value. This might explain why there is an apparent placebo response in control groups. 3. Conditioning theory: Placebo is in a way a behavioural intervention. Patients, who have learnt that receiving a medication will improve symptoms, will be showing a conditioned response of improvement when a placebo is administered. Learned associations producing placebo effects can be acquired through conditioning, especially for immune or endocrine conditions.  According to classical conditioning models of placebo effects active medications are Unconditioned Stimuli and the vehicles in which they are delivered (i.e., the pills, capsules, syringes, etc.) are Conditioned Stimuli. The medical treatments that people experience during their lives constitute conditioning trials, during which the vehicles are paired with their active ingredients leading to the unconditioned response of therapeutic benefits initially. These repeated pairings endow the pills, capsules, and injections with the capacity to evoke therapeutic effects as Conditioned Responses later on.  During placebo treatment, the belief of the patient in being treated may result in selective attention to symptom improvement and expectation. The momentary experience of symptom improvement may then act as a reward and positively reinforce preceding changes of autonomic function. Thus, visceral learning due to a mechanism similar to operant conditioning may occur, in which the reward is internally provided  Placebo responses are mediated by conditioning when unconscious physiological functions, such as hormonal secretion, are involved, whereas they are mediated by expectation when conscious physiological processes, such as pain and motor performance, come into play, although a conditioning procedure is performed. 4. The role of endogenous opioids: Endogenous opioids (e.g. endorphins) play a significant role in mediating placebo-induced analgesia. Interestingly, placebo-induced analgesia is partially reversed by administering the opioid antagonist naloxone. Dopamine reward system is being increasingly implicated in placebo effects in psychotropic research. The nature of placebo response in depression is compared with the antidepressant-induced response in depression. Placebo response starts abruptly, occurs early in treatment and is less likely to persist (Quitkin et al., 1991). But the antidepressant response is often gradual, occurs later and is more likely to persist. But the neurobiological correlates of the responses may not be truly © SPMM Course different as shown by Mayberg et al. (2002). Mayberg et al. (2002) observed that the patients in their study whose depression relented after treatment with either fluoxetine or placebo had nearly identical positron emission tomography (PET) brain scans. The ACC is an important anatomical component of the dopaminergic as well as an opioid system and has been activated during placebo analgesia. # 06 - 5. Drug approval # 5. Drug approval © SPMM Course 5. Drug approval Any drug must undergo the following steps before approval is granted by regulatory agencies such as FDA in the US and MHRA in the UK. 1. Preclinical Animal Studies: The pathway a drug must undergo before approval and marketing start with animal studies where the molecule is demonstrated to have specific actions. These extensive preclinical animal studies must be carried out at least on two different animal species. Mutagenicity, carcinogenicity and organ system toxicity are studies at this phase. 2. Human trials – volunteers phase 1: (safety) An investigational new drug then enters human trials. The first phase consists of determining if the drug is safe for human subjects. It is administered to a small group of volunteers and safety; tolerability and pharmacokinetics of the drug are ascertained. They are usually open or uncontrolled studies. 3. Human trials – patients phase 2: (effectiveness) In phase 2 effectiveness is studied in hundreds of patients with target disease in comparison to placebo to see if it works at all against the disease. The main methods are controlled trails or small randomized controlled trials. 4. Human trials – patients phase 3: (superiority or equivalence to standard looking for comparative efficacy) and tolerance profile) In phase 3 the drug undergoes extensive doubleblind RCT to determine how well does it work and what are the common side effects. 5. Human trials – post-marketing surveillance phase 4: Phase 4 takes place if all the previous phases are successfully crossed – the drug undergoes an approval process by regulatory bodies and post-marketing surveillance ensues. Less common side effects, which sometimes could lead to drug withdrawal, can be picked up when large scale prescribing takes place during postmarketing surveillance observations. Psychotropic Drugs Adverse effects detected by post marketing surveillance 1. Nefazadone Hepatotoxicity 2. Droperidol, Thioridazine QT prolongation on ECG 3. Sertindole Sudden cardiac death 4. Thalidomide (analgesic) Phocomelia 5. Nomifensine Hepatotoxicity 6. Zimeldine Hypersensitivity reactions and Guillain-Barre syndrome 7. Remoxipiride(sulpiride group) Aplastic Anaemia 8. Mianserin Blood dyscrasias 9. MAOIs Cheese reactions 10. Clozapine Agranulocytosis # 07 - 6. Medication adherence # 6. Medication adherence # 08 - Adherence measurement tools # Adherence measurement tools © SPMM Course 6. Medication adherence  Compliance is defined as the extent to which a person’s behaviour coincides with medical advice. o Implies sole patient’s responsibility o Criticized as paternalistic.  Adherence includes the concept of patient choice: both clinician and patient share the responsibility for adherence. o In most research, definitions for adherence are usually dichotomous, but adherence is rarely an all-or-nothing phenomenon.  Concordance is based on the notion that the therapeutic alliance between the prescriber and patient is a negotiation process, with equal respect for both the patient’s and clinician’s agenda Adherence measurement tools  Self-report methods:  For example, using the Tablet Routines Questionnaire, which assess the daily routines for taking medication and the proportion of drug an individual has missed in the previous week and last month (Scott and Pope, 2002)  Pill counts  Adherence (%) can be calculated as (number of pills taken ÷ number of pills prescribed) × 100 (Azrin and Teichner, 1998)  Electronic methods  Electronic devices have been developed which can be attached to the tablet bottle. They record the time and date on every occasion that the bottle is opened  Prescription monitoring  The frequency of prescription dispensing for an individual can be monitored as a proxy measure of adherence  Saliva, plasma and urine assay tests  Most objective measures  Not available for all psychiatric drugs – expensive, invasive and have limited value in assessing partial adherence, leading to overestimate of adherence to long half-life drugs. Non-adherence rates are reported as 40–60% for antipsychotics, 18–56% for mood stabilizers and 30–97% (median 63%) for antidepressants. Nonadherent patients with schizophrenia are 3.5 times more likely than adherent patients to relapse within 2 years. # 09 - Factors affecting adherence # Factors affecting adherence # 10 - Improving adherence # Improving adherence © SPMM Course Factors affecting adherence  Patients with poor insight may still take medications – accepting label is less important than enhancing awareness of drug effects  Dose strength – the relationship between dose strength and adherence is probably curvilinear, with very low doses being associated with poor efficacy and very high doses with excessive side-effects  The health belief model of adherence outlines four main belief categories that a patient considers before making a decision regarding prescribed medications: 1. Benefits 2. Costs 3. Susceptibility 4. Secondary benefits of medication and adherence. Improving adherence Adherence enhancement is possible if the patient’s perceptions are altered. Most patient/family directed psychoeducational programmes focus primarily on imparting knowledge without focusing on attitudinal and behavioural change; hence they are largely ineffective in enhancing adherence. Factors with no influence on adherence Factors with no influence on adherence •Age at illness onse •Age at first hospitalization •Sex •Socioeconomic status, •Marital status •Ethnicity Factors that reduce adherence: Factors that reduce adherence: •Asymptomatic stage of illness •Cognitive deficits •Comorbidity – alcohol and substance misuse •Devaluation of medication effects by the physician •Fear of side-effects. •High frequency of daily doses •Homelessness •Lack of insight (most common cause) •Long duration of illness (chronic diseases) •Oral formulations have poorer adherence than depots •Past history of non-adherence •Polypharmacy •Prophylactic or maintenance treatments •Psychopathology of hostility, suspiciousness and disorganization Factors that increase adherence Factors that increase adherence •Presence of family support •Liquid or sublingual forms •High enthusiasm fromclinican •Good patient-clinician relationship •Continued access to clincians © SPMM Course  Cognitive-based interventions target the patient’s attitudes and beliefs towards medication to influence the personal construction of the meaning of medication and illness (Zygmunt et al., 2002).  Behaviour-modification interventions assume that behaviour is learnt and can be modified. Patients are provided with instructions and strategies (e.g. reminders, selfmonitoring tools, cues and reinforcements) to improve adherence (Zygmunt et al., 2002).  Motivational interviewing enables the patient to express personal reasons for and against improving their treatment adherence.  Compliance therapy is a brief intervention based on motivational interviewing and cognitive approaches. In compliance therapy, a patient’s ambivalence towards medication is explored initially, followed by a discussion of the consequences of medication cessation. Analogies with chronic physical illness are made, and the pros and cons of medication are considered during the course of treatment. © SPMM Course Notes prepared using excerpts from:  Deb, S et a (2008). International guide to prescribing psychotropic medication for the management of problem behaviours in adults with intellectual disabilities. World Psychiatry; 8(3); 181-86  Ernst, E. (2001) Towards a scientific understanding of placebo effects. In Understanding the Placebo Effect in Complementary Medicine. Theory, Practice and Research (ed. D. Peters), pp. 17–30. London: Churchill Livingstone.  Ian M Anderson & Ian C Reid. Fundamentals of clinical Psychopharmacology (2nd edition)  Kaur H, Mariappan TT, Singh S. Behavior of uptake of moisture by drugs and excipients under accelerated conditions of temperature and humidity in the absence and presence of light Part-III, Various drug substances and excipients. Pharma Technology 2003:52-56  Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA: The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002; 159:728-737  Oken BS . Placebo effects: clinical aspects and neurobiology (2008), 131, 2812^2823  Patel, M & David, A. Medication adherence: predictive factors and enhancement strategies Psychiatry, 3, 10:41-44.  Quitkin, FM et al (1991) Heterogeneity of clinical response during placebo treatment. American Journal of Psychiatry, 148, 193 -196  Rajagopal, S. The placebo effect. Psychiatr Bull 2006 30: 185-188  Sadock, BA & Sadock, VA (ed). Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins; 8th edition  Ter Riet et al (1998) Is placebo analgesia mediated by endogenous opioids? A systematic review. Pain, 76, 273 -275  The use of drugs in Psychiatry; John Cookson, David Taylor and Cornelius Katona. (5th edition)  Vallance, AK. Something out of nothing: the placebo effect. Advan. Psychiatr. Treat., July 1, 2006; 12(4): 287 - 296. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 12 - 42_Pharmacokinetics # 01 - 1. Principles of pharmacokinetics # 1. Principles of pharmacokinetics # 02 - A. Absorption # A. Absorption # 03 - Oral administration # Oral administration © SPMM Course 1. Principles of pharmacokinetics Pharmacokinetics refers to the time course and disposition of drugs in the body (what the body does to the drug). The pharmacokinetics for the same drug will differ to some extent on the basis of the route of administration of the drug. Commonly utilized routes of administration of psychotropic drugs include oral, intramuscular, intravenous and rectal routes. Other possible routes include inhalation, topical, subcutaneous, sublingual and intra-arterial but are not generally used in psychiatric practice Pharmacokinetics involves the processes of (ADME); Absorption, Distribution, Metabolism, and Elimination. We will consider each of the above processes in further detail below. A. Absorption The route of administration and chemical properties of a drug influences its absorption. The various factors that affect rate of absorption include  The form of the drug (e.g. enteric coating of a tablet slows down its disintegration in the stomach)  The rate of blood flow at the site of administration (higher the blood flow, greater will be the rate of absorption)  Solubility of the drug which depends on the pH of the drug, size of particles in the formulation and the pKa of the drug (pKa is the pH at which precisely half of the drug is in its ionized form) Oral administration This is one of the most common routes of drug administration. It leads to a variable plasma concentration, as the absorption may be erratic and subject to metabolism by liver and gut mucosa (first-pass effect). Drugs absorbed from the gut undergo extensive metabolism before entering the systemic circulation. The main mechanisms of absorption of drugs from the GI tract are 1. Active transport 2. Passive diffusion (most common mechanism) 3. Pore filtration Factors influencing absorption of drugs from GI tract include  Intestinal motility  Gastric emptying  Gastric and intestinal pH  Intestinal microflora  Area available for absorption © SPMM Course  Integrity of blood flow  Presence or absence of food Poor oral absorption leads to lower bioavailability of the drug in plasma compared to intravenous administrations. This is mainly due to lack of absorption from the intestine related to the presence of inhibitory factors like food or gastric acid or due to changes in intestinal motility e.g. having diarrhea or vomiting can affect drug absorption. The presence of food delays gastric emptying. The anticholinergic activity of some psychotropic drugs like tricyclic antidepressants, opiates, etc. can lead to delayed gastric emptying. The intestinal flora or intestinal wall enzymes can have drug-metabolizing activity, which could affect the rate of absorption. For e.g. Chlorpromazine is sulfated in the gut; this reduces its absorption. Site of absorption: The small intestine is less acidic than the stomach and most absorption takes place here. This is aided by a large surface area and long transit time via the small intestine. Although oral administration occurs primarily in the small intestine, the absorption of many ‘slow or sustained release’ drugs occurs in the large bowel. Special preparations: With oral administration, the rate and sometimes the extent, of absorption are largely determined by disintegration and dissolution of the dosage form, both being important for absorption. Tablets and capsules must disintegrate into smaller pieces to expose a greater surface area for absorption. Enteric coating slows down the rate of disintegration. Disintegration is often prolonged by hard compaction or by incorporating wax in a drug matrix. As a result of this, such modified release preparations can prolong the effects of the drugs and reduce peak plasma concentrations and therefore may reduce side effects (E.g. lithium, carbamazepine, sodium valproate, quetiapine XL) Liquids or syrups are more quickly absorbed than tablets because disintegration and dissolution are not required. Dissolution rate is dependent on P-GLYCOPROTEIN Presence of reverse transporters such as Pglycoprotein can affect drug absorption. P glycoprotein pumps certain drug molecules actively out into gut lumen from the gut cells. Inhibition of P-glycoprotein (e.g. by grapefruit juice) can increase absorption of certain medications. The “grapefruit juice effect” is due to components of grapefruit juice - bergamottin, 6,7-dihydroxybergamottin, and naringenin – that significantly increase drug oral bioavailability by selectively and rapidly downregulating intestinal (but not liver) CYP3A4 and to a lesser extent, CYP1A2. This effect is greatest for drugs with high first pass metabolism such as calcium antagonists felodipine and nimodipine, terfenadine, carbamazepine, triazolam and midazolam (to some extent diazepam), simvastatin and methylprednisone. Grapefruit also significantly affects buspirone and pimozide. # 04 - Intramuscular administration # Intramuscular administration # 05 - Intravenous routes # Intravenous routes © SPMM Course 1. Size of drug particle 2. Solubility of the drug 3. Properties of intestinal fluid (e.g. p H) Intramuscular administration With IM administration, absorption occurs over 10-30 minutes. It avoids most of the first pass metabolism. This route could be used in an emergency (acute disturbance, sedation etc.) or for maintenance medications (depot injections). The rate of absorption of drugs administered intramuscularly is dependent on blood flow and aqueous solubility. Lipid soluble drugs are rapidly absorbed; drugs with a relative low molecular weight are better absorbed. Increased muscle blood flow e.g. after muscular exercise increases the rate of absorption. Depot preparations of solutions of drugs in inert oil allowing delay absorption. Intravenous routes IV administration is the most rapid method of absorption and quickest route for achieving therapeutic concentration. It is used mainly in emergency situations. IV administered drug enters systemic circulation rapidly with no first-pass metabolism (100% bioavailability). IV route also carries the higher risk of sudden and life-threatening adverse effects. # 06 - B. Permeation # B. Permeation: © SPMM Course B. Permeation: Permeation of a drug is defined as the lipid membrane permeability of the drug molecule. After oral administration, a drug may be incompletely absorbed e.g. only 40% of a dose of chlorpromazine reaches the systemic circulation. This is mainly due to lack of absorption from the gut. Lipophilicity: Inherent properties of certain drugs can also affect their absorption e.g. highly hydrophilic drugs cannot cross the lipid cell membrane while highly lipophilic drugs will struggle to cross the water layer in the extracellular space. Drugs such as atenolol are too hydrophilic to be absorbed easily, and have a low bioavailability as a result. Apart from lipid solubility, concentration gradient affects permeation. Only free drug forms contribute to the concentration gradient. Hence, protein binding indirectly affects permeation. Permeation can take place either via simple diffusion i.e. along concentration gradient without any specific transport mechanism or facilitated diffusion i.e. along concentration gradient but ‘facilitated’ by the presence of carrier specific mechanisms. Active transport refers to transport against concentration gradient where ATP dependent energy expenditure takes place. Surface area and vascularity of the gut mucosa are important with regard to absorption of drugs into the systemic circulation. Only the nonionized form of a drug can cross lipid membranes of a cell. Many drugs are either weak acids or weak bases. These substances exist in either nonionized or ionized forms in equilibrium, in relation to the pH of the environment and their pKa (the pH at which the molecule is split into 50% ionized and 50% nonionized forms). The ionized form is more water-soluble than the nonionized form. As a consequence, ionized drug is more or less trapped in the glomerular filtrate and does not get reabsorbed. Hence, renal clearance is higher for ionized drugs. A weak base can be ionized by acidifying urine; a weak acid by alkalinising urine. Hence for salicylate (aspirin) overdose, and barbiturate overdose, alkalinization helps to reduce toxicity. Acidification may help in the elimination of amphetamines and phencyclidine (but often complications associated with this procedure overrides any benefits). # 07 - C. Distribution # C. Distribution: © SPMM Course C. Distribution: Distribution of a drug refers to ‘where’ in the body it can be found. Drugs are not evenly distributed throughout the body. Some drugs are confined to the body fluids only, but others accumulate in particular tissues. Drug distribution is influenced by various factors. 1. Hemodynamic factors like cardiac output, regional blood flow. Organs with the highest blood perfusions such as the brain, kidneys, and liver receive the highest distribution and redistribution is seen in the second distribution phase to tissues such as skeletal muscles, adipose tissues and skin. 2. Plasma protein binding 3. Permeability factors- higher the lipid solubility of the drug, the greater its rate of entry into cells. 4. Blood-brain barrier 5. Blood- CSF barrier Distribution can be viewed as the drug achieving equilibrium between different compartments. An approximation of this property is provided by the two compartment model; body is divided into a central compartment made of the plasma and a peripheral compartment made up of fat and other tissues, which vary with age, sex and weight. Distribution of a drug leads to a fall in the plasma concentration (central to peripheral shift) and is most rapid after intravenous administration. Protein binding: The distribution of a drug depends on how protein bound it is. When in the blood, many drugs are bound to circulating plasma proteins. It is the unbound fraction of the drug (free fraction) that can be active i.e. bind to receptors, pass across blood brain barrier, etc. Generally equilibrium exists between the fraction of bound and unbound molecules. Reduced protein-binding increases the free drug fraction and, therefore, the effect of the drug. Plasma protein binding is usually reversible (not covalent). Therefore, changes in protein binding can have profound effects on the availability of the drugs. Drugs that are highly protein bound (>90%), such as phenytoin, are most prone to interactions mediated by this mechanism. For example, diazepam displaces phenytoin from plasma proteins, resulting in an increased plasma concentration of free phenytoin and an increased risk of adverse effects. The effects of protein displacement are usually not of clinical significance, as the metabolism of the affected drug increases in parallel with the free drug concentration. The result is that, although the plasma level of the free drug rises briefly, the increased metabolism rapidly restores the level to the previous steady state. Therefore, any untoward effects of the interaction are normally short-lived # 08 - Blood brain barrier # Blood-brain barrier © SPMM Course (Chadwick et al., 2005). Protein binding interactions become relevant in a renal disease where proteinuria can occur. The principle plasma protein responsible for binding to acidic drugs is albumin while α1-acid glycoprotein is the primary binding protein for alkaline drugs. Most psychotropic drugs are basic, and they may bind to, for example, alpha-1 acid glycoprotein and lipoproteins. Protein binding is 95-99% for drugs like diazepam, chlorpromazine, amitriptyline and imipramine. Protein binding is 90-95% for phenytoin, valproate, and clomipramine. Volume of distribution: Vd =Q/Cp, where Vd-volume of distribution, Q-quantity of drug and Cp-plasma concentration at the time of administration (‘zero time’). Vd refers to an apparent (not true) volume in which an ingested drug is distributed in the body. The higher the Vd, the lower the plasma concentration. Vd tells us about the characteristics of a drug. When Vd is high, this indicates that the drug has a high affinity for tissues outside body water such as brain and fat. The Vd gives some idea of the whereabouts of the drug in the body. A low value (say 10 or 20 litres) suggests that the drug is concentrated in the blood itself. A high value (say 500 or 1000 litres) indicates that the drug is concentrated in the cells or fatty tissues and not the blood. Increased lipid solubility is associated with increased volume of distribution. This is the case for most psychotropic drugs at physiological pH. If a drug is highly protein bound, its plasma concentration will be high (as proteins exist in plasma), resulting in lower Vd. In other words, Vd is restricted by the total plasma volume for highly protein bound drugs. Tissue binding (e.g. fat or muscle) and accumulation of drugs results in low plasma concentration and, as a result, a high Vd. Hence, competition for protein binding can alter Vd. Blood-brain barrier The distribution of a drug to the brain is governed by 3 factors 1. Brain’s regional blood flow 2. Blood-brain barrier 3. Drug’s affinity for receptors in the brain Blood-brain barrier is a structural and functional barrier comprised of the capillary endothelium of the brain, which possesses tight junctions, acting in unison as a single sheet or membrane. © SPMM Course This barrier prevents proteins and other molecules such as immunoglobulins from entering or leaving the brain’s blood supply. It also protects the brain from the entry of bacteria, viruses and maintains an osmotic gradient and maintains the cerebral glucose compartment differently from the periphery. Factors that could affect the permeability of the BBB include fever, head injury, hypoxia, hypercapnia, retroviruses, inflammation, vasculitis, hypertension, cerebral irradiation, and aging. The integrity of the BBB can be measured in different ways e.g. by measuring leakiness to labeled IgG molecules or gadolinium. The ability of a drug to pass blood brain barrier depends on its molecular size, lipid solubility and ionic status. Unionized molecules that are freely available and less protein bound are transported across the barrier easily. In general higher the lipid-water partition coefficient, greater the ability to cross the barrier. Exceptionally there are few molecules that pass the barrier effectively in spite of having a low lipid-water partition coefficient. These have specific carrier mechanisms e.g. aminoacid transport system (this is stereospecific; so l- amino acids not d- amino acids are easily transferred). L-dopa, l-tryptophan and valproate have specific carrier mechanisms. Some small molecules diffuse readily into the brain and CSF from cerebral circulation e.g. lithium ion. Some areas of the brain around the ventricles (circumventricular organs) lack BBB; e.g. subfornical organ, area postrema of the medulla and the median eminence. These circumventricular organs allow the transfer of many compounds from blood to brain. This may have a survival benefit as certain toxic substances stimulate area postrema and induce nausea and vomiting. There is no evidence that inhaled medications bypass the BBB. But to some extent, nasal sprays can reach the brain via olfactory epithelium and bypass the barrier. Anaesthetic agents do not increase the permeability of the blood-brain barrier. In addition to BBB, a blood- cerebrospinal fluid barrier also exists. This is seen in the choroid plexus. Here the tight junctions are located between adjacent epithelial cells, as opposed to adjacent endothelial cells in the case of BBB. # 09 - D. Bioavailability # D. Bioavailability: © SPMM Course D. Bioavailability: Bioavailability refers to how much of an administered drug reaches its target. It is the extent to which the drug reaches the systemic circulation when taken by a patient orally or parenterally, compared with the same quantity of drug given intravenously. In other words, it is the fraction that circumvents the first pass effect and actually reaches the systemic circulation. Plotting plasma concentration against time, for a given dose, provides oral bioavailability. The area under the curve (AUC) after a single dose is proportional to the amount of drug in plasma and allows determination of the fraction of the dose absorbed-the bioavailability. The area under the curve obtained for orally administered drug divided by the area under the curve obtained for intravenous administration of the same dose gives the bioavailability fraction. It is determined by three factors: 1. Absorption 2. Distribution 3. Elimination (metabolism and or excretion). When a drug is administered intravenously, the availability of the drug is 100%. In other words, the amount of drug that enters systemic circulation following IV administration is 100%. This is not the case with extravascular or non-parenteral administrations such as oral, per rectal, inhalational, intramuscular or subcutaneous routes. The reduction in amount reaching circulation is related to the degree of absorption and the effect of ‘first-pass’ metabolism, also called presystemic metabolism. This metabolism is prominent in the gut mucosa, liver and to some extent in the muscle tissue. This explains why higher doses are generally needed orally as compared to intramuscularly. Certain examples of drugs that can undergo a high degree of firstpass metabolism include imipramine (only 30-80% of the oral dose enters systemic circulation) and fluphenazine (only 10% of oral dose enters systemic circulation). Hepatic impairment can reduce first pass metabolism, requiring adjustment of dosages of drugs that are metabolized by the liver. Bioequivalence: It is a measure of comparability of plasma levels of two different formulations of the same active compound when given at same dose and the same route of administration. Two products are said to be bioequivalent when the graphical trace of their plasma level plot against time are superimposable. For this to happen, the two compounds must have the same bioavailability and rate of absorption. Bioequivalence is an important feature to be considered when changing from one brand to another brand of the same compound e.g. camcolit vs. priadel # 10 - E. Metabolism of drugs # E. Metabolism of drugs: © SPMM Course for lithium carbonate or Clozaril vs. zaponex for clozapine. E. Metabolism of drugs: Xenobiotics refer to the mechanism by which a foreign agent such as a drug molecule is metabolized and eliminated from our body. The metabolism or biotransformation of a drug renders it less lipid-soluble and more water-soluble. Therefore, the products of such metabolism are more readily eliminated from the body. The liver is the principal site of metabolism, but metabolism can occur in the gastrointestinal tract, plasma, lungs, kidneys, suprarenal cortex, placenta, skin, and lymphocytes. The four major metabolic routes are oxidation, reduction, hydrolysis, and conjugation. There are 2 phases of drug metabolism.  Phase 1 metabolism includes oxidation, reduction and hydrolysis (often mediated by CYP system, see below), as a result of which a molecule (could be active or inactive) suitable for conjugation is produced. It is not essential that a drug undergo phase 1 metabolism in order to undergo phase 2 metabolism e.g. lorazepam, temazepam and oxazepam undergo direct phase 2 reactions. (As a result, in patients with alcoholic liver disease, oxazepam is favoured for alcohol detoxification instead of chlordiazepoxide which requires intact liver enzymes for phase 1 clearance)  Phase 2 metabolism involves conjugation reactions such as glucuronidation, as a result of which polar compounds (mostly inactive) that are excretable in bile or urine are formed. A drug or drug metabolite from a phase 1 reaction is conjugated to a polar (water soluble) group by phase 2 metabolism. The result of this would be a water-soluble conjugate that can undergo renal excretion easily if it has a relative molecular mass of less than 300. If the relative molecular mass is more than 300, then the excretion would take place through bile. Metabolism usually yields inactive metabolites that are more polar and are easily excreted. Metabolism could also transfer some inactive pro-drugs into therapeutically active metabolites. Cytochrome P450 enzymes: Most psychotherapeutic drugs are oxidized by the hepatic cytochrome P-450 enzyme system. The human CYP enzymes comprise several distinct families and subfamilies. The most studied is CYP2D6. Together with CYP3A4, this constitutes nearly 90% of all psychotropic metabolism. The CYP enzymes are responsible for the inactivation of most psychotherapeutic drugs. These enzymes act primarily in the endoplasmic reticulum of the hepatocytes and cells of the intestine. Therefore, any cellular pathophysiology caused by viral hepatitis or cirrhosis may affect the © SPMM Course efficiency of drug metabolism by the CYP enzymes. There are 3 ways in which drug interactions may influence the CYP system. It includes induction, non-competitive inhibition, and competitive inhibition. Genetic variations in the hepatic enzymes affect the rate of metabolism. Between 5 and 10% of Caucasians lack the enzyme CYP2D6 and are poor metabolizers of corresponding substrates. Up to 15-20% of East Asians are poor metabolizers of CYP2C19 substrates. The table below gives the list of some psychotropics with CYP-mediated drug interactions. Some of the important pharmacokinetic drug interactions involving psychotropics include  SSRIs especially fluvoxamine and fluoxetine inhibit CYP system. Fluoxetine increases plasma tricyclic antidepressants via 2D6 and 2C19. Fluvoxamine increases plasma clozapine concentrations. Clozapine levels may be increased 10-fold by the addition of fluvoxamine, which can induce seizures.  Carbamazepine decreases the plasma concentration of several drugs including contraceptive pills.  Most antidepressants can inhibit the metabolism of warfarin via a complex mechanism resulting in potentially serious bleeding.  Tricyclics and haloperidol compete with each other for same metabolic enzymes.  Carbamazepine and phenobarbitone can induce their own metabolism.  Alcohol, smoking and brussel sprouts are CYP inducers. Grapefruit juice and caffeine inhibit CYP system CYP enzyme Major psychotropics metabolized Effects of psychotropics CYP2D6 All TCAs, fluoxetine, paroxetine, trazodone, nefazodone, valproate, all neuroleptics, risperidone. Paroxetine, to some extent fluoxetine, neuroleptics, amitriptyline and clomipramine inhibit 2D6. CYP3A4 (Most prominent in gut wall mucosa) Clomipramine, fluvoxamine, mirtazapine, nefazodone, Carbamazepine, most benzodiazepines. Stimulated by carbamazepine and barbiturates. Inhibited by calcium channel blockers, fluoxetine, and nefazodone. Smoking induces CYP1A2 via PAH. © SPMM Course Autoinduction: Carbamazepine is metabolized by the hepatic CYP2D6, synthesis of which in turn is induced by carbamazepine. As a result of this autoinduction, the rate of metabolism of carbamazepine (and other P450 substrates) gradually increases over the first several weeks of treatment. The initial steady state may be attained within 4 to 5 days, but autoinduction may delay final steady state until 3 to 4 weeks after treatment initiation. Hence, the level of carbamazepine must be monitored, and its dose often needs to be raised during this early phase of treatment. Chlorpromazine can also induce its own metabolism to some extent. Effect of smoking and caffeine: Smoking and caffeine affect glucuronidation reaction via UGT enzyme and CYP1A2. Drugs which are not dependent on CYP1A2 or UGT for their metabolism are unaffected by smoking or caffeine consumption. For example, risperidone and aripiprazole (metabolized by CYP2D6 and CYP3A), quetiapine (mainly metabolized by CYP3A), and ziprasidone (mainly metabolized by an aldehyde oxidase and CYP3A) are unaffected. But the metabolism of clozapine and olanzapine is mainly dependent on CYP1A2 and UGTs. Because caffeine competitively inhibits CYP1A2, it increases the levels of clozapine and olanzapine while Polyaromatic Hydrocarbons (PAH) in cigarettes induce the enzyme. The effects of inhibitors (caffeine) are seen sooner than those of inducers (smoking), which require fresh synthesis of CYP1A2 enzymes to produce an effect (de Leon, 2004). ALCOHOL BREAKDOWN Four distinct pathways for ethanol degradation have been described - 3 oxidative pathways and 1 non-oxidative pathway. Each of the oxidative pathways starts with the oxidation of ethanol to acetaldehyde, which is then oxidized to acetate for subsequent extra-hepatic activation to acetylCoA. The first pathway which contributes for >90% breakdown in Caucasians, utilizes cytoplasmic alcohol dehydrogenase, the second oxidative pathway uses the endoplasmic reticulum Microsomal Ethanol Oxidizing System (MEOS or CYP450 2E1) and the third pathway uses peroxisomal catalase. The nonoxidative pathway for ethanol metabolism is less well characterized but produces fatty acid ethyl esters (FAEEs) as primary end products. # 11 - F. Excretion # F. Excretion: © SPMM Course F. Excretion: The major routes of drug excretion are via urine, faeces and bile. Psychotropic drugs are also excreted in sweat, sebum, tears, saliva and breast milk. Both active forms and inactive metabolites can be excreted. Ionized and non-lipid soluble compounds are the most suited forms for renal excretion. The factors influencing excretion include  Increased age (decreases excretion)  Reduction in renal blood flow e.g. dehydration  Renal impairment leading to decreased renal function  Alterations in re-absorption: urine pH. (Changes in the p H of the tubular filtrate can alter the rate of elimination of the drugs. Normally urine is weakly acidic and good for excretion of drugs such as tricyclics and amphetamines. Alkaline diuresis is required to enhance elimination of drugs such as aspirin or phenobarbitone in overdose) and low sodium (Low sodium increases lithium reabsorption and decreases excretion leading to consequent toxicity) Clearance: Clearance is the term used to describe the rate of elimination of a drug. Clearance is defined as the volume of blood cleared of a particular drug in unit time. Total body clearance depends on renal and nonrenal clearance such as sweat, bile, etc. Clearance is directly proportional to the volume of distribution. Cl=k x Vd, Where the constant of proportionality, k, is the first order elimination constant. Clearance is specific for each drug and does not depend on drug concentration in plasma (because if concentration increases, elimination will also increase under first order kinetics). It represents the relationship between the rate of drug elimination (t1/2) and plasma level. For drugs with first order kinetics, clearance is constant irrespective of dose consumed because the rate of elimination is directly proportional to plasma level. Renal elimination without significant liver breakdown is seen for drugs such as lithium, amisulpride, sulpiride, gabapentin, acamprosate and amantadine. Both sulpride and amisulpride have up to 90% elimination via renal route – a minor portion is excreted via the biliary system. Amisulpride produces 2 weak metabolites following limited hepatic breakdown. Half-life: The half-life of a drug refers to the time taken for the plasma concentration of a drug to halve. It is represented by the expression ‘t1/2’. Following intravenous injection, there is a rapid # 12 - G. Elimination kinetics # G. Elimination kinetics: © SPMM Course fall in the plasma drug concentration, which is caused by redistribution of the drug from the blood circulation into other tissues. The time taken for this redistribution to halve the initial peak concentration is the distribution half-life. Following this, the process of drug elimination occurs. The time taken by this elimination process to halve the plasma drug concentration is the elimination half-life. Most often, clinicians are interested in the elimination half-life. G. Elimination kinetics: Drugs can undergo two different types of clearance (similar to absorption) when administered. When a constant fraction of drug is cleared per unit time, it is called as first order kinetics. This means that when the amount of drug in plasma or dose of administered drug increases, the clearance proportionately increases as a stable fraction of plasma concentration. In other words, the higher the amounts of a drug present, the faster the elimination. When represented graphically, first-order elimination follows an exponential decay versus time. Using this exponential curve, the time to eliminate 50% of a given amount (or time to achieve a decrease in plasma level to 50% of original) is the elimination half-life (t1/2). For example, if t1/2 is 2 hours for a drug A then the plasma concentration changes as follows 100mg/ml (2hours) 50mg/ml (2hours)  25mg/ml (2hours) 12.5mg/ml Most psychotropic drugs follow first order kinetics. In first order kinetics, the rate depends only on the drug concentration. It is not dependent on any other rate-limiting step. When the system facilitating such clearance of drugs gets saturated, drugs follow zero-order kinetics. Here a constant amount, not a fraction, of the drug is cleared per unit time. This means that irrespective of the amount of drug in plasma or dose of drug administered, the body clears only a fixed unit of the drug. As such, increasing dose might result in serious toxicity in this case. Certain drugs have propensity to undergo zero order kinetics even at therapeutic dose levels. Here the concept of half-life does not hold true as ‘half life’ depends on the dose administered. 100mg (2hours) 80mg (2hours)  60mg (2hours) 40mg In the above example, 20mg of the drug is metabolized in every 2 hours. The apparent ‘half-life’ of 100mg dose is about 5 hours, but the apparent ‘half-life’ of 80mg dose is only 4 hours. Slow release preparations (e.g. lithium MR, depot preparations) follow zero-order absorption kinetics; drugs that rapidly saturate enzymes such as alcohol and phenytoin follow zero-order elimination kinetics. In very high supratherapeutic doses, saturation of enzymes can happen for drugs such as fluoxetine, wherein first order elimination switches to become zero order. Note that in zero order kinetics, the rate does NOT depend on the drug concentration; it depends on some other rate limiting step e.g. availability of enzymes, slow release formula, etc. © SPMM Course Steady state: When a drug is administered episodically, the plasma values acutely rise immediately after administration and then fall when the continuous input of drug does not take place. But before the fall in levels reaches a flat trough, the next dose gets administered (depending on t ½ of the specific drug, dosing interval varies). Hence, the actual plasma level starts building up gradually with every subsequent dose. It is estimated that it takes 4-5 t½ for a drug to reach the steady plasma level. When steady state is reached, fluctuations in plasma level do not get eliminated. But the average plasma concentration between 2 successive doses remains the same. Steady state is reached when for a given drug, rate in = rate out. The time to reach steady state is dependent on the elimination t½ of a drug; the actual level of the steady state is independent of the frequency of administration; instead it depends on the actual dose administered. Loading doses can help achieving steady state more rapidly. # 13 - 2. Indices of safety and efficacy # 2. Indices of safety and efficacy: © SPMM Course 2. Indices of safety and efficacy: Quantal or dose-response curves: Quantal curves plot the percentage of a population showing a specified, predefined categorical drug effect against the dose or log dose administered. The doseresponse curve plots the drug concentration against the continuous effects of the drug. Using these curves, the median effective dose, or median toxic doses can be determined. The median toxic dose is the dose at which 50% of patients experience a specific toxic effect, and the median effective dose is the dose at which 50% of patients have a specified therapeutic effect. In addition, using these curves the range of intersubject variability in drug response could be studied. Steep D-R curves reflect little variability; flat D-R curves indicate great variability in patient sensitivity to the effects of a drug. The therapeutic index can be determined using these curves. Therapeutic index: It is the relative measure of the toxicity or safety of a drug. It is defined as the ratio of the median toxic dose to median effective dose. In other words, it is the ratio of the minimum plasma concentration causing toxic effects to that causing a therapeutic effect. This can vary according to the toxic symptom specified for a given drug. For example, the gastrointestinal toxicity of lithium can occur at a lower plasma concentration than that for seizures. In the laboratory this is usually determined using the median lethal (LD50) and median toxic dose (TD50) in animal studies. In humans, this is identified using ‘minimal’ effective and ‘minimal’ toxic doses using trial data. Note that the term therapeutic index is only relevant when considering dose-dependent side effects; it is not useful when studying idiosyncratic reactions. Therapeutic index range: Certain drugs such as lithium, carbamazepine and phenytoin have a narrow range of plasma levels within which the efficacy is optimum and toxicity is less evident; crossing this range on higher side will increase toxicity while on the lower range will reduce efficacy. Drugs with the low therapeutic index or narrow therapeutic range will require plasma monitoring. Therapeutic window: This term is often confused with therapeutic safety range. In fact, this term is used to describe a specified plasma concentration value, only within which certain drugs appear to have a therapeutic efficacy. This does not concern the side effects or toxicity. Imipramine, nortriptyline, and desipramine have a curvilinear relationship when plasma levels are plotted against the therapeutic response, i.e. very high or very low levels do not help the patient. # 14 - 3. Variables affecting pharmacokinetics # 3. Variables affecting pharmacokinetics: # 15 - A. Changes in the elderly # A. Changes in the elderly © SPMM Course 3. Variables affecting pharmacokinetics: A. Changes in the elderly Domains Change Effect Body composition An increase in total body fat. A decrease in total muscle mass (lean body mass). A decrease in total body water. A larger volume of distribution and longer half-life of lipophilic chemicals because of their increased sequestration in fat. e.g. benzodiazepines excretion slower in the elderly Plasma protein Decrease in plasma protein binding capacity in elderly individuals Nearly 15-25% - due to higher proteinuria and to some extent due to lesser plasma protein synthesis by the liver. Albumin decreased; protein affinity decreased; acid glycoprotein increased. Higher free drug plasma concentration – increased metabolism and clearance of the free drug. More frequent protein binding interactions. Phenytoin is affected Liver Hepatic metabolism not altered much. Decreased hepatic blood flow occurs. Liver withstands aging to considerable extent unless associated physical frailty present. No changes noted up to age 60 - 80. After 80, CYP system declines. Phase 2 (conjugation) metabolism is not affected (Hence lorazepam better than diazepam for elderly). Decreased hepatic first pass effect. Higher oral bioavailability of certain agents. Kidney Decreases in renal blood flow have been approximated at 10% per decade beginning after the fourth decade - leads to reduced creatinine clearance and GFR. More frequent toxicity of renally eliminated agents (e.g. lithium). GI tract Absorption is not greatly affected. GI blood flow is diminished. Gastric pH is increased as acidity drops. Slower but nearly equal absorption of oral administered drugs. Decreased gastric first pass metabolism noted. A reduction in the gastric wall content of dopa decarboxylase Leads to a 3-fold increase in the concentration of levodopa in the elderly. Brain receptors Decreased number of brain acetylcholine postsynaptic receptors; choline acetyltransferase is diminished, level of brain acetylcholinesterase also decreased during aging. Some of these counterbalance each other. On the whole anticholinergic side effects more pronounced leading to increased frequency of delirium on polypharmacy. Kidney mass has been reported to be substantially reduced in old age, by approximately 20 to 25% between the age of 30 and 80 years. Renal blood flow reduces with age even in those with normal health. Renal blood flow decreases by about 10% per decade after the age of 20. By age 80, RBF # 16 - B. Changes in neonates # B. Changes in neonates: # 17 - C. Changes in pregnancy # C. Changes in pregnancy: # 18 - D. Changes with renal impairment # D. Changes with renal impairment: © SPMM Course may be 600ml/min as compared to 1200ml/min in young adults. Creatinine measurements can yield spurious results; hence GFR formulas must be used to correct for age and other variables. Nearly 40% renal function is lost by the age 80. The average decline is around 10mL/min/1.73m2 per decade after age 30. This takes an adult GFR from 130mL/min/1.73m2 to a value of 80mL/min/1.73m2 when the age is 80 (The Baltimore Longitudinal Study). B. Changes in neonates:  Neonates have a higher proportion of total body water and extracellular body water  Neonates have a lower proportion of adipose tissue.  The glomerular filtration rate is lower in those aged less than 3-5 months  Neonates have lower gastric acidity and have an increased gastric emptying time  Neonates have a more permeable blood—brain barrier  The microsomal enzyme activity in the liver is lower in those than 2 months  Neonates have a lower plasma concentration of albumin C. Changes in pregnancy: Pregnancy is associated with several pharmacokinetic changes:  Delayed gastric emptying,  Decreased GIT motility,  Increased volume of distribution (5%),  Decreased drug-binding capacity,  Decreased albumin level  Induced liver metabolic pathway,  Increased GFR & renal clearance. Psychotropic medication usually passes from the maternal blood to the foetus due to lack of strong barrier, but rate and amount of transfer are variable. Higher doses are associated with higher serum level in the infant. D. Changes with renal impairment:  Benzodiazepines should be used with caution  The half-life of diazepam remains unchanged in end-stage renal disease, but its metabolite, desmethyldiazepam, may accumulate, causing excessive sedation.  The half-life of lorazepam is increased from 8–25 hours in healthy adults to 32–72 hours in end-stage renal disease  At a low level of renal function, lorazepam dosage should be reduced by 50% to avoid © SPMM Course excessive sedation.  Imipramine and amitriptyline can be given at their usual dosage as renal impairment does not increase their half-lives  Half normal dose is used for citalopram in patients with renal impairment or in elderly  The half-life of paroxetine is considerably increased with severe renal impairment, requiring dosage reduction.  The dosage of fluoxetine and fluvoxamine does not have to be reduced in the elderly or patients with renal impairment  Sertraline manufacturers do not recommend its use in renal impairment  Haloperidol does not require a dose reduction in renal impairment unless excessive sedation or hypotension occurs.  Amisulpride is renally excreted almost exclusively. Hence, renal failure will be a relative contraindication to use this drug. Product monograph suggests alternate day dosing or dose reduction if no other alternatives are possible.  Risperidone and its active metabolite 9-hydroxy-risperidone are substantially excreted in the urine so that in renal impairment the elimination half-life is prolonged  Lithium is best avoided or given at low dosages. # 19 - 4. Clinically relevant kinetics and interacti # 4. Clinically relevant kinetics and interactions: # 20 - A. Tricyclic antidepressants # A. Tricyclic antidepressants: © SPMM Course 4. Clinically relevant kinetics and interactions: A. Tricyclic antidepressants:  The tricyclics are orally well absorbed but have variable time to achieve peak plasma concentration (1 to 12 h).  Many of them have active metabolites – see table below.  Nearly 7-9% Caucasians are slow metabolizers (measured by debrisoquin hydroxylation) of tricyclics due to CYP2D6 polymorphism (Up to a 40 times difference in plasma TCA concentrations can occur as a result).  Children clear more tricyclics from their body whereas the elderly clear less.  Most tricyclics have a long half-life (close to 24 h) that allows once-daily dosing. They readily cross lipid barriers such as blood-brain barrier and placenta.  They are extensively bound to plasma proteins e.g. Imipramine 80-95%.  For TCAs plasma (not serum) levels are measured to assess therapeutic dosing. The levels are determined after 5-7 days when steady state is reached, and 8-12hrs after last dose to avoid false peaks earlier when absorption is occurring. A sigmoidal curve where proportional doseresponse plateaus at a particular dose is noted for imipramine and desipramine. For nortriptyline a clear therapeutic window is seen between 50 to 150ng/ml. This inverted U is not due to decreased responsivity secondary to side-effects.  Amitriptyline and clomipramine decrease the metabolism of morphine and may contribute to opioid toxicity through UDP glucuronyl transferase interaction. (Chadwick 2005) Antidepressant Active metabolite Imipramine desipramine Amitriptyline nortriptyline Trazodone, nefazodone mCPP Fluoxetine norfluoxetine Sertraline desmethylsertraline © SPMM Course Drugs Mechanism Effect Quinidine, cimetidine, fluoxetine, paroxetine, phenothiazines, disulfiram, methylphenidate Inhibit TCA metabolism Increase plasma TCA levels Smoking, phenytoin, carbamazepine, OC pills and barbiturates Induce metabolism Reduce TCA levels Phenothiazines Mutual inhibition of metabolism Both antipsychotic and TCA levels increase Anticoagulants TCAs increase warfarin levels High risk of bleeding Clonidine TCAs reduce clonidine levels Hypertensive crisis MAOIs Synergistic serotonergic enhancement esp. clomipramine TCAs reduce tyramine entry via monoamine reuptake channels Higher risk of serotonin syndrome Lower risk of cheese reaction l-dopa TCAs reduce absorption of l-dopa Lowers l-dopa efficacy in Parkinsonism Morphine Amitriptyline and clomipramine decrease the metabolism through UDP glucuronyl transferase interaction Increased opioid toxicity # 21 - B. SSRIs # B. SSRIs © SPMM Course B. SSRIs  The SSRIs are rapidly absorbed. Sertraline availability may be increased by the presence of food.  Most are highly protein bound except escitalopram which is 56% bound.  Fluoxetine is metabolized to norfluoxetine, which has similar activity on 5-HT reuptake as fluoxetine. The half-life of norfluoxetine is 4–16 days while t1/2 of fluoxetine itself is 4–6 days.  Similarly, sertraline metabolite has longer half-life but unlike norfluoxetine it is not a potent reuptake inhibitor.  Desmethylcitalopram is a potent noradrenaline uptake inhibitor but not produced sufficiently and weakly crosses the blood–brain barrier.  Fluvoxamine and paroxetine do not have active metabolites.  Both fluoxetine and paroxetine are capable of inhibiting their own clearance at clinically relevant doses. As such, they have nonlinear pharmacokinetics: changes in dose can produce proportionately large plasma levels.  The half-life is not related to time to onset of action, but it is relevant for discontinuation reactions. Fluvoxamine Sertraline Escitalopram Citalopram Fluoxetine Paroxetine Lower end: Greatest nonlinearity of kinetics Unpredictable side effects © SPMM Course  Selectivity: Citalopram is the most selective (and escitalopram) while paroxetine is the most potent. Fluoxetine weakly inhibits noradrenaline reuptake and binds to 5-HT2C receptors; sertraline weakly inhibits noradrenaline and dopamine reuptake. Paroxetine has significant anticholinergic activity at higher dosages and binds to nitric oxide synthase. Fluoxetine & olanzapine when taken together increase brain concentrations of noradrenaline.  Dosing: Apart from depression and GAD, panic disorder, OCD, OCD spectrum disorders and bulimia respond to SSRIs. OCD may need a higher dose for several months for the effects to become evident. Fluoxetine treatment of bulimia is best given together with psychotherapy. Again higher dosages are required. SSRIs are useful in premenstrual dysphoria (PMDD) where sertraline or paroxetine used either daily or only during luteal phase produces a positive effect. Intermittent dosing is usually as effective as continuous administration. Beneficial effects are seen very quickly in one to two days, but proof of efficacy is lacking.  Fluvoxamine reduces the clearance of both diazepam and its active metabolite, Ndesmethyldiazepam, there is a strong likelihood of substantial accumulation of both. Accordingly, diazepam and fluvoxamine should not ordinarily be co-administered.  Citalopram is metabolized by CYP2C19 initially and then by CYP2D6. CYP3A3 and CYP3A4 are responsible for demethylation of sertraline. Drug CYP450 Profile Interacting psychotropic drug Effect Clinical notes Fluoxetine Inhibits 2C19, 2D6. Partially metabolized by 2D6. All TCAs especially Clomipramine Imipramine (both 2C19 & 2D6), Citalopram, Sertraline, Moclobemide, Duloxetine, Mirtazapine Venlafaxine. Levels of these drugs increase in plasma. Potential TCA toxicity. Associated with therapeutic benefit? Effect may last up to 2 weeks after stopping fluoxetine. Paroxetine Predominantly metabolized by 2D6. Inhibits 2D6 All TCAs Citalopram, Fluoxetine, Fluvoxamine, Duloxetine, Mirtazapine, Venlafaxine. Levels of these drugs increase in plasma. Potential TCA toxicity, may be associated with therapeutic benefit when combined. May have non-competitive inhibition resulting in unpredictable effect in combinations. © SPMM Course  The autoinhibition of CYP2D6 is responsible for nonlinear pharmacokinetics of paroxetine and at least partially for the nonlinear pharmacokinetics of fluoxetine.  Fluvoxamine reduces the clearance of theophylline approximately 3-fold via CYP1A2 inhibition. Therefore, if theophylline is co-administered with fluvoxamine, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine.  When fluvoxamine is administered with warfarin, warfarin plasma concentrations increases by 98% and prothrombin times are prolonged. Hence, anticoagulant dose must be adjusted accordingly. Fluvoxamine Inhibits 1A2, 2C19, 3A4 Clomipramine, Doxepine, Trimipramine Duloxetine, Mirtazapine Citalopram, Escitalopram, Sertraline Trazodone. Levels of these drugs increase in plasma. Potential TCA toxicity. Duloxetine Inhibits 2D6, similar to SSRIs. All TCAs Citalopram, Fluoxetine, Paroxetine, Fluvoxamine, Mirtazapine, Venlafaxine. Levels of these drugs increase in plasma. Potential TCA toxicity especially at higher dose - may not be clinically meaningful at lower doses. Desipramine, Clomipramine Inhibits 2D6 All TCAs Citalopram, Fluoxetine Fluvoxamine, Duloxetine, Mirtazapine Venlafaxine. Can increase levels of these drugs Potential serotonin toxicity. SSRI Plasma elimination half-life Linearity of pharmacokinetics Single dose Multiple dose [active metabolite] Paroxetine 10h. 21h. Nonlinear Fluvoxamine 11h. 14h. Nonlinear Sertraline 26h. 26h. [36h.] Linear Citalopram 33h. 33h. Linear Fluoxetine 1.9 days 5.6 days [7-15 days] Nonlinear # 22 - C. Other antidepressants # C. Other antidepressants © SPMM Course C. Other antidepressants The MAOIs are all rapidly absorbed. For the irreversible MAOIs the half-life does not correlate with duration of action as the effects on the MAO enzyme are irreversible and new enzyme needs to be synthesized for restoration of normal activity - a minimum of 5 to 7 days. Hence, it is recommended that for drugs that can interact fatally with MAOIs (irreversible) - the safest recommendation is to wait 2 weeks before starting. The combination of MAOIs and pethidine (meperidine) can produce either a depressive (pronounced sedation due to opioid toxicity) or excitatory reaction (related to serotonin excess: agitation, hyperpyrexia and cardiovascular collapse, coma, and death). Pethidine, in particular, has a serotonin releasing property and some reuptake inhibition property. Pethidine must never be used in the presence of MAOIs because of the risk of this fatal excitatory interaction. Morphine has fewer propensities to cause this interaction. Amphetamine also induces serotonin release, while methylphenidate does not. The latter is relatively safe in terms of serotonin toxicity with MAOIs. Venlafaxine has low protein binding; it has t1/2 around 3.5 hours. Venlafaxine is well absorbed per orally. An extended-release formulation of venlafaxine is available, facilitating once daily administration. The metabolite O-desmethyl venlafaxine (ODV) has a half-life of 9 hours. It is metabolized by hepatic cytochrome P450 (CYP) 2D6. Venlafaxine has no enzyme-inducing properties. Duloxetine has t1/2 of about 12 hours – it is extensively metabolized by hepatic enzymes CYP450 and highly protein bound. Trazodone and nefazodone undergo extensive hepatic metabolism, and one major metabolite is m-chlorophenylpiperazine which stimulates 5-HT receptors. Trazodone is readily absorbed and has a half-life of 5 to 9 hours. Trazodone is a weak inhibitor of serotonin reuptake and antagonist of serotonin 5-HT2A and 5-HT2C receptors. The active metabolite of trazodone is mchlorophenylpiperazine (mCPP) is 5-HT2C agonist with t1/2 around 14 hrs. mCPP can cause migraine, anxiety, and weight loss. Trazodone has an acute sedative effect, which is useful in the treatment of agitation, anxiety, and insomnia. Antianxiety effects of trazodone appear earlier than antidepressant effects. Trazodone can increase levels of digoxin and phenytoin and warfarin. CYP 3A4 inhibitors can increase mCPP by reducing its breakdown leading to an increase in side effects. Buspirone has a short half-life of 2-11 hours. Hence it is given three times daily. Buspirone has an active metabolite called 1-pyrimidinylpiperazine (1-PP) – which has some degree of activity # 23 - Terms used to describe therapeutic effects of # Terms used to describe therapeutic effects of antidepressants © SPMM Course compared to buspirone but achieves higher brain concentration in the brain. Buspirone acts as a partial agonist on serotonin 5-HT1A receptors – presynaptic agonism leads to inhibition of release of serotonin, with consequent antianxiety effects. Postsynaptic agonism leads to antidepressant activity. St John’s wort: It acts via multiple monoamine reuptake inhibition. It is a CYP inducer and can interact with warfarin, OCPs and antiepileptics, decreasing their efficacy. Terms used to describe therapeutic effects of antidepressants Mirtazapine reaches peak plasma concentrations within 2 hours; it binds to plasma proteins (85%) and has a bioavailability is approximately 50%, owing to extant first-pass metabolism. It follows first-order linear elimination kinetics over a dose range of 15 to 80mg. The elimination t ½ ranges from 20 to 40 hours. Metabolism is mediated by the CYP2D6 and CYP3A4; thus paroxetine and fluoxetine, which inhibit the CYP system, can increase plasma concentrations of mirtazapine by 1/5th to 1/3rd but usually there are no clinical consequences. Carbamazepine causes a 60% decrease in plasma concentrations. Mirtazapine has no inhibitory effects on CYP isoenzymes. Agomelatine undergoes extensive first-pass metabolism with a low bioavailability. It is extensively protein bound (95%) and has a half-life of 2.3 hours. It is mostly metabolized by CYP1A2 (90%) and CYP2C9 (10%). •minimal or <25% decrease in baseline severity of sx non-response non-response •25-50% reduction in baseline severity (sx still evident) partial response partial response •>50% reduction, but still some sx evident partial remission partial remission •no sx; returning to normal function (<6months from last episode) remission remission •return to fully sx state when in remission relapse relapse •extended remission sustained for longer than 6-12 months recovery recovery •onset of a new episode of depression when in recovery recurrence recurrence # 24 - D. Mood stabilisers # D. Mood stabilisers © SPMM Course D. Mood stabilisers Lithium is orally well absorbed but not metabolized in the liver; it is renally excreted. Lithium carbonate and citrate are not bioequivalent preparations; hence the careful prescribing practice is required. Lithium is rapidly and completely absorbed after oral administration. Lithium takes 45 days to achieve a steady state in healthy young males. It is not protein bound. Lithium’s plasma half-life is around 18 hours initially but later after 1 year of chronic use increases to 36 hours. Lithium is excreted via the proximal tubules where sodium is also filtered. Hence, any loss of body sodium can increase lithium reabsorption as compensation in error leading to toxicity. Hence maintaining sodium homeostasis is important in patients on lithium therapy. Agents increasing lithium levels Agents decreasing lithium levels Toxicity with normal levels ACE inhibitors Osmotic diuretics Carbamazepine – increased antithyroid effect and neurotoxicity Loop diuretics Caffeine Atracurium – increased neuromuscular blockade Fluoxetine Aminophylline Haloperidol, clozapine – increased neurotoxic effects NSAIDs Theobromine, Theophylline Calcium channel blockers – increased neurotoxicity Thiazides Carbonic anhydrase inhibitors Metronidazole – increased neurotoxicity Valproate is available as semisodium compound (divalproex) and as sodium salt of the valproic acid. Divalproex consists of half valproic acid and half sodium valproate. Semisodium compound is somewhat better tolerated. Valproate is well absorbed, with a bioavailability close to 100%. It is quite hydrophilic, with a low volume of distribution. Valproate has t1/2 of 9 to 16 hours and is highly (90%) protein bound. This binding is saturable so that at higher doses a greater percentage of the drug may be in the free form. At higher doses, the increased free fraction may remain in the plasma compartment (rather than escaping into the tissues) and thus be cleared by the liver. This may yield ‘‘sublinear’’ kinetics so that with higher plasma concentrations, greater increases in dose may be required to yield the desired increase in plasma level (Graves, 1995). Binding interactions occur so that VPA can increase free diazepam. Carbamazepine has a tricyclic structure and undergoes hepatic metabolism. It has an erratic absorption and a bioavailability of about 80%. It is about 75% bound to plasma proteins. Carbamazepine induces its own breakdown. Before autoinduction of the epoxide pathway (via induction of CYP3A3/4), the half-life of CBZ is about 24 hr, and the clearance is about 25 mL/ min. After autoinduction (2 to 4 weeks into therapy), the half-life falls to about 8 hr, and clearance rises # 25 - E. Typical antipsychotics # E. Typical antipsychotics: © SPMM Course to about 75mL/min. The active CBZ-10,11-epoxide (CBZ-E) metabolite has a half-life of about 6 hr. The conventional form needs to be given in multiple divided doses while extended release can be given twice a day. A steady-state plasma concentration of 4 to 12 ng/ml is therapeutic. Verapamil and diltiazem can increase carbamazepine levels and cause clinical toxicity, but this does not occur with other calcium channel blockers nifedipine and nimodipine. Also, carbamazepine decreases nimodipine and felodipine levels. Valproate inhibits epoxide hydrolase, increasing the plasma carbamazepine-epoxide levels, often without altering total plasma carbamazepine levels. Valproate also displaces carbamazepine from plasma proteins, increasing free carbamazepine. Patients can have neurotoxicity due to elevated plasma carbamazepine - epoxide levels in spite of normal plasma total carbamazepine levels. Carbamazepine reduces warfarin efficacy. Erythromycin can produce carbamazepine toxicity. Gabapentin has no significant mood stabilizing effects though it is useful to treat anxiety in bipolar patients. It is not bound to plasma proteins, is not metabolized and is 100% excreted in the urine. Gabapentin has a half-life of about 6 hrs (4 to 9) and a clearance similar to that of creatinine (120 ml/min, similar to the glomerular filtration rate), so that increased physical activity may increase GBP clearance. The bioavailability of gabapentin is not dose-proportional; it decreases as the dose increases. When gabapentin is given in 3 divided doses, at 900 mg per day the bioavailability is approximately 60%, but at 2400 mg per day it drops to 34% and at 4800 mg per day it is only 27%. Gabapentin does not induce or inhibit hepatic metabolism. It is not bound to plasma proteins and displays linear pharmacokinetics at usual dosages. Consequently, drugdrug interactions are not an issue with gabapentin. It is usually given three times a day. In patients with normal renal function, steady state is reached after 1 to 2 days of taking a stable dose of gabapentin. The dose that a patient takes should not be increased until steady state has been reached (or some time later) so that the effects of the previous dosage can be assessed. Lamotrigine achieves peak concentrations within about 3 hours postdose with an oral bioavailability of about 98%. It is 56% plasma protein bound with t½ of 24 to 36 hours. Enzymeinducing drugs (phenytoin, phenobarbital or carbamazepine) reduce the half-life of lamotrigine whereas valproate increases the half-life. Lamotrigine itself does not affect CYP450 in most cases but increases levels of carbamazepine-10,11-epoxide, the metabolite of carbamazepine. E. Typical antipsychotics:  Typical antipsychotics are well absorbed when administered both orally or parenterally. Peak plasma levels are reached in 30 min after intramuscular injection and 1 to 4 h after oral injection. Steady state is achieved in 3 to 5 days.  The half-life for elimination is in the range of 10 to 30 h. # 26 - Depot atypicals # Depot atypicals © SPMM Course  Lipid storage and brain retention are significant; depot forms of haloperidol or fluphenazine may persist for 1 to 3 months.  Thioridazine has an active metabolite mesoridazine, and loxapine produces 7hydroxyloxapine.  Typical antipsychotics are mainly substrates of CYP1A or CYP2D6, or both and can inhibit 2D6.  Chlorpromazine has highly variable absorption rate (around 37% bioavailability) for different persons and has nearly 100s of metabolites.  Antacids can decrease absorption of phenothiazines; this leads to reduced plasma concentration and therapeutic effect of phenothiazines Interactions: Enzyme inducers Carbamazepine, phenytoin, ethambutol, barbiturates - reduce antipsychotic levels. Clearance inhibitors SSRIs, TCAs, cimetidine, erythromycin, ciprofloxacin, and ketoconazole can inhibit metabolism – increase antipsychotic levels. Depot atypicals Depot drug Preparation Kinetics Flupenthixol decanoate Esterified in coconut oil Peak levels 3–7 days post IM. Apparent half-life of 17 days Fluphenazine decanoate Esterified in sesame oil Peak levels are 24h post-IM. The apparent half-life of 7-14 days. Smoking reduces levels Haloperidol decanoate Esterified in sesame oil Peak levels 7 days post IM. The apparent half-life of 3 weeks. Smoking reduces levels Perphenazine decanoate Esterified in sesame oil Peak levels 1-7 days post IM. Apparent half-life of 2 weeks Pipotiazine palmitate Esterified in coconut oil Peak levels 1-2 weeks post IM. Apparent half-life of 2 weeks Zuclopenthixol decanoate Esterified in coconut oil. Contrast this depot from zuclopenthixol acetate preparation used for rapid tranquillisation Peak levels 1 week post IM. The apparent half-life of 7-20 days. # 27 - F. Atypical antipsychotics # F. Atypical antipsychotics: © SPMM Course F. Atypical antipsychotics: All atypicals are orally well absorbed. Drug Half life Chlorpromazine equivalents (100mg/day CPZ or 2mg Haloperidol) Risperidone 15hrs 2 mg/day Clozapine 16hrs 50 mg/day Quetiapine 6hrs 75 mg/day Olanzapine 30 hrs 5mg/day Aripiprazole 90hrs 7.5 mg/day From Woods SW. J Clin Psychiatry. 2003 Jun;64(6):663-7.  Risperidone undergoes extensive first-pass hepatic metabolism to 9-hydroxyrisperidone, an active metabolite. CYP 2D6 catalyzes hydroxylation of risperidone to 9-hydroxyrisperidone. Risperidone is 90% protein bound; its metabolite is 77% bound.  Paliperidone is the major active metabolite of risperidone (9-OH). It is a potent 5HT2 blocker apart from partially blocking D2 receptors. Its efficacy and side effects are the same as risperidone. It comes in a sustained release preparation similar to methylphenidate XL wherein gradual water absorption delivers the drug molecules slowly. Once daily administration is sufficient; there is no need to titrate the dose.  Quetiapine has a shorter half-life of 6 to 12 hours, and multiple daily dosing is required; though with longer use, as pharmacodynamic receptor action has longer duration once daily dosing may be sufficient.  Aripiprazole and its active metabolite dihydro aripiprazole have exceptionally long half-lives of 75 (nearly 3 days) and 94 hours respectively, and steady state concentrations are achieved after 14 days. Aripiprazole is metabolized by CYP 3A4 and CYP 2D6 enzymes. It is highly (99%) protein bound.  Atypical depots o Aripiprazole depot: no need to refrigerate; once monthly; gluteal administration only; only 2 weeks oral dose tapering needed. o Paliperidone depot does not need oral tapering; once monthly; no need to refrigerate; primarily renal excretion. o Risperidone microspheres are used in depot preparations; they release the active drug at therapeutic levels only 3 weeks after gluteal or deltoid injection. Long-acting risperidone should DEPOT KINETICS Some long-acting injections (such as risperidone, pipotiazine) show delayed as well as prolonged release. These require adeqaute cover with oral antipsychotics after first dose is administered. Steady-state plasma levels are often delayed for 2–3 months. During this time, plasma levels are likely to rise substantially even when dosages are not increased, thus producing dose-dependent side effects. Dose–response relationships are not clearly understood for most LAIs. Test doses are often used but may not be sufficient to assess tolerability in longer-term use. # 28 - G. Antidementia drugs # G. Antidementia drugs: # 29 - H. Other drugs # H. Other drugs: © SPMM Course be supplemented with oral risperidone for 3 weeks. Requires refrigeration as it is granular, not ester-based. o Olanzapine depot is a crystalline salt composed of olanzapine and pamoic acid with a half-life of 30 days and steady state reached at 12 weeks. Oral supplementation of olanzapine is not required. G. Antidementia drugs:  Tacrine is poorly absorbed with short t1/2. It is metabolized by CYP 1A2 hepatic enzymes.  Donepezil has an oral bioavailability around 100%, with linear pharmacokinetics. The drug reaches steady state in about two weeks. Its t1/2 is long - 70 hours, enabling once-daily dosing. Donepezil is extensively bound to plasma proteins, and while a part is excreted unchanged the other is extensively metabolized by CYP 2D6 and 3A4 hepatic enzymes to active and inactive metabolites.  The oral bioavailability of rivastigmine is about 40% up to a dose of 3 mg, after which this increases non-linearly. The t1/2 of rivastigmine is just 1.5 hours. The drug undergoes hydrolysis by cholinesterase itself, with minimal hepatic involvement. It is excreted almost entirely in the urine as the sulfate of the decarbamylated metabolite.  The oral bioavailability of galantamine is about 90%; it has low protein binding (18%). It undergoes metabolism by CYP2D6 and CYP3A4 enzymes while one-third is excreted unchanged in the urine.  Memantine has low protein binding (45%) and a long half-life of 60–80 hours. Approximately half the dose of memantine is excreted unchanged in the urine; the remainder undergoes hepatic conversion to inactive metabolites. Drugs that alkalinize the urine (e.g., carbonic anhydrase inhibitors) reduce the clearance of memantine. H. Other drugs:  Methylphenidate is absorbed well orally and achieves peak plasma levels in 1-2hrs with t1/2 2-3 hrs necessitating multiple daily dosing. This is obviated by sustained release preparation that can be given once daily.  Modafinil reaches peak plasma concentrations in 2 to 4 hours and has a half-life of 15 hours.  Atomoxetine has a t1/2 5 hours and is metabolized by the CYP 2D6 pathway. SSRIs may raise atomoxetine levels. # 30 - Benzodiazepines # Benzodiazepines: © SPMM Course Benzodiazepines: Drug Duration of action Effect Diazepam, chlordiazepoxide, clonazepam, flurazepam Long-acting Can have more than 200hrs t1/2 in genetically slow metabolizers. Also, toxicity can take 1 – 2 weeks to be evident when higher doses are given. Lorazepam, oxazepam, temazepam, Alprazolam Intermediate or short acting Severe withdrawal phenomena but the lesser risk of daytime impairment and daytime sedation. Rebound insomnia and anterograde amnesia more often seen in short t1/2. Lorazepam t1/2 15 hours; temazepam somewhat shorter – 10 hours. Triazolam Very short acting Used in anaesthesia Diazepam is well absorbed orally - oral bioavailability nearly 100%. Peak plasma concentration is reached in 15 - 90 minutes after oral administration; has a second peak at 6 - 12 hours due to enterohepatic recirculation. Diazepam is widely distributed - highly lipophilic (so CSF concentration more or less equals plasma concentration) with 95-99% plasma protein binding. It has a slow elimination t½ 30 h (ranges between 20 - 100 h). It also takes a long time to reach steady state (5 -6 days). It gets extensively metabolized in the liver with 3 active metabolites: Nordiazepam or desmethyldiazepam (principal metabolite – could accumulate due to long t1/2), Oxazepam and Temazepam. “Z”-hypnotics  Zolpidem, zaleplon, and eszopiclone are quickly and completely absorbed when given orally. Food may delay absorption by an hour.  Lack of active metabolites of zolpidem, zaleplon, and eszopiclone avoid the accumulation and hang over effects.  NICE's appraisal committee concluded that no compelling evidence of a clinically useful difference exists between the Z-drugs and short-acting benzodiazepines in terms of effectiveness, adverse effects, or potential for misuse or dependence. But this is controversial. Z HYPNOTICS Zopiclone / Eszopiclone (enantiaomer) Onset within 45 mins; half-life 4 to 5 hours (acts up to 8 hours) Benzodiazepine receptor selective for alpha 1 subunit; eszopiclone is the only Z-hypnotic indicated for sleep maintenance therapy (US FDA) – others are used for initiation problems. Zaleplon Onset within 30 mins; half-life 1 to 2 hours (acts up to 4 hours). Shorter half-life and quick onset – makes it suitable for those with sleep initiation problems; not so helpful for the maintenance of sleep. Zolpidem Onset within 30 mins; half-life 1 to 4 hours (acts up to 6 hours). Shorter half-life and quick onset – makes it suitable for those with sleep initiation problems; not so helpful for the maintenance of sleep. Less hangover effect. © SPMM Course Notes prepared using excerpts from:  Chadwick, B. et al. Potentially hazardous drug interactions with psychotropics. Advances in Psychiatric Treatment (2005) 11: 440-449  Davis, J et al (2006) Switch or stay? Am J Psychiatry 163:2032-2033,  De Leon, J. (2004) Psychopharmacology: Atypical Antipsychotic Dosing: The Effect of Smoking and Caffeine. Psychiatric Services. 55 (5): 491-493.  Lieberman & Tasman, Handbook of Psychiatric Drugs.  Mendelson WB, et al. The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev. 2004;8:7-17.  Palaniyappan, L., Insole, L. & Ferrier, IN. The safety and efficacy of antidepressant combinations: A review. Adv Psych Treatment. In press.  Puri, BK. Drugs in psychiatry- Oxford Medical Publications; ; 13-37  Sandson NB, Armstrong SC, Cozza KL: Med-Psych Drug-Drug Interactions Update An Overview of Psychotropic Drug-Drug Interactions. Psychosomatics 2005;46:464–494.  Schrier, RW. Diseases of the Kidney & Urinary Tract: Clinicopathologic Foundations of Medicine. Lippincott-Wilkins, 2007 Pg 301  Tamminga, C & Davis, JM Schizophrenia Bulletin vol. 33 no. 4 pp. 937–946, 2007  Taylor D. Psychopharmacology and adverse effects of antipsychotic long-acting injections: a review. The British Journal of Psychiatry Nov 2009, 195 (52) S13-S19  http://www.drugs.com/pro/fluvoxamine.html  Phipps A & Turkington, D. Psychiatry in the renal unit. http://apt.rcpsych.org/content/7/6/426 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgments have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information # 13 - 43_Pharmacodynamics # 01 - 1. Introduction # 1. Introduction © SPMM Course 1. Introduction The term pharmacodynamics refers to the study of the mechanism of action of drugs (the effect of drugs on the body). Most psychotropics affect neurotransmitters of the brain. This effect can occur at various levels. Level of action in neurotransmission cycle Examples Synthesis L-tryptophan, l-dopa Storage Reserpine depletes NA and DA. Release from storage Amphetamine stimulates release of NA and DA Reuptake SSRI, TCA, cocaine – dopamine reuptake, Bupropion – dopamine & Noradrenaline reuptake Degradation MAO inhibitors, Acetyl cholinesterase inhibitors e.g. donepezil Pre synaptic receptors Clonidine, lofexidine at alpha2. Post synaptic receptors Most antipsychotics at D2 Partial agonism Aripiprazole – D2; Buspirone 5HT1A; Clonazepam – BDZ receptor; Buprenorphine – opioid receptor mu Antagonism Flumazenil for benzodiazepines, antipsychotics at D2 Full agonism Benzodiazepines at GABA-A complex, bromocriptine for dopamine Second messengers Lithium at inositol level. Refer to Neurochemistry SPMM Notes for more details of different neurotransmitters, their structure and receptor actions. # 02 - 2. Receptor mechanisms # 2. Receptor mechanisms © SPMM Course 2. Receptor mechanisms The ‘receptor’ of a drug can be defined generally as the cellular component to which the drug binds and through which the drug initiates the pharmacodynamic effects on the body. There are 2 major superfamilies; Ionotropic or metabotropic receptors.  Ionotropic: Theses are ligand-gated ionic channels. Their activation leads to a rapid transient increase in membrane permeability to either positive cations like sodium or calcium or negative anions like chloride. It causes excitation or inhibition of the postsynaptic membrane. Examples are nicotinic acetylcholine receptors, GABA-A receptors, glutamate receptors and serotonin 5HT 3.  Metabotropic: These produce slower response involving so-called G-proteins which bind to the intracellular portion of the receptor and activate a second messenger. Altered second messenger levels result in changes in the phosphorylation state of key proteins rendering them active or inactive. Examples are Dopamine (D1-5), Noradrenaline, and Serotonin 5HT1-7 except 5-HT 3, muscarinic acetylcholine receptors and opioid receptors (mu). Ionotropic receptors result in quick response (GABAA, a benzodiazepine); G protein coupling (metabotropic) is a comparatively slower process (most antipsychotics, antidepressants. Kinetics of receptor binding: A drug can be an agonist for a receptor and can stimulate the biological activity of the receptor or could be an antagonist that inhibits the biological activity.  Full agonists produce a maximal response. The measure of the degree of response is usually measured against physiological neurotransmitter efficiency for any given receptor.  Partial agonists cannot elicit a maximal response and are less effective than full agonists. Examples are Aripiprazole, buspirone and buprenorphine. Partial agonists have a ceiling effect. The degree of response of a partial agonist depends on availability of physiological neurotransmitter in the vicinity; i.e. when maximal dopamine is available, partial agonist aripiprazole can actually inhibit the dopaminergic transmission as a less efficient molecule competes with more efficient molecule. In dopamine deficient states, the same partial agonist can enhance dopaminergic effects.  An inverse agonist is an agent that binds to the same receptor but produces the opposite pharmacological effect. No clinical drug acts via this mechanism but several have been researched especially at GABA complex.  Antagonists are drugs that interact with receptors to interfere with their activation by neurotransmitter or other agonistic molecules. © SPMM Course Types of antagonism  Competitive antagonism can be reversed completely by increasing the dose of the agonist drug. Competitive antagonists reduce the potency (minimal dose needed to produce an effect) but not the efficacy (maximal response produced) of agonists. Examples of competitive antagonism include atropine at muscarinic receptors and propranolol at betaadrenergic receptors.  Noncompetitive antagonists alter the receptor site in some way so increasing the dose of the agonist drug can reverse the effects only partially. Non-competitive antagonism reduces both the potency and the efficacy of agonists. Therefore, non-competitive antagonists not only shift the curve to the right but also reduce the maximum effect. For example, ketamine and phencyclidine are noncompetitive NMDA antagonists. Irreversible antagonists bind irreversibly to the target site e.g. most traditional MAOIs.  Pharmacological antagonism refers to the opposing action of two molecules by acting via same receptors. Physiological antagonism refers to the opposing action of two molecules by acting via different receptors e.g. acetylcholine vs. adrenergic actions.  Chemical antagonism refers to the opposing action of two molecules by acting via chemical reactions. This is not seen in psychotropics, but heparin and protamine reaction is an example. Most drugs bind reversibly to receptors, and the response is proportional to the fraction of receptors occupied (law of mass action). As the concentration of drug increases, the responses increases until all receptors are occupied giving a dose-response curve. Receptors can be up-regulated or down-regulated by drugs. With therapeutic use, agonists may cause down-regulation (desensitivity) or reduction in receptor numbers while antagonists may have the opposite effect- upregulation (hypersensitivity) or increase in receptor numbers. The potency of a drug with receptor binding action refers to the amount of the drug needed to produce a particular effect compared to another standard drug with similar receptor profile (‘vigor’). The potency of a drug is determined by; a. The proportion of the drug reaching the receptor b. The affinity for the receptor c. Efficacy Affinity refers to the ability of the drug to bind to its appropriate receptor (‘affection’). Drugs that bind readily to a receptor are described as having high affinity for that receptor and, in general, the higher the affinity and the more receptor a drug occupies, the more potent it is. © SPMM Course Efficacy refers to how well the drug produces the expected response i.e. the maximum clinical response produced by a drug (‘productivity’). Efficacy depends on affinity, potency, duration of receptor action in some cases and kinetic properties such as half-life, among other factors. Haloperidol is more potent than chlorpromazine as approximately 5 mg of haloperidol is required to achieve the same effect as 100 mg of chlorpromazine. These drugs, however, are comparable in the maximal clinical response achievable using them i.e. equally efficacious but not equipotent. # 03 - 3. Modes of therapeutic action for psychotrop # 3. Modes of therapeutic action for psychotropics # 04 - Antipsychotic drugs # Antipsychotic drugs © SPMM Course 3. Modes of therapeutic action for psychotropics Antipsychotic drugs In general all antipsychotics act via varying degrees of D2 blockade. Aypical drugs show selectivity for D2 receptors and also show high 5HT2: D2 blocking ratio. Specific actions are listed below. DRUG MECHANISM Amisulpride Both D2 and D3 antagonism. Similar dose-dependent pre & postsynaptic profile to sulpride. Some degree of limbic selectivity and 5HT7 activity also noted. Aripiprazole Partial dopamine agonist at D2. Also 5HT2A antagonist. Exhibits a Goldilocks’ phenomenon -stabilising action wherein anatagonising DA at sites of excessive dopamine such as mesolimbic zones while mimicking DA (agonism) at dopamine deficient zones such as mesocortical areas that are linked negative symptoms. Does not produce much change in tuberoinfundibulum where normal DA levels are expected in schizophrenia. Aripiprazole acts on both postsynaptic D2 receptors and presynaptic autoreceptors. Asenapine D2 antagonist and serotonin 5HT2A blocker (similar to olanzapine). Has potent alpha-2 blockade effect. Sublingual; allegedly weight and prolactin-neutral. Licensed for use in mania. Chlorpromazine, promazine The moderate antimuscarinic effect in addition to D2 blockade. Highly sedative phenothiazine drugs. Clozapine A High ratio of 5HT2 to D2 blockade; also blocks D4 and 5HT6 receptors. Has notable alpha 1 antagonism and anticholinergic and antihistaminic properties. Weak D1 and D2 affinity. Also binds 5HT3. Proposed to have a faster dissociation rate (similar to quetiapine) hence a hit and run profile is noted. Lurasidone D2 antagonist and serotonin 5HT2A blocker (similar to risperidone). Also has a high affinity for serotonin 5HT7; partial agonist at 5HT1A receptors. Has minimal affinity for alpha-1 (less orthostatic effect) and histamine receptors (thus may be weight neutral) Olanzapine Atypical antipsychotic. Has high 5HT2 / D2 blockade ratio. Potent D4 blockade and 5HT6 blockade also noted. It has significant anticholinergic and some antihistaminic effects. Paliperidone A metabolite of risperidone. Similar mechanism of action Quetiapine Similar to clozapine – hit and run profile on D2. Compared to other atypicals it has somewhat lesser 5HT2A blockade. Significant anticholinergic effects similar to olanzapine. Risperidone Serotonin-Dopamine Antagonist - Atypical Antipsychotic. Has high 5HT2A antagonistic property. In higher therapeutic doses can bind to D2 in a similar fashion to typicals and can lead to extrapyramidal and prolactin related side effects. Sulpiride Pure D2 antagonist. At low doses presynaptic receptors blocked (helps negative symptoms?); above 800mg/day doses, affects postsynaptic D2 – reducing positive symptoms. Thioridazine, pericyazine, D2 antagonists. Marked antimuscarinic effect. Less EPSEs than other typicals. © SPMM Course pipotiazine Thioxanthenes Exhibit stereoisomerism. D2 antagonists – typical antipsychotics. Ziprasidone Atypical antipsychotic with 5-HT2A and D2 blockade. Antagonizes 5-HT1D, 5-HT2C, D3, D4 receptors. Poor affinity for muscarinic effects; some antihistaminic property noted. Agonistic at 5-HT1A; also some serotonin and norepinephrine reuptake inhibition noted. Zotepine Atypical antipsychotic with 5HT2A, 5HT2C, D1, D2, D3, D4 antagonism. Potent noradrenaline reuptake inhibitor. Potent antihistaminic activity and some NMDA antagonism. # 05 - Antidepressant drugs # Antidepressant drugs © SPMM Course Antidepressant drugs DRUG MECHANISM Agomelatine Agomelatine enhances norepinephrine and dopamine neurotransmission through 5HT2C antagonism. It is also a direct agonist at melatonin (MT1 and MT2) receptors. GABA interneurons tonically inhibit noradrenergic circuits (from locus coeruleus) and dopaminergic circuits (from ventral tegmentum) projecting to the prefrontal cortex. Serotonin via 5HT2C stimulation drives these GABA interneurons. Thus, norepinephrine and dopamine circuits are inhibited by the normal tonic release of serotonin onto 5-HT2C receptors (Stahl, 2007). Thus agomelatine, through 5HT2C inhibition, acts as norepinephrine and dopamine disinhibitor (NDDI). Antidepressant with possible sedative effects. Amoxapine Tetracyclic with dibenzoxazepine structure. Has both dopamine antagonistic and serotonin-noradrenaline reuptake inhibition effects. So claimed to have significant antipsychotic properties in addition to antidepressant effects. Similarly, extrapyramidal side effects are seen more often than other tricyclic. Bupropion Dopamine and noradrenaline reuptake inhibitor. Used to help quit smoking and in depression. It is noted to increase the efficiency of noradrenergic transmission and reduce total norepinephrine turnover. It has no antimuscarinic activity. Some degree of competitive nicotinic antagonism. Buspirone Partial agonist on serotonin 5-HT1A receptors. At presynaptic levels, it is mostly a full agonist, which inhibits the release of serotonin, with consequent antianxiety effects. Partial agonist action at postsynaptic receptors appears to account for the antidepressant activity. Citalopram SSRI, most selective of all SSRIs for serotonin reuptake. Occurs in a racemic mixture of which s isomer has pharmacological activity. But r- enantiomer inhibits the action of s- enantiomer; hence if escitalopram is used (s- enantiomer) lesser dose is sufficient. Clomipramine Tricyclic – regarded as most potent; higher SRI selectivity than other TCAs but lesser selectivity than SSRIs. Desipramine Tricyclic with least anticholinergic action but lethal on overdose. Duloxetine SNRI similar to venlafaxine. Said to have a better profile for psychosomatic pain and neuropathic pain. Levothyroxine & Liothyronine Levothyroxine is T4; liothyronine is T3 – both are thyroid hormones; suppress TSH and acts as an adjuvant in resistant depression. The exact mechanism of antidepressant effects unknown – possibly via neuroendocrine changes. Lithium Lithium is thought to act via the second messenger system. It putatively enhances serotonin transmission by 1. Increasing tryptophan uptake into neurons 2. Enhancing serotonin release 3. Downregulation of 5HT1A, 1B and 2 receptor subtypes is also noted on chronic administration. 4. Directly inhibiting glycogen synthase kinase-3 (GSK-3) and also 5. Competing with magnesium directly at several important regulatory enzymes such as inositol-monophosphatase (IMPase), which catalyzes inositol second messenger system. © SPMM Course According to the inositol depletion hypothesis, inhibition of IMPase by lithium reduces myoinositol and phosphoinositide phosphate (PIP-2), leading to therapeutic efficacy. Further, through an increase in intracellular sodium, it may also affect Na+K+ pump and reducing dopamine synthesis in dose-dependent fashion. Milnacipran SNRI similar to venlafaxine. New drug Levomilnacipran also acts similarly Mirtazapine 5HT2A antagonism, alpha 2 antagonism, anti histaminic and anti 5HT3 properties noted. Mianserin has similar profile, but it is not antihistaminic; instead it has anticholinergic properties. Moclobemide Reversible inhibitor of MAO-A selectively. Nefazadone 5HT2 antagonist with some serotonin reuptake inhibition and mild norepinephrine reuptake inhibition. Has some alpha 1 antagonistic effect. Produces mCPP as a metabolite. Paroxetine Selective Serotonin Reuptake Inhibitor – most potent of all SSRIs in serotonin reuptake blockade, but not specific – has significant antimuscarinic action. Phenelzine Monoamine Oxidase Inhibitor – increased availability of monoamines including serotonin and noradrenaline may explain the mechanism of antidepressant action though disputed. Pindolol Beta blocker with intrinsic sympathomimetic activity. Also 5HT1A antagonism – tipped to enhance the onset of action of SSRIs through this mechanism. Reboxetine Noradrenergic specific reuptake inhibitor (NARI) Selegiline Monoamine Oxidase Inhibitors – selective for B at normal therapeutic doses; selectivity lost when a patch is applied at higher doses, leading to some antidepressant action. SSRIs Reuptake inhibition at somatodendritic areas takes place soon after administration – this leads to down regulation of somatic autoreceptors for serotonin and as a consequence inhibitory tone on serotonergic transmission is lost; the serotonergic output is facilitated. (see below) Tranylcypromine Monoamine Oxidase Inhibitors. Irreversible, non-selective. Positive enantiomer better MAOI, negative enantiomer better reuptake inhibitor. Trazodone 5HT2A/2c antagonism and some alpha 2 blockade. Alpha 1 blockade and antihistaminic properties also noted. Feeble reuptake inhibition at serotonin transporters. Tricyclics Monoamine reuptake inhibition (see below). The varying degree of noradrenaline and serotonin reuptake inhibition. Very minimal negligible effect on dopamine. Clomipramine is the most serotonin specific. Secondary amines are more noradrenergic. Venlafaxine SNRI. Serotonin noradrenaline reuptake inhibitor. Acts as an SSRI in lower (<150mg) doses. Vilazodone Mechanism not fully understood but selective serotonin reuptake inhibition and also a partial agonist action at serotonergic 5-HT1A receptors (the chemical structure is close to trazodone and nefazodone) Vortioxetine A structure similar to reboxetine but predominantly an SSRI-like effect. In addition, also shows 5HT3 antagonism and 5HT-1A agonism. © SPMM Course Selectivity of antidepressants: The ratio of concentration required to produce equivalent inhibitions of serotonin (5-HT) to Noradrenalin is shown below.  Amitriptyline 1:1  Clomipramine 1:7  Fluoxetine 150:1  Citalopram >2000:1 Inhibition of nerve terminal NE neuronal uptake system Increase in synaptic concentrations of NE Desensitization of inhibitory Alpha2-adrenoceptors in the terminal Increase in neuronal NE release Further increase in synaptic concentrations of NE Desensitization of postsynaptic Beta adrenoceptors without affecting postsynaptic Alpha1-adrenoceptor sensitivity 5HT Reuptake inhibition at somatodendritic areas Increase in local concentrations of 5HT Desensitisation of inhibitory 5HT1A autoreceptors in the soma Increase in neuronal 5HT release Increase in synaptic concentrations of 5HT Desensitization of presynaptic 5HT1B receptors without affecting postsynaptic 5HT1A sensitivity Mechanism of TCA Action Mechanism of SSRI Action # 06 - Mood stabilizers # Mood stabilizers © SPMM Course Mood stabilizers DRUG MECHANISM Carbamazepine Prolongs sodium channel inactivation. As a consequence, calcium channel inactivation is prolonged. It also reduces glutamate neurotransmission, adenosine A1 receptor antagonism and increase in brain catecholamine activity. It inhibits peripheral benzodiazepine receptors and reduces limbic kindling. It interferes with glial cell steroidogenesis. GABApentin GABA analogue structurally - binds to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system. Acts on l-amino acid transport and thus can increase GABA availability in the brain. It crosses BBB via this l-AA transport. Has a high-affinity site in GABA-A complex; but no benzodiazepine-like actions noted. Lamotrigine Blockade of voltage-sensitive sodium channels leading to modulation of glutamate and aspartate release; some effect on calcium channels. Some inhibition of serotonin reuptake and weak inhibition of 5-HT3 receptors. Levetiracetam Indirectly enhance GABA system. Anticonvulsant with weak evidence against mania. Oxcarbazepine A metabolite of carbamazepine; similar mechanisms proposed. Pregabalin GABA analogue structurally (similar to gabapentin). Like gabapentin, pregabalin binds to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system. This may subtly reduce the release of certain neurotransmitters. It may as well influence GABergic neurotransmission. It has anti-epileptic, analgesic (neuropathic pain) and anxiolytic effects. It is more potent than gabapentin hence has a higher therapeutic index and fewer dose-related side effects. Tiagabine Tiagabine is a potent and selective reuptake inhibitor of GABA. It also has mild antihistaminic effects. Topiramate Topiramate is a fructose derivative; it is a selective inhibitor of Glutamate AMPA receptors, blocks Na+ receptors, and has indirect GABAergic activity by potentiating the action of GABAA receptor. Valproic acid Unknown- speculated to act via increased GABA release, decreased GABA metabolism, increased neuronal responsiveness to GABA and increased GABA receptor density, inhibition of phosphokinase C similar to lithium and functional dopamine antagonism. Vigabatrin VIGABATRIN expands as Vi- GABA- TR-transaminase IN- inhibitor. The name explains the mode of action. # 07 - Sedatives & Hypnotics # Sedatives & Hypnotics © SPMM Course Sedatives & Hypnotics DRUG MECHANISM Benzodiazepines Act via a particular site called omega site in GABA-A complex. All are agonists except clonazepam, which is a partial agonist. They facilitate GABA action on GABA-A complex – thus facilitating inhibitory neurotransmission via chloride ions. They have no direct agonistic action in the absence of GABA. They do not increase the number but the frequency and duration of chloride channel opening. Chloral hydrate, paraldehyde and meprobamate Barbiturate like agents. Probably potentiate GABAergic neurotransmission. Paraldehyde is cyclic ether. They have a poor safety profile and hence none of these are in clinical use currently. Flumazenil Benzodiazepine antagonist Ramelteon Ramelteon is a melatonin receptor full agonist with high affinity and selectivity for human melatonin receptors MT1 and MT2 over the MT3 receptor. It decreases sleep latency and increases sleep time across all ages; the dose-response curve is flat with no significant difference in efficacy between the 16-mg or 64-mg doses of ramelteon. It may have lower abuse potential than other hypnotics Thiopental Act directly on GABA-A complex and facilitate GABA transmission by opening chloride channels and enhancing hyperpolarisation. At lower doses, barbiturates enhance GABA by decreasing the rate of GABA dissociation and increasing the duration (not a number) of GABA-activated chloride channel opening. At slightly higher concentrations, barbiturates directly activate chloride channel opening even in the absence of GABA, an action that is not shared by benzodiazepines. Zolpidem, Zaleplon, Zopiclone, eszopiclone Z-drugs act via GABA A complex but act differently than benzodiazepines. Benzodiazepines occupy all 3 subunits of the ω receptor, but Z-drugs occupy only certain subunits. e.g,. zolpidem and zopiclone acts on ω1 receptors – hence no muscle relaxant, anxiolytic and anticonvulsant effects noted. Also, slow wave sleep is unaffected. Zaleplon occupies all 3 ω receptors. Zopiclone occurs as a racemic mixture where only s-isomer is active (eszopiclone). Z HYPNOTICS Given their selectivity on BDZ-receptor subunits, Z-drugs are less likely to impact sleep stages and have a lower risk of tolerance and dependence compared with benzodiazepine hypnotics Zopiclone is the least selective of all Z-drugs # 08 - Addiction pharmacology # Addiction pharmacology © SPMM Course Addiction pharmacology DRUG MECHANISM Alcohol Intercalates into the fluid cell membrane; decreases NMDA sensitivity; increases GABA sensitivity; down-regulates calcium channels; up-regulates nicotine receptor gated sodium channels. Amphetamine Acts via releasing stored monoamines especially noradrenaline and dopamine. Hence a central sympathomimetic. Buprenorphine Partial opioid agonist. Lower doses – mild agonism; higher doses – antagonistic effects. Cannabis Acts via cannabinoid receptors. CB1 is central and activated by 11OH tetra hydro cannabinoid. This inhibits GABA tone in the substantia nigra and other areas. May be related to increased dopamine activity at reward centres. CB2 is peripheral immune-related and seen in spleen and thymus. (Endogenous cannabinoids called anandamides are derived from arachidonic acid; their function is unclear) Clonidine, lofexidine Presynaptic alpha 2 agonist – reduces central sympathetic tone. Opioid receptors on locus coeruleus projections reduce noradrenergic tone on long-term use. The cellular machinery compensates via up-regulation of adenylate cyclase and maintains sympathetic tone in a chronic user. Sudden withdrawal leads to increased adrenergic firing rate (withdrawal symptoms); hence alpha 2 autoreceptor stimulation which reduces central sympathetic tone helps in opioid withdrawal. Dexfenfluramine & Fenfluramine Produce massive serotonin release from nerve endings. [Fen-Phen was an off-label combination of fenfluramine and phentermine used for promoting weight loss but fenfluramine (and dexfenfluramine) was withdrawn due to irreversible serotonergic damage, valvular regurgitation and pulmonary fibrosis]. Disulfiram Inhibits aldehyde dehydrogenase. Leads to accumulation of acetaldehyde if alcohol is consumed producing unpleasant reactions. Levomethadyl acetate (LAAM) Long-acting opioid agonist; potentially similar use as methadone. Withdrawn due to prolonged QT and torsades de pointes. Pure mu agonist. LSD 5HT2A partial agonism producing hallucinogenic effect MDMA Has 2 isomers  R(-) isomers produce LSD-like effects and the S(+) isomers have amphetamine-like properties LSD-like action is mediated via serotonin release from presynaptic neurons. In the long term, this can damage serotonergic tracts irreversibly. Methadone Opioid receptor agonist. Longer acting than heroin and orally available. Pure mu agonist. Naloxone Short-acting opioid mu antagonist Naltrexone Longer acting opioid mu antagonist Phencyclidine Noncompetitive NMDA antagonist similar to ketamine; also binds to sigma receptors Varenicline Varenicline (Champix) is a partial agonist at the α4β2 unit of nicotinic acetylcholine receptor. It assists smoking cessation by relieving nicotine withdrawal symptoms and reducing the rewarding properties of nicotine. # 09 - Anti dementia drugs # Anti dementia drugs © SPMM Course Anti dementia drugs DRUG MECHANISM Donepezil, Galantamine, Rivastigmine Cholinesterase Inhibitors. The act by inhibiting acetyl cholinesterase enzyme that breaks down acetylcholine centrally. Rivastigmine inhibits both the acetyl and butylcholinesterase while donepezil and galantamine are acetyl specific. Galantamine also has nicotine agonistic properties. Memantine Blockade of N-methyl-d-aspartate (NMDA) glutamate receptors. Unlike ketamine, which is a high-affinity noncompetitive blocker, memantine is a non-competitive blocker with low affinity and binds only to actively open NMDA channels. Its receptor dissociation rate is relatively fast, and so it does not accumulate and interfere with normal NMDA activity.  Acetylcholine is inactivated by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Cholinesterase inhibitors increase the amount of ACh available through inhibition of these enzymes.  An acetylcholinesterase inhibitor can work at either of two sites on AChE, an ionic subsite or a catalytic esteratic subsite; Tacrine and donepezil act at the ionic while physostigmine and rivastigmine act at the catalytic esteratic subsite.  Tacrine, and to some extent rivastigmine are non-selective inhibitors of both AChE and BChE.  CNS specific inhibition of AChE can occur with donepezil.  Binding to the AChE sites may be either reversible or irreversible, and may be competitive or noncompetitive with acetylcholine.  Galantamine is a competitive drug while tacrine is a non-competitive inhibitor.  AChE tetramer, G4, is located on the presynaptic membranes while a monomer, G1, is found on postsynaptic membranes. Although G4 is decreased along with the neuronal loss in AD, postsynaptic cholinergic receptor neurons and G1 ACh are not decreased significantly with AD or aging. Rivastigmine and to some extent galantamine are highly selective for the postsynaptic G1 monomer while donepezil is not selective. RILUZOLE It is approved for use in Motor Neuron Disorder. It is unclear whether this would help features of fronto-temporal dementia associated with MND. It prolongs survival by nearly 10% for more than a year of treatment. Riluzole’s mechanism of action is via 1. Sodium channel blockade 2. High-voltage calcium channel blockade 3. NMDA-glutamate receptor antagonism. It preferentially blocks the sodium channels in damaged neurons, reducing calcium flow and indirectly preventing excitotoxic damage. # 10 - Miscellaneous drugs # Miscellaneous drugs © SPMM Course Miscellaneous drugs DRUG MECHANISM Amantadine Used in Parkinsonism. It augments dopaminergic neurotransmission through an unknown mechanism. Dextroamphetamine Methylphenidate Methylphenidate, dextroamphetamine, and amphetamine are indirectly acting sympathomimetics – induce the release of dopamine and Noradrenaline from presynaptic neurons. Dextroamphetamine and methylphenidate are also weak inhibitors of catecholamine reuptake and inhibitors of monoamine oxidase. Atomoxetine Tricyclic like structure – phenylpropanolamine derivative. Selective inhibitor of the presynaptic noradrenaline reuptake (NARI) similar to the antidepressant reboxetine. Benztropine, Biperiden, Orphenadrine, Procyclidine Anticholinergic drugs. Used in the treatment of EPSEs induced by antipsychotics. Carbidopa Carbidopa inhibits aromatic-L-amino-acid decarboxylase (DOPA Decarboxylase). Administered together with l-dopa as Sinemet to reduce the peripheral conversion of dopa to dopamine. Carbidopa cannot cross the blood-brain barrier. Dantrolene Directly affects the formation of actin-myosin complexes in skeletal muscle through ryanodine calcium channel inhibition. Diphenhydramine, Hydroxyzine, Promethazine, Cyproheptadine. Antihistaminic drugs against central histamine H1 receptor. Cyproheptadine has both a potent antihistamine and serotonin 5-HT2 receptor antagonist properties. All of these agents have some antimuscarinic properties too. Cyproheptadine was used as anti-anorexic agent, and also to treat delayed ejaculation associated with SSRI use. Levodopa Dopamine precursor used in parkinsonism; is combined with carbidopa to reduce peripheral conversion to dopamine. Modafinil Activates hypocretin-producing neurons possibly through alpha 2 and/or alpha-1 adrenergic agonist properties (alerting effects) or some noradrenaline reuptake blocking effects; the stimulating effect of modafinil can be attenuated by prazosin. Pemoline Indirectly stimulates dopaminergic activity - but it has little actual sympathomimetic activity. A stimulant. Withdrawn due to hepatotoxicity. Reserpine Depletes the stored dopamine and other monoamines from vesicles. Can lead to depression and suicide. Sildenafil Phosphodiesterase-5 Inhibitor. Propranolol . Beta-adrenergic antagonist. Lipophilic and so can pass blood brain barrier and can have central actions. Reduces akathisia and peripheral signs of sympathetic overdrive seen in anxiety Pramipexole, ropinirole, apomorphine Apomorphine, pramipexole, and ropinirole are dopamine agonists - bind about 20 times more selectively to dopamine D3 than D2 receptors. Bromocriptine is less selective 2:1. Pergolide is most selective 5:1. Bromocriptine and pergolide are ergotamine derivatives. Pramipexole is a nonergot dopamine agonist. Apomorphine is structurally related to morphine and other opioids. Sumatriptan 5HT1D and 1F agonist Yohimbine It is an alpha 2 antagonist sometimes used in treating erectile dysfunction. © SPMM Course Lorcaserin, phentermine-topiramate combination, and naltrexone-bupropion combination are novel FDA approved treatment approaches to tackle obesity. These drugs are promoted as anorectic agents, similar to fenfluramine-phentermine combination ('fen-phen'), rimonabant, and sibutramine (all of the latter 3 which fell out of favour due to various adverse effects). Lorcaserin is a serotonin 2C receptor agonist; it is prescribed twice daily with an instruction to discontinue if 5% weight loss is not achieved by 12 weeks. The commonest side effect is a headache. In diabetic patients, this drug can induce hypoglycaemia. Phentermine is a sympathomimetic amine while topiramate is an antiepileptic drug. This combination is used in an extended-release preparation. Side effects include paraesthesia, dysgeusia and dizziness. Naltrexone is an opioid antagonist while bupropion is an aminoketone antidepressant that promotes weight loss in subjects even as a standalone drug (so a prescription of bupropion is not advised in those with a history of eating disorders). # 11 - 4. Neurochemical effects of ECT # 4. Neurochemical effects of ECT © SPMM Course 4. Neurochemical effects of ECT  Repeated subconvulsive electrical stimulation in animals reduces the seizure threshold – this process is called kindling. ECT does NOT produce a kindling effect; in fact it protects against kindling in animal studies. Thus, it can be termed an anti-kindling agent. As a result, dosing may need to be increased over the course of treatment to achieve the same seizure-inducing effect.  Hippocampal neuronal loss occurs in kindling. But ECT results in neurogenesis in the rat. This could be mediated by an increased expression of brain-derived neurotrophic factor and its receptor,  Blood–brain barrier permeability acutely increases following ECT but returns to baseline within 24 hours  Imaging studies show that ECT is not associated with markers of cell loss or damage e.g. there is no change in myelin basic protein immunoreactivity or neuron-specific enolase in serum. Tau protein, neurofilament and S-100 beta protein, markers of neuronal and glial damage, are also unchanged after ECT.  EEG shows delta and theta activity after applying ECT. This pattern returns to normal after 3 months of the end of treatment.  An increase in 5HT2 receptors are noted in rodents after applying electrical stimulation; this change is opposite to the changes noted after administering antidepressant drugs. But note that using a [18F] setoperone PET scan Yatham et al. (2010) have now demonstrated that unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT2 receptors in individuals with depression.  ECT also reduces β noradrenergic receptors and increases noradrenaline turnover. Further alpha 2 receptors are reduced after ECT, similar to antidepressants. Variables affected by ECT Changes Neurotrophic factors Increase in NGF,BDNF, NF3. Cell growth and synaptic connectivity Increased esp. In hippocampus Hormones Increased cortisol, prolactin, TSH coincides with good response. TRH gene expression increased in animals. Vasopressin, ACTH, oxytocin and opioid endorphins also increase consistently. Neurotransmitters and their receptors 5-HT-, NA-, cholinergic-, glutaminergic- and GABAergic systems, adenosine A1-receptor & 5-HT2A – all decrease in sensitivity. Activation of DA transmission and stimulation of 5-HT in hippocampus and amygdala. # 12 - 5. Psychopharmacogenetics # 5. Psychopharmacogenetics © SPMM Course 5. Psychopharmacogenetics Psychopharmacogenetics focuses on how polymorphisms in genes affecting the mechanism of action of a drug’s effect and/or metabolism (both peripheral and central) can influence an individual’s clinical response to the drug, in terms of both therapeutic efficacy and adverse effects. Drug Effect Biological substrate Nicotine replacement Response to nicotine replacement (esp. in women) Dopamine receptor DRD2 variant Clozapine Drug response No association with DRD2 variants DRD3 Ser9Gly polymorphism – controversial DRD4 polymorphisms– no correlation 5HT2A receptor polymorphism – associated 5HT2C receptor polymorphism – associated 5HT transporter linked polymorphic region (5HTTLPR) – associated CYP2D6 variations – overall efficacy not affected Methylphenidate Poor response of ADHD symptoms. Homozygosity for the 10-repeat allele at DAT1 Clozapine Agranulocytosis HLA loci variants Typical antipsychotics No association with DRD2 variants DRD3 Ser9Gly polymorphism – associated DRD4 polymorphisms– no correlation 5HT2A receptor polymorphism - associated Typical antipsychotics Extrapyramidal symptoms, postural hypotension & excess sedation Poor metabolizers of CYP2D6 Typical antipsychotics Acute akathisia Polymorphisms in DRD3 and DRD2 Typical antipsychotics Tardive dyskinesia DAT polymorphism, 5-HTTLPR and the tryptophan hydroxylase (TPH) polymorphism and to some extent CYP1A2 polymorphisms Typical antipsychotics Hyperprolactinaemia & NMS DRD2 polymorphism © SPMM Course The serotonin transporter (5-HTT) protein acts as the primary mechanism for removing 5-HT from the synaptic cleft. Two polymorphisms have been identified within the human 5-HTT, an insertion/deletion polymorphism in the promoter region (5-HTTLPR) results in a short (s) and a long (l) variant, and a VNTR polymorphism in intron. # 13 - 6. Ethnopharmacology # 6. Ethnopharmacology © SPMM Course 6. Ethnopharmacology Ethnicity is defined as a self-ascribed belongingness to a group with common geographical origins, race, language, religion, etc., which transcends kinship and neighbourhood. Ethnic categories retain a strong racial component. Race on the other hand is largely perceived by appearance and attributed to biological and genetic traits. Culture is a shared system of concepts or mental representations established by convention and reproduced by traditional transmission. Differences exist in the placebo response, compliance, doctor-patient relationship, social stress and health beliefs. The following are differences in the pharmacology of drugs administered. Absorption and availability  Caucasians appear to have lower plasma levels of tricyclic antidepressants and attain plasma peaks later when compared with Asians (of Far Eastern ancestry as well as those from the Indian subcontinent). These differences have been attributed to a greater incidence of slow hydroxylation among Asians when compared with Caucasians  Maximal haloperidol concentration in plasma after rapid tranquillisation is significantly high for Asians than Caucasians (Lin & Finder, Am J Psychiatry 140:490-491, 1983). Metabolism  In the CYP system, variations in CYP2D6 are largely determined by genetic factors. (CYP2D6 metabolizes a number of antidepressants, antipsychotics, beta-adrenoceptor blockers, and antiarrhythmic drugs). The CYP2D6 variation is called debrisoquine/sparteine polymorphism: 4 groups exist – 1. Poor metabolizers: develop side effects quickly. Caucasians - the highest rate of poor metabolizers (nearly 7%). East Asians - lowest – 1%. These 7% Caucasians and 1% East Asians lack this enzyme, and so are poor metabolizers of risperidone and tricyclics 2. Intermediate metabolizers: higher in Asians (most Asians fall into this group – hence have more side effects though good drug efficacy) 3. Extensive metabolizers 4. Ultrarapid metabolizers: need high doses. 33% North Africans have multiple copies of CYP2D6, and so are ultra-rapid metabolizers. They require higher doses of risperidone. Only 5% Caucasians and 1% East Asians are ultra-rapid. 25% Indians may have this variant.  CYP2C19 enzyme participates in the metabolism of omeprazole, propranolol and psychotropic drugs such as hexobarbital, diazepam, citalopram, imipramine, clomipramine, sertraline and amitriptyline. The incidence of poor metabolizers of CYP2C19 substrates is © SPMM Course much higher in Asians (15–30%) than in Caucasians (3–6%). CYP2C19 polymorphism is mephenytoin related.  Unlike CYP2D6, the variations in CYP3A4 often influenced by environmental (e.g. diet) factors.  Nearly 40% Asians and around 60% South American Native Indians lack Aldehyde dehydrogenase enzyme in sufficient amounts to metabolise alcohol – this serves as a natural deterrent in these communities. Pharmacodynamics The long form serotonin transporter polymorphism in Caucasians is associated with better SSRI response and tolerance while the opposite is true in South East Asians. Low COMT variant is seen in less than 20% of Asians and Africans, but nearly 50% of Caucasians show low variant. Adverse effects  A well-known example from general medicine is that of Isoniazid – East Asians are most likely to be rapid acetylators and suffer from hepatotoxicity. But they have lesser peripheral neuropathy seen in slow acetylators.  Chinese people had higher levels of extrapyramidal side-effects with haloperidol, and their blood levels were comparably high on equivalent dosages.  On the administration of antipsychotics, Asian subjects were reported to produce greater serum prolactin levels than Caucasian subjects. This remains statistically significant after controlling for the difference in haloperidol concentrations, suggesting that the two groups differ in their dopamine receptor-mediated response.  A summary of some relevant ethnic effects is given below. African Americans Asians  Increased diagnosis of schizophrenia but decreased diagnosis of depression  Have more side effects with lithium, tricyclics  Higher tardive dyskinesia with antipsychotics.  Better, rapid response to tricyclics and lorazepam, but poor response to fluoxetine.  More depot medications received by African Americans.  It is best to start at half of the standard dosage of all psychiatric medications  Clozapine better effect in lower serum range, but higher incidence of agranulocytosis  Taiwanese have lower required therapeutic level of lithium.  Metabolise TCA slowly.  Asians use herbal remedies more often than others. # 14 - Gender differences in psychopharmacology # Gender differences in psychopharmacology © SPMM Course Gender differences in psychopharmacology  Antipsychotic response is shown to be superior in women  In chronically ill population, men are found to require twice as high a dose as women for effective maintenance.  Women have higher antipsychotic plasma levels than men after receiving the same dose of the drug.  The enzyme CYP1A2 appears to be less active in women than in men, leading to relatively higher blood concentrations of olanzapine and clozapine in women.  The volume of distribution of lipophilic drugs, such as antipsychotics, is greater in women than in men  In women, the blood volume is smaller, but lipid compartments are larger. This prolongs the half-life of antipsychotics in the body, leading to accumulation over time, a phenomenon that becomes important when administering depot injections. After a steady state is achieved, dosing intervals for women should be longer than for men.  Acute dystonia, long thought to be more prevalent among men, has been shown now to be more frequent in females at equivalent doses. Earlier clinical studies had not taken into account the fact that young male patients were commonly given higher doses than women.  Pulmonary embolism (a rare problem seen with drugs that have an affinity for the serotonin 5-HT2A receptor) and tardive dyskinesia appear to be more common in women. © SPMM Course Notes prepared using excerpts from:  Appleby, L. et al (Ed) Postgraduate psychiatry: Clinical and scientific foundations. 2nd ed. Page 65  Bhugra, D & Bhui, K. Ethnic and cultural factors in psychopharmacology. Advances in Psychiatric Treatment (1999), vol. 5, pp. 89-95  http://www.dlc-ma.org/Resources/Health/Ethnic%20Psychopharmacology.html  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007  Poolsup et al. Pharmacogenetics and psychopharmacology. Journal of Clinical Pharmacy and Therapeutics (2000) 25, 197-220  Seeman, M. (2004) Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry 161:1324-1333.  Shiloh, R., Nutt, D. & Weizman, A. (2000). Atlas of psychiatric pharmacotherapy. Martin Dunitz, London.  Stahl, S. M. Essential psychopharmacology : neuroscientific basis and practical application 2nd ed Cambridge University Press 2000  Tsapakis, E. M., Basu, A. & Aitchison, K. J. (2004) Clinical relevance of discoveries in psychopharmacogenetics. Adv Psychiatr Treat, 10, 455-465.  Yudkin, P. (2004) Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. BMJ, 328, 989 -990.  Maixner D& Taylor MA. The efficacy and safety of electroconvulsive therapy. In Effective Treatments in Psychiatry. ed. Tyrer P. Cambridge University Press, 2008.  Wahlund, B., & von Rosen, D. (2003). ECT of major depressed patients in relation to biological and clinical variables: a brief overview. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 28, S21-6.  Yatham, L. N., Liddle, P. F., Lam, R. W., Zis, A. P., Stoessl, A. J., Sossi, V., ... & Ruth, T. J. (2010). Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression. The British Journal of Psychiatry, 196(6), 474-479. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 14 - 44_Adverse_Drug_Reactions # 01 - 1. Types of adverse reactions # 1. Types of adverse reactions © SPMM Course 1. Types of adverse reactions Type of reaction Mnemonics Features A: dose-related Augmented e.g., Lithium toxicity – ataxia, coarse tremors, vomiting. B: non-dose related Bizarre Idiosyncratic e.g. malignant hyperthermia, or lamotrigine induced Steven Johnson syndrome C: dose and time related Continuous use Related to cumulative drug use—e.g. long term lithium use and renal damage D: delayed effect Delayed Not due to dose per se but due to the length of use of a medication e.g. tardive dyskinesia in some cases. E: Withdrawal End of use Related to abrupt discontinuation e.g. SSRI discontinuation reaction, opioid withdrawal effects, etc. Tolerance is defined as the need to use increased doses of a drug to maintain a clinical effect. Tolerance is seen for both therapeutic effects and side effect. This may be due to decreased sensitivity of the target receptors due to down-regulation (decrease in numbers in case of agonists), up-regulation (increase in number of receptors in case of antagonists), or reduced responsivity without alterations in receptor numbers. Drugs with similar pharmacological actions can exhibit cross-tolerance e.g. benzodiazepines and barbiturates. Sensitization (aka reverse tolerance) manifests when sensitivity to a drug effect increases over time i.e. the same dose typically produces more pronounced effects as treatment progresses. This is reported with the street use of cocaine. Note that up or down-regulation can be a mechanism of therapeutic effect e.g. in case of SSRIs, the 5HT1A autoreceptors in somatodendritic zones undergo downregulation secondary to increased serotonin availability in the vicinity when reuptake is blocked; this in turn leads to an increase in serotonergic tone of the neurons. Withdrawal: When drugs are administered for a reasonable period of time, a physiological adaptation develops which on withdrawal of the drug can get disturbed and leads to withdrawal symptoms. Abrupt withdrawal of treatment especially for an agent with shorter elimination half-life leads to clinically significant withdrawal symptoms. Hypnotics, opiates, barbiturates, SSRIs, Venlafaxine are some of the drugs associated with discontinuation reaction or withdrawal symptoms. The variables influencing withdrawal symptoms are listed below: © SPMM Course 1. Half life Methadone has less withdrawal than heroin as methadone has longer t1/2 2. Range of action Paroxetine has anticholinergic properties; withdrawal causes cholinergic rebound=d symptoms 3. Enzyme interference Paroxetine inhibits its own metabolism via CYP2D6. So withdrawal leads to loss of inhibition Æ excessive paroxetine breakdown Æ sudden steep drop in levels Æ withdrawal symptoms 4. Active metabolites Fluoxetine has active metabolite norfluoxetine with long half-life – hence it produces fewer withdrawal symptoms 5. Rate of withdrawal Slow, gradual tapering is the best. 10% dose reduction every 2 weeks is advocated for benzodiazepines. 6. Co-prescribed drug effects Prescribing an enzyme inducer can reduce the effects of a drug acutely if its metabolism depends on the induced enzyme; Similarly prescribing an antagonist can precipitate withdrawal symptoms. This is the rationale for leaving at least 72 hours before prescribing naltrexone for an opioid detoxified patient. 7. Receptor profile Full agonists on withdrawal produce more discontinuation reactions than partial agonists e.g. clonazepam produces lesser benzodiazepine withdrawal symptoms. Sustained-release preparations influence the absorption kinetics– not elimination kinetics, hence upon withdrawal, the drop in plasma levels occur at same rate in both XL and plain preparations; e.g. venlafaxine XL has similar discontinuation reaction as venlafaxine normal release. But depot preparations have less withdrawal propensity that corresponding oral drugs. # 02 - 2. Mechanism of adverse effects # 2. Mechanism of adverse effects © SPMM Course 2. Mechanism of adverse effects Side effect Receptor Agitation α  2 blockade, 5HT2A/2C stimulation, DRI Akathisia D2 blockade, 5HT2A stimulation (hence some data on mirtazapine, 5HT2A antagonist, reducing akathisia) Delirium Anticholinergic effect (antimuscarinic) EPSE D2 blockade reduces with 5HT2A antagonism Hyperthermia Antimuscarinic action, in serotonin syndrome, may be mediated via 5HT2A/2C Insomnia α 1 stimulation, 5HT2Astimulation (hence SSRIs cause insomnia) Amnesia (memory defects) Anticholinergic effects, GABAA stimulation Hyperprolactinaemia D2 blockade, 5HT1A stimulation Disrupted slow wave sleep SWS is maintained by 5HT2A inhibition; 5HT2A stimulation disrupts sleep architecture Sweating Cholinergic effect and increases with noradrenaline reuptake inhibition Postural hypotension α  1  antagonism Appetite loss 5HT2A stimulation (antihistaminics can increase appetite) GI discomfort, nausea, vomiting 5HT3 stimulation Weight gain 5HT2C antagonism and antihistaminic effects Anticholinergic effects Blurred vision, exacerbation of narrow-angle glaucoma, delirium, and photophobia due to mydriasis, dry secretions, constipation, tachycardia, decreased sweating, urinary retention and hyperthermia. Anorgasmia α  1  antagonism,  5HT2A/2C  stimulation  (delayed  ejaculation  in   SSRIs).  Retrograde  ejaculation  due  to  α  1  block,  anticholinergic   and antihistaminic effects. Tardive dyskinesia Supersensitivity of dopamine receptors, which develops because of prolonged therapy with dopamine-blocking drugs Impotence α  2  blockade,  5HT2A/2C  stimulation.  5HT2A/2c  stimulation  can   also reduce libido. Priapism α  1  blockade Obsessions 5HT1D stimulation can induce obsessions. 5HT1A and 2A stimulation reduce OCD. Pathological gambling Habituation of dopamine receptors on repeated use of dopamine agonists (e.g. levodopa) leading to dopamine dysregulation syndrome (DDS) © SPMM Course Weight gain: No single mechanism can explain the complex metabolic phenomenon of weight gain. Antihistaminic effects, 5HT2A/2C antagonism, insulin resistance (valproate and olanzapine) are noted. Genetic factors seem to involve 5-HT2C receptor. Drugs with a strong 5-HT2C affinity will have a greater impact on body weight of patients with a specific variant of polymorphism of the 5-HT2C receptor promoter regions. Low-potency antipsychotics (chlorpromazine and thioridazine) produce more weight gain and sedation than high-potency agents (haloperidol and fluphenazine). # 03 - 3. Antipsychotics adverse effects # 3. Antipsychotics - adverse effects # 04 - Extrapyramidal effects # Extrapyramidal effects © SPMM Course 3. Antipsychotics - adverse effects Extrapyramidal effects Acute extrapyramidal syndromes such as acute dystonia, akathisia and parkinsonism are noted with high potency drugs more than low-potency drugs. Tardive dyskinesia and dystonia, perioral tremor (rabbit syndrome) are chronic late side effects. PET studies have indicated that 60%–80% occupation of D2 receptors is associated with antipsychotic efficacy. Higher occupancy levels are associated with an increased risk of acute extrapyramidal symptoms as well as hyperprolactinemia from the blocking of D2 receptors on anterior pituitary mammotrophic cells that normally are tonically inhibited by dopamine produced in the hypothalamic arcuate nucleus. Antipsychotic drugs which have the propensity to induce Parkinsonism (trifluoperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than the endogenous ligand dopamine to D2, while the drugs with low Parkinsonism-inducing propensity (quetiapine, clozapine etc) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the loosely bound ones are weaker in potency and thus require higher doses to be clinically effective, but can be titrated faster. These loosely-bound drugs may also dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than the traditional tightly bound antipsychotic drugs (though ths does not seem to be the case for clozapine). Drug-induced parkinsonism is seen in 15-20% of patients treated with antipsychotics, seen within 90 days of treatment (5 to 90) and is characterized by muscle stiffness, cogwheel rigidity, shuffling gait, stooped posture, and drooling. The pill-rolling tremor of idiopathic Parkinsonism is not seen in drug-induced EPSEs - but a regular coarse tremor is seen. Elderly and female are under higher risk. Low potency drugs and those with higher anticholinergic effects cause less EPSEs. It is thought that higher than 80% receptor occupancy of brain D2 by antipsychotics can cause EPSEs. Atypical drugs cause low EPSEs probably due to anticholinergic effects, HT2A antagonism or less avidity of binding i.e. hit and run profile especially for clozapine and quetiapine. Anticholinergics can be used for short period of up to 6 weeks to treat the parkinsonian symptoms. As tolerance can develop for EPSE, the anticholinergics should be withdrawn after 4 to 6 weeks; also, longer chronic anticholinergic prescription increases the risk of TD. The rabbit syndrome is a tremor affecting the lips and perioral muscles and occurs late in the course of treatment. © SPMM Course Dystonias are brief or prolonged contractions of specific groups of muscles resulting in symptoms such as oculogyric crises, tongue protrusion, trismus, torticollis, blepharospasm. Rarely pharyngeal dystonia can occur resulting in dysarthria, dysphagia, and even respiratory choking. Dystonias occur early in treatment course and can reduce compliance. It is often seen in younger men receiving a high dose of high-potency medications. It is more common with IM administration. Dopaminergic hyperactivity in the basal ganglia occurring when plasma levels fluctuate may be the mechanism behind dystonias. Dystonias show spontaneous fluctuations, response to reassurance and to anticholinergic drugs. Akathisia includes both subjective and objective - feelings and signs of restlessness. (Possibly due to higher D2 occupancy in striatum). Patients may exhibit inability to relax, jitteriness, pacing, rocking with alternation of sitting and standing. Akathisia can be caused by not only neuroleptics but also antidepressants and sympathomimetics. Dose reduction, changing the drug or adding beta blocker/anticholinergic drugs or benzodiazepines or cyproheptadine are recommended. Akathisia may be associated with an increase in absconsion, suicides and violence if left undiagnosed and untreated in some cases. Tardive dyskinesia is a late side effect occurring in nearly 25% patients usually only after (at least 6 months) 1 – 2 years of treatment. It presents as abnormal, involuntary, irregular choreoathetotic movements of the muscles of the head, limbs, and trunk. Perioral movements are the most common. In some serious cases, patients may have breathing and swallowing muscles involved leading to aerophagia and grunting. TD is exacerbated by stress but is absent during sleep. The absence of insight about the movement disorder is striking in patients. Most cases remit spontaneously. Elderly have a poor spontaneous resolution. Tardive dyskinesia is less likely to remit in elderly patients than in young patients, however. Clozapine can reduce the risk and also treat TD. Dose reduction, withdrawal of the drug, switch to newer atypicals or adding clonazepam can be considered. Neuroleptic Malignant Syndrome Can occur at any time during treatment with neuroleptics RISK FACTORS FOR TARDIVE DYSKINESIA Female gender Elderly Diabetics Previous brain damage Affective illness rather than pure psychotic disorder Children Learning disabled Afro-Caribbean race Long term co-prescription of anticholinergics Frequent drug holidays – will lead to high dose prescription with each relapse # 05 - Agranulocytosis # Agranulocytosis © SPMM Course Consists of the tetrad of extreme hyperthermia, severe muscular rigidity and confusion, and autonomic fluctuations (BP and pulse rate). Patients may be akinetic and mute. Increased WBC count, creatinine phosphokinase, liver enzymes, plasma myoglobin, and myoglobinuria are noted. Subacute onset in 24 to 72 hours, and if untreated lasts 10 to 14 days. More common in young men, after agitation and when using high potency drugs especially in rapid tranquillisation situations. Dopaminergic drugs on withdrawal can produce NMS. The mechanism may be related to dopamine blockade or hypothalamic sympathetic dysregulation. The mortality rate is around 20-30% if untreated and higher if depot is used. Symptomatic management of vital signs instability, fluid replacement and prevention of renal failure secondary to myoglobinuria and prevention of aspiration pneumonia are main treatment methods after immediate stopping of offending psychotropic. Dantrolene, Bromocriptine or amantadine can be used. Low potency or atypical must be used following recovery for an antipsychotic prescription. Agranulocytosis Occurs in around 1 per 100 patients on clozapine. This is 15 to 30 times higher than the risk associated with phenothiazines and olanzapine. The maximum risk is between 4 and 18 weeks, and after a year the risk is same as with phenothiazines. Weekly monitoring of the white cell count is required for 26 weeks in most countries, with the frequency decreasing to biweekly or monthly thereafter. In the UK, yellow, green and red signals are used in WBC monitoring. When a result is red, clozapine must be stopped and never tried again. If yellow, then monitoring frequency must be increased until a green signal is obtained again. Benign neutropenia is common especially in south Asian and Afro-Caribbean race. Lithium can increase WBC count albeit transiently. Some anecdotal evidence supports using lithium in patients with benign ethnic neutropenia in preparation for clozapine use. But lithium and clozapine together can increase the risk of seizures and confusion. Clozapine, when combined with carbamazepine, phenytoin, propylthiouracil, sulfonamides, and captopril, can increase the risk of agranulocytosis further. Paroxetine may precipitate clozapine-associated neutropenia. Many side effects of clozapine such as salivation, sedation, and weight gain, fatigue and lowering of seizure threshold are dose related. But agranulocytosis and myocarditis can occur at any dose. # 06 - Sexual dysfunction # Sexual dysfunction: # 07 - Other side effects # Other side effects © SPMM Course Transient leucopenia can occur with typical neuroleptics. But agranulocytosis is the rare effect. Sexual dysfunction: Increased dopaminergic transmission can enhance sexual arousal and penile erection. Hyperprolactinaemia can result in loss of sexual arousal and erectile dysfunction in men; amenorrhoea, reduced sexual desire and hirsutism in women. Antipsychotics reduce sexual performance both directly by reducing dopaminergic transmission and indirectly through inducing hyperprolactinaemia. 43% of those taking antipsychotics report sexual dysfunction at some point, not all of this attributable to the drug. Neuroleptic agents commonly cause ejaculatory problems. Total inhibition of ejaculation (dryejaculation),  reduced  ejaculatory  volume  and  ‘retrograde’  ejaculation  are  the  various  effects   associated with conventional neuroleptics and also clozapine, risperidone and olanzapine. Drug-induced priapism is  related  to  simultaneous  α1-adrenergic blockade and anticholinergic activity. The most commonly reported associations are with antipsychotic drugs (20% of all reported priapisms) followed by trazodone. Antipsychotics implicated in this problem include risperidone, chlorpromazine clozapine, olanzapine and thioridazine. The risk is doseindependent and can occur at any time during the course of treatment (duration-independent). Priapism is a urological emergency and can lead to permanent impotence if untreated. Dopaminergic agonist bromocriptine is used to treat sexual dysfunction in men that is associated with hyperprolactinaemia. Other side effects Seizure threshold is lowered especially by low potency antipsychotics. Molindone may be the least epileptogenic. This is a dose-dependent effect. Chlorpromazine is the most sedating typical antipsychotic – mediated by H1 antihistaminic action – tolerance usually develops for this effect. Low potency agents can also cause anticholinergic syndrome (see TCAs). Neuroleptics can decrease cardiac contractility, increase circulating levels of catecholamines, and prolong atrial and ventricular conduction time. Low-potency drugs are more cardiotoxic than high-potency drugs. ECG shows QT and PR prolongation, blunting of the T waves, and ST depression. Thioridazine and droperidol, in particular, can cause torsade de pointes. Antipsychotic related sudden death may be due to cardiac arrhythmias or even seizures asphyxiation or malignant hyperthermia. Drugs causing QT prolongation are associated with more sudden deaths (e.g. thioridazine). Postural hypotension is most common with © SPMM Course low-potency drugs, and tolerance develops soon. Patients should avoid all caffeine and alcohol, drink plenty of fluid and liberal salt in food. Low-potency drugs can cause weight gain but not as much as is atypical drugs. Nearly 50% of men taking antipsychotics report ejaculatory and erectile disturbances. Thioridazine is particularly associated with decreased libido and retrograde ejaculation in men. Allergic dermatitis and photosensitivity can occur with low-potency agents. Long-term chlorpromazine use can cause blue-gray discoloration of skin areas exposed to sunlight. This is reversible. Irreversible retinal pigmentation is associated with the use of high dose thioridazine (above 1000 mg a day). An early symptom of the side effect can sometimes be nocturnal confusion associatd to difficulty with night vision. This pigmentation is irreversible and can progress even after stopping thioridazine. Chlorpromazine related pigmentation of the anterior lens and the posterior cornea is seen as whitish brown stellate granular deposits noted in slit lamp – this is benign and not vision impairing. This can resolve gradually unlike thioridazine related retinal damage. Chlorpromazine is associated with cases of obstructive or cholestatic jaundice especially in the first month of treatment associated with rash and eosinophilia. Immediate discontinuation and avoidance of rechallenge are advised. Haloperidol isone of the safest typical antipsychotics in overdose. After an overdose, the electroencephalogram (EEG) shows diffuse slowing and low voltage. QT prolongation: Prolongation of the QT interval is mediated by blockade of the rapid component of the delayed rectifier potassium current (IKr) responsible for repolarisation of cardiac Purkinje cells and myocardial cells. Many drugs, including certain antipsychotics and antidepressants, bind to this potassium channel and thereby decrease the outward movement of potassium. Some antipsychotics – especially droperidol, pimozide, sertindole and thioridazine – have a greater capacity than others to cause IKr blockade. InAdvertent IntraVascular injection event (IAIV) or postinjection delirium sedation syndrome (PDSS) has been described after olanzapine pamoate (long-acting depot) injections. Within 20 min to 3 hours of injection, patients present with sedation, confusion, dizziness, altered speech/dysarthria, and somnolence, symptoms that are consistent with those reported in the case of oral olanzapine overdose. Rarely deep coma may ensue. Medical hospitalization and supportive medical care are usually sufficient to ensure full recovery (usually within 3–72 hours). This effect is linked to accidental punctures of a vessel or injections into a rich capillary bed during administration, leading to quick dissolution and release of free olanzapine. Eli Lilly has recommended a postinjection # 08 - Metabolic syndrome # Metabolic syndrome © SPMM Course observation period of at least 1 - 3 hours in a healthcare facility and to avoid driving or operating heavy machinery in the 24 hours after injection. Metabolic syndrome Metabolic syndrome is a cluster of disorders comprising obesity (central and abdominal), dyslipidaemias, glucose intolerance, insulin resistance (or hyperinsulinaemia) and hypertension. It is highly predictive of type 2 diabetes mellitus and cardiovascular disease. Diabetes Mellitus is twice as prevalent among schizophrenia cohorts than in the general population Unaffected first-degree relatives of patients with schizophrenia share a propensity for type 2 diabetes mellitus (19-30%); this suggests a genetic association between these two disorders Schizophrenia patients have 3 times greater intra-abdominal fat (IAF) than the control group, increasing the risk for metabolic syndrome. In the pre-antipsychotic era over 15% of drug-naïve individuals with first-episode schizophrenia had impaired fasting glucose levels, hyperinsulinaemia and high levels of cortisol. Both typicals and atypicals increase the risk of metabolic syndrome in schizophrenia manifold. But antipsychotics cannot explain all the metabolic dysfunctions noted in schizophrenia. The frequency of metabolic syndrome was 2-4 times higher in a group of people with schizophrenia treated with either typical or atypical antipsychotics. MOST Olanzapine / clozapine quetiapine risperidone ziprasidone aripiprazole/ lurasidone LEAST World Health Organization criteria for metabolic syndrome World Health Organization criteria for metabolic syndrome •Insulin resistance and/or impaired fasting glucose and/or impaired glucose tolerance AND two or more of the following: •Waist - hip ratio >0.90 (men), >0.85 (women) OR body mass index 30 kg/m2; •Triglyceride level 1.7 mmol/l OR high-density lipoprotein <0.9 mml/l (men), <1.0 mmol/l (women); •Blood pressure 140/90 mmHg (or treated hypertension); •Microalbuminuria. (This is not presented in some revised criteria for metabolic syndrome) © SPMM Course In Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial baseline data (n = 689), the metabolic syndrome was prevalent in 51.6% of female patients and 36.0% of male patients. Females with schizophrenia have a higher risk than males with schizophrenia when compared with a reference population. Mean weight increases during the first year of therapy o 12 to 14lb for clozapine (5 to 6 kg) o 15 to 26lb for olanzapine (7 to 12kg) o 6 to 12lb for quetiapine (2.5 to 5kg) o Up to 5lb for risperidone (2 to 2.5kg) o Less than 2lb for Ziprasidone and aripiprazole For patients with schizophrenia, the best-studied options for weight control include diet and exercise. But controlled behavioral programs for weight reduction in schizophrenia have high dropout rates and are not always accessible. Switch to relatively weight neutral drugs can be considered in resistant cases. CATIE summary CATIE stands for Clinical Antipsychotic Trials of Intervention Effectiveness. The study design was double-blind pragmatic RCT. 1493 patients with chronic schizophrenia (mean duration of illness = 14 years), 57 sites, 2001 to 2004 Olanzapine, quetiapine, Risperidone, ziprasidone (added later in the trial), perphenazine Primary  outcome  is  a  ‘real-world’  measure  – discontinuation for any reason, either patient-initiated or physician initiated 76% power to detect 12% difference in primary outcome Irrespective of the prescribed drug – 74% discontinued treatment in 18 months (surprisingly high despite naturalistic design). The median time to stop was 4.6 months. Olanzapine had lowest discontinuation rate (still 64%) – but highest side effect burden. 64% discontinued olanzapine; 75%, perphenazine; 82%, quetiapine; 74%, risperidone; and 79%, ziprasidone. Olanzapine caused most weight gain while quetiapine caused most anticholinergic symptoms; perphenazine had highest EPSE related discontinuation. Those who did not respond after 18 months (those who discontinued for the ineffectiveness of therapy) were re-randomised in phase 2 trial (n=99), and Clozapine was compared to other atypical agents (efficacy pathway). Clozapine had lowest discontinuation rate – median at 10 months. This time-to-discontinuation was nearly 3 times longer than time-to-discontinuation with the other SGAs. Quetiapine had comparatively less EPSEs. As a part of the phase 2 CATIE study (tolerance pathway) those who terminated phase 1  for  ‘‘intolerable  side   effects’’  (444  volunteers)  were  tested  with  olanzapine,  risperidone,  quetiapine,  or  ziprasidone. Of these treatments, olanzapine and risperidone had equivalent effectiveness, and both were better than quetiapine or ziprasidone by significant but modest margins. CATIE Controversies o Quite complicated study design and many outcomes were analysed from the dataset. o Decisions to add ziprasidone to the protocol was made after recruitment began o Perphenazine was used only in one randomized phase (phase 1) of the study generating controversy. © SPMM Course o The decision to use double-blinded treatments decreased the resemblance of the study procedures to those of routine clinical care The mean doses used remain controversial though it is claimed that the study was designed to be pragmatic and not purely experimental. CUtLASS summary: CUtLASS stands for Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study It is an unblinded randomised controlled trial comparing first-generation v. second-generation antipsychotics The primary outcome was the quality of life at 1 year and symptom measures were the main secondary outcome. 1, 227 people with schizophrenia who were being assessed by their clinical team for medication review because of poor response or adverse effects were randomised. The second-generation drugs were amisulpride, olanzapine, quetiapine or risperidone. The rate of follow-up interview was 81% at 1 year. The results showed no advantage of second-generation drugs in terms of quality of life or symptom burden over 1 year with those on first-generation antipsychotic doing relatively better. Participants reported no clear preference for either class of drug. The second phase - CUtLASS 2 trial was of similar design and compared clozapine with other secondgeneration drugs in 136 patients who had not responded well to two or more previous drugs. Results showed that there was a significant advantage for clozapine in symptom improvements over 1 year; moreover, patients significantly preferred it. # 09 - 4. Antidepressants adverse effects # 4. Antidepressants - adverse effects # 10 - Tricyclic agents # Tricyclic agents © SPMM Course 4. Antidepressants - adverse effects Tricyclic agents Side effects of TCAs are related to anticholinergic, antihistaminic and antiadrenergic properties. Clomipramine is a more selective inhibitor of serotonergic reuptake selective; desipramine is the most noradrenergic selective of TCAs. Amoxapine, nortriptyline, desipramine, and maprotiline have the least anticholinergic activity; doxepin has the most antihistaminic activity. The TCAs are less likely to cause sexual dysfunction and insomnia than the SSRIs. Amitriptyline is associated with weight gain (antihistaminic effect – weight gain can also occur secondary to 5HTc antagonism in other antidepressants). TCAs may cause QT prolongation. Even at therapeutic doses, the TCAs cause tachycardia, flattened T waves, prolonged QT intervals, and depressed ST segment. TCAs are lethal in overdose, causing cardiac arrhythmias and anticholinergic delirium. This may occur 3-4 days after overdose due to the long half-life. No specific antidote available; needs lavage and QRS monitoring. Anticholinergic delirium is characterized by symptoms often described  as    ‘Mad as a hatter, (confusion, disorientation, visual hallucinations), Hot as a hare (hyperpyrexia), Blind as a bat (loss of visual accommodation), Red as a beet (peripheral vasodilatation) and Dry as a bone (drying of mucous membranes)’. Amoxapine can cause hyperprolactinemia as it has dopamine antagonistic effects. SIADH and hyponatremia can occur with TCAs. Fine rapid tremor and dysarthria are sometimes reported with TCAs. Tricyclic agents such as amitriptyline and imipramine and the nontricyclic agents such as mianserin hydrochloride have been documented to precipitate an attack of angle closure glaucoma. TCA discontinuation: Can cause cholinergic rebound – best to reduce 25 to 50mg per 2-3 days. Discontinuation reaction may occur as early as 48 hours or as late as 2 weeks after discontinuation. Propantheline or reinstitution of withdrawn TCA can reduce cholinergic rebound symptoms. © SPMM Course NMS vs. serotonin syndrome NMS Serotonin syndrome Dopamine antagonism and suspected hypothalamic mediated sympathetic overdrive. Excess serotonin availability Onset subacute – days to weeks Sudden minutes to hours onset Resolves in 2 weeks - depending on t1/2 of offending drug Resolves as soon as excess serotonin is reduced – in 24 hours generally No myoclonus Myoclonus prominent Hypomania, not a feature Hypomania may be seen Reflexes normal or absent Hyperreflexia seen Rhabdomyolysis, resultant renal failure and acidosis occur commonly Muscle breakdown not common •Serotonin syndrome is a result of excessive serotonergic transmission in brain. Although no single mechanism appears to be responsible for all of the noted effects, most CNS symptoms are possibly mediated via 5HT 2A receptor stimulation. Mechanism of Serotonin Syndrome Mechanism of Serotonin Syndrome •It is characterized by diarrhea, myoclonus, diaphoresis, hyperactive reflexes, ataxia, hypomanic or labile mood, tremors and disorientation. • It may mimic NMS or anticholinergic syndrome in those receiving psychotropics. Features of serotonin syndrome Features of serotonin syndrome •Any serotonergic agent on overdose – including SSRI and TCA antidepressants, fenfluramine, LSD, ecstasy, anti-migraine (e.g. sumatriptan) drugs. •High risk with combinations of SSRI and MAOI or RIMA or SSRI themselves, or TCAs especially serotonergic, or SNRI, lithium or l-tryptophan. TCA and MAOI combinations. Tramadol, pethidine, meperidine can also cause serotonin syndrome on combination with the above agents. •Oxazolidinone antibacterial linezolid (which is a reversible non-selective MAOI), tetrabenazine (acts via dopamine and serotonin depletion at nerve endings), entacapone (COMT inhibitor) and selegiline are also implicated. Drugs with high risk of serotonin syndrome: Drugs with high risk of serotonin syndrome: •Withdraw the offending agent •Supportive care: correction of vital signs •Benzodiazepines •5HT2A antagonists: cyproheptadine, atypical antipsychotics, chlorpromazine (? mirtazapine – controversial reports) •In severe cases neuromuscular paralysis and intubation may be required Treatment of Serotonin syndrome: Treatment of Serotonin syndrome: # 11 - SSRI antidepressants # SSRI antidepressants © SPMM Course CPK elevation common; WBC also elevated These laboratory abnormalities are less frequent in serotonin syndrome SSRI antidepressants Nausea, vomiting, anorexia, and diarrhea are common side effects of SSRIs – these are somewhat dose-dependent and can be lessened by dose reduction or a slower titration. SSRIs (similar to TCAs, but less frequently) cause weight gain in up to 30% of patients especially in long-term maintenance phase. During initial treatment insomnia and anorexia are often present. Desensitization and down-regulation of receptors may explain the reversal of the initial SSRI appetitesuppressing effects, which can ultimately lead to weight gain late during therapy. Sexual difficulties such as reduced libido, impotence, ejaculatory dysfunction, and anorgasmia are reported with SSRIs. The incidence of sexual dysfunction is nearly every 1 in 3 patients treated. Akathisia like effects, EPSEs and galactorrhea are rarely reported with SSRIs. Also, fluoxetine is associated with a change in the duration of menstrual period – significance of this is unknown. SSRIs can cause functional impairment of platelet aggregation (thrombasthenia), but not a reduction in platelet number. This can cause easy bruising or prolonged bleeding in those with gastric ulcers or bleeding diathesis. SIADH is also reported; this is often troublesome in alcoholics and the elderly causing hyponatremia, hyperkalemia, hypo-osmolality in serum and increased osmolality of urine. Stopping the offending drug, using demeclocycline and fluid restriction can help. Severe sweating especially nocturnally is seen in some patients; Terazosin is effective in counteracting sweating. Nocturnal myoclonus is reported with SSRIs. The repetitive leg movements occur every 20 to 60 seconds, with extensions of the large toe and flexion of the ankle, the knee, and the hips. Benzodiazepines and levodopa may be tried. In restless leg syndrome, patients complain of creeping deep sensations that cause an irresistible urge to move the legs – disturbing sleep. It is associated with SSRIs and treatment is possible using ropinirole or benzodiazepines and levodopa. Duloxetine, venlafaxine, citalopram, fluoxetine and paroxetine can induce acute angleclosure glaucoma. The pathophysiological mechanism of SSRI –precipitated glaucoma remains unclear; anticholinergic effects or increased level of serotonin, which cause partial pupillary dilation have been implicated. SSRI discontinuation syndrome: The abrupt withdrawal of SSRI especially paroxetine (additional cholinergic rebound) or fluvoxamine (shorter half-life), is associated with a discontinuation syndrome. It usually requires at least 4-6 weeks of treatment before © SPMM Course discontinuation and resolves spontaneously in 3 weeks. Those who have significant SSRI intolerance during treatment onset will have more discontinuation reactions. Fluoxetine is the SSRI least likely to cause withdrawal syndrome as its metabolite has a long half-life (more than 1 week), producing a slow self-tapering effect in plasma. Fluoxetine in some cases can be used to even treat discontinuation syndrome or to prevent it when stopping another SSRI agent. But a delayed withdrawal syndrome has been reported with fluoxetine in some cases. SSRI discontinuation syndrome Criterion A Discontinuation or reduction of dose of SSRI after at least 1 month use Criterion B 2 or more of the following seen within 1-7days of criterion A causing significant functional impairment and not due to a general medical condition: x Dizziness, lightheadedness, shock-like sensations (paresthesias), diarrhea, fatigue, gait instability, headache, insomnia, nausea, tremors, visual disturbances Suicide risk and SSRIs: A link between antidepressant use and suicidal ideation among those up to age 24 in short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant drugs has been reported. The average risk of suicidal thinking or behavior during the first few months of treatment in those receiving antidepressants was 4 percent while placebo produces a risk of 2 percent. Ecological studies indicate that since the introduction of large scale SSRI prescription for every 10% rise in prescription 3% decline in suicide rates has happened in certain countries. It is also noted that patients were significantly more likely to attempt/commit suicide in the month before they began drug therapy than in the 6 months after starting it. But the issue still remains controversial, and MHRA has advised against certain SSRI prescriptions in children and adolescents. SSRIs increase the risk of upper GI bleeding especially in the elderly and in those using NSAIDs. SSRIs inhibit the uptake of serotonin into platelets; serotonin is crucial for the haemostatic response of promoting platelet aggregation. Further, SSRIs also increase gastric acid secretion thus elevating the risk of gastric erosion, ulcer and bleeding. Alcohol intake and being positive for H.pylori will also increase the risk of GI bleeding when prescribing SSRIs. Antidepressants with low inhibition of serotonin reuptake (e.g. nortriptyline, doxepin, trazodone) are safer in this regard when compared to those with high inhibition of serotonin reuptake (e.g. clomipramine, paroxetine, sertraline, fluoxetine). Increased serotonergic neurotransmission can adversely affect sexual performance; this explains SSRI-induced sexual dysfunction. Some antidepressants (bupropion, mirtazapine, moclobemide, nefazodone and reboxetine) may be associated with a relatively lower incidence of sexual dysfunction. 5-HT2 antagonists, (e.g. cyproheptadine, mirtazapine), 5-HT1a # 12 - Other antidepressants # Other antidepressants © SPMM Course agonists, (e.g. buspirone) and bupropion (being a dopamine reuptake inhibitor) can reverse sexual dysfunction related to SSRI use. A nitric oxide-dependent second messenger (cGMP) mediates penile vasodilatation. cGMP is eventually broken down by phosphodiesterase type 5 enzyme. Sildenafil is an inhibitor of phosphodiesterase type 5, an action that enhances penile erection in patients with erectile dysfunction. Sildenafil (Viagra) has been tried successfully in the treatment of SSRI-induced erectile dysfunction. The side effects of sildenafil include headaches (most common), dizziness, blurred vision and a blue tinge to vision. Very rarely, persistent painful erection (priapism) can occur. Sildenafil must be avoided by patients with arrhythmias, unstable angina / uncontrolled hypertension. Other antidepressants Venlafaxine: Sweating is more common than in SSRIs and is treated by terazosin. Significant numbers of patients receiving doses above 300mg/day experience an increase in diastolic blood pressure. This risk is not restricted to those with preexisting hypertension. Mydriasis and exacerbation of angle closure glaucoma are reported with venlafaxine; significant discontinuation reactions are reported due to the shorter half-life of venlafaxine – tapering gradually over 2-4 weeks is recommended. Duloxetine has side effects similar to venlafaxine, but fewer propensities to affect blood pressure. Trazodone is associated with priapism that can be serious if unattended. The first step in the emergency management of priapism is the intracavernosal injection of an alpha1 agonist such as metaraminol or epinephrine. The risk of priapism is greatest during the early phase of treatment. Nefazodone inhibits CYP3A4 and can cause serious hepatic damage and hence not used as often now. Though anticholinergic effects are predominantly absent, alpha1 antiadrenergic effects can produce pseudo-anticholinergic symptoms. Afterimage formation similar to the LSD related tracking phenomenon is reported in up to 12% patients on nefazodone. Both trazodone and nefazodone have a favourable profile for elderly and those with cardiac illness. Bupropion has a very different side-effect profile than the conventional antidepressants. It has no anticholinergic effects, does not cause sedation or weight gain and cause almost negligible sexual side effects compared to other classes of antidepressants. It does not cause orthostatic hypotension or cardiac side effects. It can exacerbate ADHD, eating disorders and tics in those with ADHD. It can enhance sexual activity unlike SSRIs; it increases the risk of seizures in a dose-dependent fashion. Headache, insomnia, dry mouth, tremor, and nausea are the most common side effects of bupropion. Severe anxiety or panic can be exacerbated by bupropion. Due to its effects on dopaminergic neurotransmission bupropion can cause © SPMM Course psychotic symptoms as well as delirium. Bupropion can cause word-finding difficulties in some patients. Agranulocytosis is reported with mirtazapine use. Hence, signs of infection need to be promptly followed. Buspirone can increase concentrations of haloperidol. Buspirone + MAOI can cause serotonin syndrome; 2-week washout period is recommended. CYP3A4 inhibitors such as erythromycin, itraconazole, nefazodone and grapefruit juice, increase buspirone plasma concentrations. Buspirone does not cause weight gain, sexual dysfunction, discontinuation symptoms, or significant sleep disturbance. It does not produce sedation. Mianserin and mirtazapine produce drowsiness during the first weeks of treatment but has a low propensity to produce orthostatic hypotension or cardiac effects. Increased weight gain and appetite are also noted while sexual side effects are minimal. 5-HT3 blockade is associated with a reduction in nausea and vomiting; hence to treat depression associated with cancer chemotherapy, mirtazapine is a preferred option. Reboxetine is a noradrenaline reuptake inhibitor (NARI) with negligible serotonergic effects. It has a safe cardiovascular profile and can be used in the elderly. Atomoxetine belongs to the same group but not used as an antidepressant; it is used in ADHD. Reboxetine has a specific side-effect profile linked to the noradrenergic system. Urinary hesitancy has been observed in around 10% of male patients taking part in the clinical trials. Relief from this side effect could be achieved by using tamsulosin, a peripheral alpha1-receptor blocker or doxazosin with a similar mechanism of action as tamsulosin. MAOIs such as phenelzine can induce orthostatic hypotension, pedal edema and insomnia. Apart from cheese reaction, MAOIs can also cause serotonin syndrome in combination with serotonergic agents. Tranylcypromine, and phenelzine to some extent can have stimulating effects leading to insomnia – hence the last dose is best given before 6 PM. Weight gain and sexual dysfunction are also reported. Cheese reaction: o MAOIs and tyramine (and other monoamine) rich foods interact to cause cheese reaction or tyramine reaction. o Tyramine has both direct and indirect (via vesicular release) sympathomimetic actions that develop 20 min to 1 h following ingestion of food. o It is characterized by nausea, apprehension, occasional chills, sweating, restlessness and hypotension with occipital headache, palpitations, and vomiting. o Sympathetic overdrive manifests as piloerection dilated pupils and fever. If severe cerebral hemorrhage and death can occur. © SPMM Course o In terms of the frequency and severity of the hypertensive crisis, the reversible MAOIs are safer. o Food materials to be avoided include any mature cheese such as Stilton, blue cheese, old cheddar and mozzarella. Fish, cured meats, sausage must be avoided together with mature poultry, wild game etc., liqueurs and concentrated yeast extract. o An MAOI-induced hypertensive crisis can be treated with alpha-adrenergic antagonists such as phentolamine or even chlorpromazine, which is immediately available in most psychiatric wards. This can lower blood pressure in few minutes. # 13 - 5. Antimanic agents adverse effects # 5. Antimanic agents - adverse effects # 14 - Renal effects # Renal effects # 15 - Cardiac effects # Cardiac effects # 16 - Endocrine effects # Endocrine effects © SPMM Course 5. Antimanic agents - adverse effects Renal effects Certain side effects including polyuria seems to be associated with peak lithium levels; once daily instead of twice daily dosing can reduce these problems. Nearly 1/3rd of those treated will have this side effect, but tolerance develops in due course; functional antagonism of ADH by lithium ion is considered to be the underlying mechanism. Use of K+ sparing diuretics such as amiloride or spironolactone can control polyuria. Renal damage may occur in severe, prolonged toxicity – but cumulative lithium use rather than toxicity leads more commonly to renal failure in lithium users. Chronic exposure longer than 10 years induces interstitial fibrosis resulting in chronic renal damage. Lithium has a narrow therapeutic index. Lithium toxicity occurs in conditions of overdose or dehydration. Non-specific gastrointestinal symptoms usually precede the more serious neurological symptoms and renal shutdown. Immediate cessation of lithium followed by urgent medical attention is required as some patients may require a hemodialysis if levels exceed 4mEq/L. Topiramate is a weak inhibitor of carbonic anhydrase and can promote the development of renal stones. SIADH may be seen with valproate use though more common with carbamazepine; it is dependent on the dose prescribed. Oxcarbazepine is a 10-keto derivative of CBZ with an identical profile but less enzyme induction and fewer drug–drug interactions. It produces less rash and neurotoxicity but more hyponatremia than CBZ. Cardiac effects ECG effects of therapeutic lithium dose are similar to hypokalemia – with flat T waves, or inverted T. Lithium can depress sinus node activity and so is contraindicated in sick sinus syndrome. Endocrine effects Lithium can cause a variety of thyroid problems – the most common being a benign hypothyroid state. 5% patients may develop goiter, and overt hyperthyroidism is also reported in some cases. Thyroid deficiency is common in those with high risk for preexisting antithyroid antibodies (especially middle-aged women). The risk is 3-4:1 in women and is high in first 2 years of treatment. Rapid cycling patients are at higher risk. High TSH is seen in nearly 1/3rd of chronic lithium-treated patients even in the absence of clinical hypothyroidism. In resistant depression # 17 - Haematological effects # Haematological effects # 18 - Neurological effects # Neurological effects © SPMM Course and in non-responsive rapid cyclers with bipolar disorder, using thyroxine to treat subclinical hypothyroidism may be beneficial for the mood disorder. Polycystic ovaries (PCO): 25 - 33% UK population of adult females have PCO morphology notable in ultrasound. 5-26% may have actual PCOD, which is defined as having PCO in ultrasound with hyperandrogenism or LH disturbance. 10% woman on valproate have new onset PCOD. The relative risk is 7.5 for PCOD. On stopping most people remit from PCOD. The exact mechanism by which valproate might causes PCOD remains unknown, although several mechanisms are proposed. For example, valproate increases ovarian androgen production. It also can result in weight gain and insulin resistance, both risk factors for PCOD. In the liver, the drug can increase unbound testosterone. Epilepsy, for which valproate is widely used, is tipped to increase PCOD occurrence. Such association has not been established so far for bipolar disorder. Almost all patients who develop oligomenorrhea develop it in first year of treatment with valproate. Haematological effects Lithium can cause leucocytosis that can be therapeutically utilized in some cases of benign neutropenia related to clozapine use. This is not widely practiced. Around 10% of individuals taking carbamazepine will see gradual onset leucopenia in first 3months of treatment. This is reversible on continued treatment or dose reduction. Thrombocytopenia is a dose-related effect of valproate and carbamazepine – a reduction in dose is required if bruising, or bleeding gums is noted. Neurological effects Fine tremor is a common benign side effect of lithium, and coarse tremor is a sign of toxicity. Propranolol can be used in treating lithium-induced fine tremor at therapeutic levels. Lamotrigine is generally well tolerated but can cause dizziness, ataxia, headache, sedation, tremor, and nausea. Topiramate can produce word finding difficulties (anomia) and poor concentration Vigabatrin, an antiepileptic with no significant antimanic efficiency, has been tried in some openlabel trials. It has a peculiar side effect of causing visual field defects. # 19 - Gastrointestinal effects # Gastrointestinal effects # 20 - Teratogenic effects # Teratogenic effects # 21 - Skin effects # Skin effects © SPMM Course Gastrointestinal effects Valproate inhibits hepatic enzymes; in some cases the acute liver injury may occur though this is rare in clinical practice. Of persons taking valproate, 5 to 40 percent experience a persistent but clinically insignificant elevation in liver transaminases up to three times the upper limit of normal, which is usually asymptomatic and resolves after discontinuation of the drug (termed ‘transaminitis’). Liver failure is reported with valproate, lamotrigine, topiramate and carbamazepine. Risk factors include young age and combination therapy. This is caused by 2 mechanisms: 1. Metabolic toxicity e.g. due to 4-en valproate, a metabolite of valproate. 2. Hypersensitivity - doseindependent effect is resulting in fulminant failure. Severe hepatic damage associated with valproate is seen especially in those with learning disability when undiagnosed urea cycle disorders are present (less than 2 years often). Another rare side effect of valproate is acute pancreatitis. This is a hypersensitivity reaction; dose reduction will not be helpful. Hyperammonemia can be associated with coarse tremor and carbamazepine co-prescription; it may respond to L-carnitine administration. Valproate competes with carnitine transport and can induce a state of carnitine depletion especially in children and in epileptics. Teratogenic effects The most common teratogenic effect of lithium involves cardiac valves especially Ebstein's anomaly of the tricuspid valves. The risk of Ebstein's malformation in lithium-exposed fetuses is 1 of 1,000 (20 times the risk in the general population).  Lithium’s  teratogenic  effects  are  somewhat   lower than that caused by the use of valproate or carbamazepine. Lithium is excreted into breast milk, and signs of lithium toxicity in infants include lethargy, cyanosis and sluggish neonatal reflexes. Valproate causes neural tube defects as a teratogenic effect in 1% to 4% mothers. Folate-vitamin B complex supplementation for all young women of childbearing potential may reduce risk though it is best to avoid valproate totally. Learning disability and low IQ in children is the most common teratogenic effect of valproate. Skin effects Exacerbation of acne and psoriasis are associated with lithium therapy. Alopecia / hair loss occurs in 5 to 10 percent. It is not clear if zinc and selenium supplementation can reverse or prevent the latter effect. # 22 - Weight related effects # Weight related effects © SPMM Course Valproate can cause obesity, hyperandrogenism and PCOD associated with hirsutism. Anticonvulsant hypersensitivity syndrome is seen in 0.1% of patients taking anticonvulsants. Aromatic compounds (lamotrigine, carbamazepine, phenytoin and phenobarbitone) are especially risky. 5 to 20% of those taking aromatic anticonvulsants will experience a rash. Lamotrigine can cause a rash in 10% of patients. Risk factors for rash include rapid initial dose escalation, concurrent VPA, and age less than 16 years. As benign rashes cannot be distinguished from potentially serious ones, any rash requires discontinuation of the drug. Lamotrigine carries a significant risk of Steven Johnson Syndrome (SJS – risk of 1 in 3000) especially if administered together with Valproate as the enzyme inhibiting effects of Valproate may increase lamotrigine levels. SJS starts with a rash, pharyngitis and fever. Systemic involvement follows quickly if the drug is not stopped. Drug Dose-related effects Idiosyncratic reactions Carbamazepine Visual disturbances, GI disturbances, cognitive impairment, vertigo and, dizziness. Hematological reactions including agranulocytosis or aplastic anemia, idiosyncratic Stevens-Johnson syndrome, fulminant hepatic damage, and pancreatitis. SIADH is more common in the elderly Valproate Hyperammonemia, Teratogenicity, Sedation, Thrombocytopenia Hepatotoxicity, pancreatitis, rash and rarely acute dermatitis. Weight related effects Weight gain is common (70% of those taking valproate and 40% of those taking carbamazepine over 12 months will experience weight gain); valproate induced weight gain is considered to be due to impaired beta-oxidation of fatty acids, and thus independent of calorie intake. Lamotrigine is often weight neutral Topiramate is weight neutral and can even cause weight loss. Topiramate can be potentially used to counteract the weight gain caused by many psychotropic drugs. # 23 - 6. Other agents adverse effects # 6. Other agents - adverse effects © SPMM Course 6. Other agents - adverse effects Cholinesterase inhibitors: Donepezil causes nausea, diarrhea, insomnia, vomiting, muscle cramps commonly. Rivastigmine causes similar symptoms albeit at a higher frequency of some. Galantamine too has a similar profile. Tacrine is not used anymore in UK due to reports of fatal hepatotoxicity. By increasing central and peripheral cholinergic stimulation cholinesterase inhibitors, can 1. Increase the risk for GI bleeding especially in NSAID users or patients with peptic ulcer. 2. Produce bradycardia, especially in those with supraventricular conduction delay, 3. Exacerbate COPD 4. Cause urinary retention 5. Increase seizure risk 6. Prolong the effects of succinylcholine-type muscle relaxants Rivastigmine’s  metabolism  does  not  depend  on  liver  P450  enzymes,  and, therefore, no drug interactions related to the P450 system have been observed. Memantine does not inhibit or induce hepatic microsomal enzymes; because it is excreted in the urine predominantly as unchanged drug, it is unlikely to be affected by drugs that affect hepatic enzyme function. Stimulants and other drugs used for ADHD: The most common adverse effects are anxiety, irritability, insomnia, tachycardia, cardiac arrhythmias, and dysphoria with decreased appetite. Tolerance usually develops for appetite loss. Less commonly self-limited exacerbation of movement disorders, such as tics and dyskinesias, may occur. Stimulants are linked to growth suppression. Bruxism and restlessness are also reported. Pemoline is associated with fulminant hepatic failure and is no longer used widely. Dependence can occur with methylphenidate though this is rare at doses used for ADHD. Side effects of atomoxetine are appetite loss, sexual dysfunction and dizziness; severe liver injury in has also been reported. Clonidine is not a popular option for treating tics/ADHD due to high rates of hypotension associated with it. Hypnotics: Overdose of benzodiazepines can produce slurred speech, incoordination, unsteady gait, nystagmus, impairment in attention or memory, stupor or coma and behavioural changes (inappropriate sexual or aggressive behaviour, mood lability, impaired judgment etc.). # 24 - 7. Psychiatric effects of non psychiatric dru # 7. Psychiatric effects of non-psychiatric drugs © SPMM Course High-potency benzodiazepines such as triazolam can cause anterograde amnesia. Paradoxical disinhibition is seen in a few patients especially when preexisting brain damage is present. Triazolam is banned in UK since 1991 following reports of disinhibition and aggression. Benzodiazepines can produce respiratory impairment especially in those with COPD or sleep apnea. Benzodiazepines are better avoided in those with myasthenia gravis, head injury or porphyria due to this risk. Alprazolam can cause weight gain via appetite stimulation. Cleft palate and lips are teratogenic effects associated with benzodiazepines; withdrawal syndrome is seen in a neonate with third trimester use. Z-hypnotics have more potential to cause upset stomach and diarrhea compared with benzodiazepines. Eszopiclone’s  unique  temporary  side  effect  is  an  unpleasant taste. It can also cause dry mouth especially in the elderly in a dose-dependent fashion. The occurrence of benzodiazepine withdrawal syndrome depends on The duration of treatment, The dosage prescribed, The rate of tapering and The half-life of the compound. Benzodiazepine withdrawal is characterized by anxiety, diaphoresis, kinaesthetic hallucinations, restlessness, irritability, light-headedness, tremor, insomnia, autonomic hyperactivity, and weakness. In severe cases, depression, paranoia, delirium, and grand mal seizures are seen. The syndrome can occur after 1 or 2 weeks in long-acting benzodiazepines. Alprazolam and lorazepam are associated with immediate and severe withdrawal syndrome and should be tapered gradually. Using prescribed benzodiazepines for 4 weeks or less rarely results in significant withdrawal symptoms. But if used for 4 months – 5-10% have withdrawals; in 2 years – 25-45% and in 68years – 75% develop withdrawal syndrome and dependence pattern (Law et al. 2004). Slow taper at a rate of 25% per week, use of longer acting agents when tapering, avoiding longterm use of short-acting benzodiazepines, use of carbamazepine to assist discontinuation are the various strategies employed to manage withdrawal symptoms. 7. Psychiatric effects of non-psychiatric drugs © SPMM Course Non-psychiatric drugs Psychiatric side effects Beta-blockers Sedation, nightmares, dysphoria (nearly 50% in some samples) and depression. Psychiatric effects are seen only with lipophilic compounds e.g. metoprolol and propranolol. Angiotensinconverting enzyme (ACE) inhibitors Increased arousal, anxiety, fatigue, insomnia and increased psychomotor activity (4-8%) Clonidine Sedation or lethargy (35%); anxiety (3%), agitation (3%), depression (1%), and insomnia (1%). Nitrates/nitrites Delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania. Digoxin Depression and delirium (even in therapeutic levels) Statins Uncertain association with depression (evidence inconclusive) Corticosteroids Mood changes (mania more than depression), anxiety, agitation, lethargy. Dose-dependent. 1 in 6 patients has psychiatric side effects if prednisolone is prescribed in doses above 80mg/day. Symptoms start within 2 weeks. More common in females and those with past psychiatric history. Anabolic androgenic steroids Acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger. Usually dose-dependent and resolve in 1-4 weeks after stopping the steroids. Gonadotropinreleasing hormone (GnRH) agonists (e.g. leuprolide) Depressive symptoms Interferon-alpha Nearly 40% develop psychiatric side effects; ~20% experience depression. Seen in first 12 weeks of treatment. Penicillin Sedation, anxiety and hallucinations Cephalosporins Delirium Ciprofloxacin and ofloxacin Restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis,  delirium,  seizures,  or  catatonia  (incidence  ≤1%) Isoniazid Delirium, mania, depression, and psychosis. Tetracyclines Depression, insomnia, and irritability at high dosages. Antihistamines and Atropine-like psychosis © SPMM Course decongestants Proton pump inhibitors & H2antagonists used for peptic ulcer disease Confusion, agitation, depression, and hallucinations— mainly in geriatric patients with impaired hepatic-renal function. Ondansetron Anxiety Isotretinoin Severe depression and suicidal behavior. Aminophylline and salbutamol Agitation, insomnia, euphoria, and delirium Depressogenic drugs x Beta blockers x Calcium channel blockers x Interferons (alpha > beta) x Steroids x Cyproterone, progesterone x Varenicline x Isotretinoin x Ezetimibe Rimonabant: Two endocannabinoid receptors CB1 and CB2 are identified; based on the clinical observations of cannabis related increase in appetite  (the  “munchies”), researchers have studied the involvement of endocannabinoid system in the control of energy balance. Rimonabant, the first  of  the  CB1-receptor antagonists, was developed as an anti-obesity agent on the premise that blocking central cannabinoid activity might reduce food intake. But there is compelling evidence that rimonabant is associated with the development of severe adverse psychiatric events (2.5 times more depression; suicidal ideas and 3 times more anxiety). Animal studies have consistently shown that pharmacological blockade of the CB1 receptor impaired the anti depressant-reducing or anxiety-reducing actions of endocannabinoids. FDA has issued a warning now on the use of this agent. # 25 - 8. Prescribing controlled drugs # 8. Prescribing controlled drugs © SPMM Course 8. Prescribing controlled drugs 1971 MISUSE OF DRUGS ACT UK Class A drugs: Ecstasy, LSD, heroin, cocaine, crack, magic mushrooms (whether prepared or fresh), methylamphetamine (crystal meth), other amphetamines if prepared for injection o Penalties for possession: Up to seven years in prison or an unlimited fine. Or both o Penalties for dealing: Up to life in prison or an unlimited fine. Or both Class B drugs: Amphetamines, Methylphenidate (Ritalin), Pholcodine o Penalties for possession: Up to five years in prison or an unlimited fine. Or both o Penalties for dealing: Up to 14 years in prison or an unlimited fine. Or both. Class C drugs: Cannabis, tranquilisers, some painkillers, GHB (Gamma-hydroxybutyrate), ketamine o Penalties for possession: Up to two years in prison or an unlimited fine. Or both o Penalties for dealing: Up to 14 years in prison or an unlimited fine. Or both 2001 MISUSE OF DRUGS REGULATIONS Schedule Examples Regulations Coca leaf, cannabis, LSD, mescaline No recognized medicinal use. Supply is limited to research or other special purposes judged to be in the public interest.
 Requires Home Office licence to possess. Diamorphine, dipipanone, morphine, remifentanil, pethidine, secobarbital, glutethimide, amphetamine and cocaine Subject to special prescription requirements and safe custody requirements (with the exception of secobarbital). Stock drugs must be recorded in a register that meets the requirements of the 2001 Regulations, and drug stock must only be destroyed in the presence of an appropriately authorized person. The barbiturates (except secobarbital), buprenorphine, diethylpropion, mazindol, meprobamate, pentazocine, phentermine, and temazepam These drugs are subject to the special prescription requirements (except for temazepam) but not to the safe custody requirements (except for buprenorphine, diethylpropion, flunitrazepam and temazepam) or to the need to keep a register, although there are requirements for the retention of invoices for 2 years Part 1 Benzodiazepines (not temazepam) and zolpidem These drugs are not subject to the special prescription requirements or to safe custody requirements. There © SPMM Course Part 2 Androgenic and anabolic steroids, clenbuterol, chorionic gonadotrophin (HCG), non-human chorionic gonadotrophin, somatotropin, somatrem, and somatropin is no need to keep a register, although there are requirements for the retention of invoices for 2 years Weak preparations of drugs usually in other schedules, for example, morphine, codeine Exempt from all controlled drug regulations except the need to keep invoices for at least 2 years All controlled drug prescriptions should have The  patient’s  full  name,  address  and  age If  a  patient  is  homeless,  ‘no  fixed  abode’  is  an  acceptable  address   The name and form of the drug MUST be written The strength of the preparation, where appropriate The dose to be taken MUST be written The total quantity of the preparation, or the number of 
dose units, to be supplied in both words and figures 
 A patient identifier number (e.g. NHS number) should be included on prescriptions for controlled drugs Prescriptions must be signed by the prescriber with their usual signature (this must be handwritten) along with GMC number as a good practice The validity period of prescriptions for Schedule 1, 2, 3 and 4 controlled drugs have been restricted to 28 days. Schedule 2 and 3 drugs cannot be prescribed on repeat prescriptions or under repeat dispensing schemes. Patients ideally should collect the controlled drug in person after showing their identification on the first occasion and signing the back of the prescription form. Substitute opioids should be prescribed in daily instalments whenever required. Prescriptions of instalments must specify o The number of instalments o The interval between instalments, o Instructions for supplies at weekends or bank 
holidays o The total quantity to provide 
treatment for a period (this must not be exceeding 14 days generally) o The quantity to be supplied in each instalment along with the duration of the instalments  to  be  set  out  on  the  prescription,  for  example  ‘dispense  daily  for fourteen days starting on 3rd September  2015’. # 26 - 9. ADR Databases # 9. ADR Databases © SPMM Course 9. ADR Databases It is vital that adverse drug reactions (ADRs) that are hitherto unreported are detected rapidly and recorded to reduce the hazards of medical prescribing. Such reports will also trigger regulatory action to ensure further patient safety. MHRA encourages reporting adverse reaction through Yellow Card system even if it is not certain that the drug has caused it, or if the reaction is well recognised, if an overdose has been taken or if other drugs have been given at the same time. Prescribers, patients, carers and pharmacists can all use the yellow card scheme. The black triangle symbol is used to inform that a preparation is newly licensed and requires additional monitoring by the European Medicines Agency. For medicines with the black triangle symbol, the MHRA requires that all suspected reactions (including those that are not serious) be reported. For all other drugs, the yellow cards can be sued to report side effects that are serious, medically significant, or result in harm. Adverse drug reactions that result from a medication error are also reportable using Yellow cards. Term used to describe frequency Rates observed Very common Greater than 1 in 10 Common 1 in 100 to 1 in 10 Uncommon or ‘less  commonly’  in  BNF 1 in 1000 to 1 in 100 Rare 1 in 10 000 to 1 in 1000 Very rare Less than 1 in 10 000 WHO established an international system for monitoring adverse reactions to drugs (ADRs) in 1971. This is located at WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre, (UMC), in Sweden. The ADRs database held by WHO contains over three million reports of suspected ADRs. Similar reporting systems exist in many other developed nations. The Canada Vigilance Adverse Reaction Online Database and the European Medicines Agency ADR Reporting systems are some examples of other well-developed national/international ADR databases. Worsening of glaucoma: paroxetine, quetiapine, TCAs Retinal pigmn: Thioridazine Corneal deposits: CPZ Visual field defects: vigabatrin Osteoporosis: hyperprolatinaemic antipsychotics WBC suppression: ^zapines(olanz, mirtaz, cloz, carbama), mianserin Haemolytic anaemia: nomifensine Myocarditis / Pul Embolism: clozapine QT prolong: all antipsychotics esp .Thioridazine, Pimozide, droperidol Arrythmias: high dose TCAs High BP: VFX, TCAs Hypersalivation: clozapine Bruxism: stimulants Hypothyroidism: Li Fine tremors: therapeutic dose of lithium, TCAs Coarse tremors: antipsychotic Parkinsonism, Wt gain: all antipsychotics (less for APZ, ZPD), TCAs, Li, VPA, CBZ Wt loss: Topiramate, Bupropion Guillian Barre: Zimeldine Pedal oedema: MAOIs Cramps: AchEs Orthostatic hypotension: all TCAs, all antipsychotics Priapism: Trazodone, risperidone PCOD: Valproate Erectile dysfunction: all TCAs, antipsychotics Delayed ejacln or anorgasmia: SSRIs Hepatic damage: nefazodone, VPA, tacrine Enz induction: CBZ, phenytoin, barbiturates Ac. Pancreatitis: VPA P.ileus: clozapine GI bleed: SSRIs, AChEs Renal damage: Lithum Nephrolithiasis: topiramate EPSEs: all neuroleptics (less for Anticholinergic neuroleptics e.g. CPZ), higher dose atypicals Delirium: Anticholinergic TCAs, Anticholinergic antipsychotics Seizures: bupropion, clozapine Tics: stimulants Amnesia: BDZ Rashes, SJS: CBZ, Lamotrigine Thrombocytopenia: Valproate Sweating: all SSRIs, TCAs, esp. VFX Acne, psoriasis: Li Psychotropics Adverse Effects Chart © SPMM Course AchEs: Anticholinesterases, BDZ: Benzodiazepines, CBZ: carbamazepine, CPZ: Chlorpromazine VFX: Venlafaxine VPA: Valproate, SJS: Steven Johnson Syndrome, © SPMM Course Notes prepared using excerpts from: Ashton, H & Young, A. SSRIs, drug withdrawal and abuse: Problem or treatment? Selective Serotonin Reuptake Inhibitors (SSRIs): Past, Present and Future, Chapter 5, 1999. http://www.benzo.org.uk/ssri.htm Bolland, W., & Simon, C. (2008). Controlled drugs: regulations and prescribing. InnovAiT: The RCGP Journal for Associates in Training, 1(2), 163-171. Brown E & Chanlder S. Mood and Cognitive Changes During Systemic Corticosteroid Therapy. Prim Care Companion J Clin Psychiatry. 2001 Feb; 3(1): 17–21. Di Lorenzo, R & Brogli, A. Neuropsychiatr Dis Treat. 2010; 6: 573–581. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis and management. Lancet 2000; 356:1255-9. http://www.evidence.nhs.uk/formulary/bnf/current/yellow-card-scheme Jones, O. Managing a suspected adverse drug reaction. Student BMJ 2001; 09:261-304 Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007. Pg 982. Kasper, S. (2002) Managing reboxetine-associated urinary hesitancy in a patient with major depressive disorder: a case study. Psychopharmacology, 159, 445-446. Lewis S & Lieberman, J. T he British Journal of Psychiatry Mar 2008, 192 (3) 161-163 Paton C, Ferrier IN. SSRIs and gastrointestinal bleeding BMJ 2005; 331 :529 Seeman P, Tallerico, P. Mol Psychiatry. 1998 Mar;3(2):123-34. Shiloh, R., Nutt, D. & Weizman, A. (2000). Atlas of psychiatric pharmacotherapy. Martin Dunitz, London. Page 18 Sidhu KS & Balon R (2008). Watch for nonpsychotropics causing psychiatric side effects. Current Psychiatry; 7(4); 61 Swann, A. Major system toxicities and side effects of anticonvulsants. J Clin Psych 2001; 62 [16-21] Szabadi, E. (1998) Doxazosin for reboxetine-induced urinary hesitancy. The British Journal of Psychiatry, 173, 441b-442. Thakore, JH. The British Journal of Psychiatry Jun 2005, 186 (6) 455-456; UK Home Office http://drugs.homeoffice.gov.uk/drugs-laws/misuse-of-drugs-act/ DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 15 - 51_Classification # 01 - 1. Approaches to Classification # 1. Approaches to Classification © SPMM Course 1. Approaches to Classification The two major contemporary classificatory systems are ICD 10 (1992) and DSM IV (1994). American Psychiatric Association produces the DSM system. WHO commissioned ICD 10? DSM-V was released in 2013 but there has been much criticism of this system, and as of yet it has not been adopted widely except by clinicians communicating with insurers in the USA. It is anticipated that ICD11 will be released in 2017 Both classificatory systems are categorical systems of classification based on clinical descriptions. While both ICD-10 and DSM-4 are diagnostic and classificatory systems and are meant to provide reliable diagnosis, they do not provide assessment plans, case formulations or treatment plans. Various terms are used to describe the characters of classificatory systems. The concept of operationalized criteria, atheoretical approach, hierarchical organisation and multi-axial classification are important for MRCPsych Paper A exam and are described below. Operationalised approach: In DSM-III operationalised diagnosis was first introduced. Operational criteria include the use of precise clinical description of disorders, together with predefined exclusion and inclusion criteria and details of the number and duration of symptoms required for diagnosis. It enables algorithm-based clinical diagnosis using intensity, duration of the symptoms and impairment tests. This more or less equates to using a checklist for diagnosis, but some rules are necessary while some are optional for a diagnosis. Characteristic symptoms are pertinent to the diagnosis, such as the symptom of depression, which is found in many different disorders. Discriminating symptoms, e.g. thought insertion, are necessary for diagnosis since they are not found in other diseases. Pathognomonic symptoms, if present, strongly favour one diagnosis over another. Thus, they are more specific to a condition than other symptoms (e.g. flashbacks of trauma and PTSD). Inclusion and exclusion criteria: A hierarchy of symptoms, arranged in order of importance (e.g. criterion A and B etc.) often accompanies diagnostic descriptions in operationalised systems. These form the core inclusion and exclusion criteria used in practice to establish a diagnosis. Computerised scoring systems such as OPCRIT (for ICD10) facilitate the application of such operationalised diagnoses. The atheoretical approach means diseases are described according to the observed phenomenology; classification is NOT based on the understanding of what might be causing the disturbances. So various aetiological schools such as behaviourism or psychoanalysis, etc. are not employed in describing a disorder. No theory forms the basis of the classifications; only neutral observations are taken into account. The descriptive approach refers to classifying illnesses on the basis of what constitutes the illness rather than what causes it; Lack of pathogenetic knowledge of most psychiatric disorders makes this approach more rational. This forms the basis of any atheoretical classification. © SPMM Course Categorical vs. dimensional approaches: The current classificatory systems entertain categorical diagnoses only; i.e. similar to medical diseases. In other words using current systems, we can only say whether  an  individual’s  clinical  presentation  either  meets  or  does  not  meet  the  diagnostic  criteria  for  a   particular disorder. A patient either has or does not have pneumonia; she has or does not have schizophrenia, etc. Contrast this approach with measurement of blood pressure – we use a continuum from low to high along which measurement is made. (It only becomes categorical when we apply the label “hypertension”  to  indicate  that  a  patient  has  clinically  troublesome  problem  with  high  BP).  Of all psychiatric disorders, the need to develop a dimensional system for description is said to be more urgent for personality disorders. Categorical approach Dimensional approach Traditionally doctors are accustomed to thinking in terms of categories – easy to understand. All existing knowledge base about the presentation, aetiology, epidemiology, course, prognosis, and treatment is based on these categories. Categories are easy to communicate with professionals Poor validity –vague  categories  such  as  ‘Psychosis  - not  specified’  are  needed  to  include  atypical   cases. More valid as most emotional and cognitive states exist as a continuum without clear cut-off point between ill and the well. Severity can be better indicated Need to entertain many comorbid diagnoses may be prevented. Research studies using dimensional scales as end points have much greater power to detect differences in groups than do studies focusing on changes in dichotomous categories Clinical utility is questionable, as dimensions cannot be directly mapped onto clinical decisions such as starting or stopping an intervention. Hierarchical organisation is largely abandoned in DSM and somewhat maintained in ICD-10 in its organisation of chapters. Hierarchy means that certain disorders take precedence over others while making a diagnosis. This follows Jasperian ideas (Karl Jaspers: see Introduction to Psychopathology for more details) – the ladder starts from organic disorders through to substance use issues, psychosis, affective and neurosis up to personality issues. If a disorder on top of the hierarchy can explain the observed symptoms, then a diagnosis should not be entertained from down below the hierarchy even if the constellation of symptoms are suggestive of such a diagnosis. To understand the concepts of hierarchy consider the following example. Dementia and other brain-based organic disorders can be associated with any type of psychiatric problem. But a separate diagnostic label is not used for each of these  psychiatric  syndromes.  For  example,  ‘schizophrenic  symptoms’  occurring  in  the  course  of   Huntington’s  disease  or  temporal  lobe epilepsy or severe learning disability do not change the diagnosis  to  ‘schizophrenia’  in  these  cases.  Other examples include the co-occurrence of depression and agoraphobia, depression and OCD, organic delirium and psychosis – in all these cases the first diagnosis is primarily entertained instead of the second even if the symptoms could be explained by # 02 - Structure of ICD 10 # Structure of ICD-10 © SPMM Course both diagnoses in a given patient at a point of time. This hierarchy is generally non-reflexive, i.e. each disorder tends to manifest the symptoms of those lower down but not those of disorders higher up. Despite such a hierarchical construct, co-morbidity can be still entertained, and this is explicitly encouraged when using DSM. For example, alcohol used disorder can be comorbid with depressive disorder. Multi-axial approach: Recently there has been an upsurge of interest in the multi-axial system for achieving a complete diagnosis.  This  method  helps  in  a  more  ‘holistic  assessment’ of an individual patient. o The multi-axial version of ICD-10 uses three axes. Axis 1 - the mental disorder (also personality disorder and mental handicap); Axis 2 - the degree of disability; and Axis 3 - current psychosocial problems. o The multi-axial system of DSM uses 5 axes. Axis I - Clinical Disorders; Axis II - Personality Disorders/ Mental Retardation; Axis III - General Medical Conditions; Axis IV - Psychosocial and Environmental Problems; Axis V - Global Assessment of Functioning. Note that child and adolescent mental disorders have a different axial system in DSM-IV. Structure of ICD-10 The first ICD in 1855 was concerned with a nomenclature of causes of death. World Health Organization (WHO) in 1948 adopted this version after many revisions and called ISCD 6 - Sixth Revision of the International Statistical Classification of Diseases, Injuries and Causes of Death. The ICD-10 is a general medical classification system intended for worldwide, multi-specialty use. ICD-10 classification is easy to follow and has been tested extensively all over the world in more than 51 countries and has been found to be generally applicable. ICD-10 includes 21 chapters. The Roman numeral V and the letter F denote the position of mental and behavioural disorders as the fifth chapter in the WHO classification as a whole. The disorders are identified using an open alpha-numeric system in the form Fxx.xx  from  F00  to  F99.  The  letter  ‘F’  identifies   the disorder as a mental or behavioural disorder; the first digit refers to the broad diagnostic grouping (e.g. psychotic, organic etc.); and the second digit refers to the individual diagnosis. The digits, which follow the decimal point, the code for additional information specific to the disorder such as sub-type, course, or type of symptoms. For example, F33.10 refers to recurrent depressive disorder, current episode moderate with the somatic syndrome. The Schedule for Clinical Assessment in Neuropsychiatry (SCAN), the Composite International Diagnostic Interview (CIDI), and the International Personality Disorder Examination (IPDE) are assessment instrument developed based on the ICD-10framework. Four versions of the ICD-10 classification of mental disorders exist, suitable for different purposes. # 03 - Structure of DSM IV # Structure of DSM-IV # 04 - Newer Classification Systems # Newer Classification Systems # 05 - Proposed changes to ICD 11 # Proposed changes to ICD-11 © SPMM Course o ICD-10: CDDG (clinical descriptions and diagnostic guidelines) - for clinical, educational and service use. It is mainly used by psychiatric practitioners and gives clinical descriptions of each disorder together with the diagnostic criteria. o ICD-10: DCR (diagnostic criteria for research) contains more restrictive and clearly defined clinical features with explicit inclusion, exclusion, and time-course criteria, and is suitable for identification of homogeneous patient groups for research purposes. o ICD-10: Primary care version - focuses on those disorders prevalent in primary care settings and contains broad clinical descriptions, diagnostic flowcharts, and treatment recommendations. o ICD 10: Clinical Coding Manual - Short glossary containing the coding together with brief descriptions can be used as a quick reference by practitioners, as well as by administrative and secretarial staff. It is suitable for clerical workers and for coding purposes. Structure of DSM-IV While ICD-10 is a wider general medical classification, DSM-IV describes only mental disorders. DSM-IV uses a closed, numeric coding system of the form xxx.xx. A single version of DSM-IV is used for both clinical and research purposes. DSM takes a descriptive approach, and the characteristic signs and symptoms of each disorder should be present before a diagnosis is made. It is neutral and atheoretical regarding the causes of mental disorders and does not subscribe to any models of causation of disorders such as cognitive theories, learning theories, etc. Its diagnoses are non-hierarchical, which implies that more than one diagnosis can be made. An important step included in the development of DSM-IV was the attempt to strengthen the reliability of classification. The inter-rater agreement for Axis 1 disorders is very high (0.73 and 1.00) and has repeatedly demonstrated greater diagnostic stability over time. Newer Classification Systems Proposed changes to ICD-11 ICD-11 is under preparation and consultation now and is expected to be released by 2017. Some of the significant changes expected in ICD-11 are highlighted below. Note that these are subject to updates and revisions. x Presumed aetiological groupings rather than conventional symptom-based groupings employed for placing each disorder in a chapter x Neurodevelopmental disorders will be set in chapter 1 x Bipolar disorders will be split from depressive disorders and placed in a separate chapter x Dissociative disorders will be split from stress-induced disorders x OCD will be separated from anxiety disorders x Factitious disorders will be placed in a separate chapter x Conditions related to substance use will be split into various chapters x No restriction in number of character places when coding the disorders # 06 - Summary of major changes to DSM 5 # Summary of major changes to DSM-5 © SPMM Course Summary of major changes to DSM-5 DSM-5 is comprised of three sections: Section 1: An introduction and guidance to use; Section 2: An outline of the diagnostic categories with the newly revised chapters; Section 3: Includes a list of conditions that require further research before their consideration as formal disorders. It also includes details on cultural formulations. A multiaxial system that separately identified personality disorders (Axis II) and medical conditions (Axis III) has been modified. The new multiaxial system now includes only three axes - psychiatric disorder, psychosocial and environmental factors associated with them, and the severity of associated disability. In effect, this means personality disorders are treated with the same importance as other psychiatric disorders. This has moved DSM’s  multiaxial  system  closer  to  ICD’s  multiaxial  system. A brief note on other major changes is given below. Further details are provided downstream when discussing the major disorders. •Removal of 'bizarre' delusions •Removal of subtypes of schizophrenia •3 core symptoms recognised (delusions, hallucinations and disorganised speech) •Changes in schizoaffective criteria Psychosis Psychosis •Dysthymia & chronic depression merged •Bereavement no longer an exclsuion for depression •Premenstrual dysphoric disorder is a new diagnostic entity Mood disorder Mood disorder •Asperger's syndrome removed and merged with autism as ASD •ADHD age criteria relaxed Developmental disorders Developmental disorders •Anorexia diagnosis does not require amennorhea •Bingeing frequency required to diagnose bulimia relaxed •OCD and PTSD moved out of Anxiety Disorders to separate chapters •New labels: Hoarding Disorder, Excoriation Disorder, DMDD - Disruptive Mood Dysregulation Disorder introduced Other changes Other changes # 07 - 2. Psychoactive substance use disorders # 2. Psychoactive substance use disorders © SPMM Course 2. Psychoactive substance use disorders Mental and behavioural disorders due to psychoactive substance use are dealt in Chapters F10 to F19 in ICD-10. Substances discussed here include alcohol, opioids, cannabinoids, sedatives, cocaine, other stimulants including caffeine, hallucinogens, tobacco, solvents and the use of multiple substances. Various clinical syndromes associated with the use of substances are described: Syndromes Subdivisions Acute intoxication Transient disturbances in the level of consciousness, cognition, perception, affect or behaviour, or other psychophysiological functions and responses. Usually related to dose/levels of consumed substance Symptoms need not always in accord with the expected physiological properties of the drug (e.g. a depressant can cause agitation). Harmful use A pattern of substance use that is causing damage to physical or mental health. Should not be diagnosed if dependence syndrome or substance-induced psychosis are diagnosed. Dependence Cognitive and behavioural phenomena indicating that the use of The substance takes on a much higher priority for a given individual than other previously salient behaviours. A checklist of features is described to diagnose each dependence syndrome (also see Edward & Gross criteria given below). Withdrawal state The syndrome occurs on absolute or relative withdrawal of a substance after repeated and prolonged use. Withdrawal Delirium Withdrawal accompanied by confusional state Psychotic disorder Psychotic phenomena that occur during or immediately after psychoactive substance use (esp. auditory hallucinations and paranoid delusions) Amnesic syndrome Chronic impairment of recent memory with relatively preserved remote memory and immediate recall. Late-onset disorders Changes in cognition, emotion and personality or behaviour that persist beyond the period of expected physiological effects of the consumed substance. ICD10  has  a  diagnostic  code  for  ‘harmful  use’ where the actual damage is caused to the drinker physically or mentally, but he has no dependence pattern (yet). In contrast, DSM-IV upholds the concept  of  ‘abuse’ which refers to maladaptive use 1. Despite problems in social, occupational, physical and psychological domains 2. In hazardous situations 3. At least one month, recurring over a longer period usually. 4. But not dependent on alcohol. ©"SPMM"Course" 8" ! ICD10"alcohol"dependence"requires"at"least"3"out"of"following"list"satisfied"in"last"12"months:" 1. Intense"desire"to"drink"alcohol" 2. Difficulty"in"controlling"the"onset,"termination"and"the"level"of"drinking" 3. Experiencing"withdrawal"symptoms"if"alcohol"is"not"taken" 4. Use"of"alcohol"to"relieve"from"withdrawal"symptoms" 5. Tolerance"as"evidenced"by"the"need"to"escalate"dose"over"time"to"achieve"same"effect" 6. Salience"–"neglecting"alternate"forms"of"leisure"or"pleasure"in"life" 7. The"narrowing"personal"repertoire"of"alcohol"use." ! DSMDIV"alcohol"dependence"requires"at"least"3"out"of"following"list"lasting"for"at"least"a"month:" 1. Consuming"alcohol"for"longer"period"and"in"larger"amounts"than"intended" 2. Unsuccessful"attempts"to"cut"down" 3. Experiencing"withdrawal"symptoms"if"alcohol"is"not"taken" 4. use"of"alcohol"to"relieve"from"withdrawal"symptoms" 5. Tolerance"as"evidenced"by"the"need"to"escalate"dose"over"time"to"achieve"same"effect" (at"least"50%"increase"from"start)" 6. Salience"–"most"time"of"life"spent"on"pursuing"alcohol"directly"or"indirectly" 7. Failure"in"role"obligations"and"physical"health" 8. Giving"up"alternate"pleasures" 9. Continued"use"despite"knowing"the"harm"caused" " ! " " " " " " " " " Edwards"&"Gross"criteria"(1976)"for"dependencem • Narrowed"repertoirem • Salience"of"alcohol"seeking"behaviour • Increased"tolerance • Repeated"withdrawals • Drinking"to"prevent"or"relieve"withdrawals. • Subjective"awareness"of"compulsion • Reinstatement"after"abstinence # 08 - 3. Organic disorders # 3. Organic disorders © SPMM Course 3. Organic disorders Chapter F00 in ICD-10 discusses organic disorders such as dementia. Major categories include dementia  of  Alzheimer’s  disease,  vascular  dementia,   dementia in other diseases classified elsewhere (includes  CJD,  Parkinson’s  dementia  etc.),  organic amnesic syndromes, delirium, other mental disorders due to brain damage (includes organic hallucinosis, catatonic disorder, mild cognitive disorder etc.) and personality change due to brain damage. Depressive pseudodementia: This is not a separate diagnostic entity, but a descriptive term often used in old age psychiatry. Depression in elderly patients may present as dementia clinically. This is called depressive pseudodementia. Here the patient complain of memory impairment, difficulty in sustaining attention and concentration and reduced intellectual capacity. Major clinical features differentiating pseudo-dementia from dementia are tabulated below Pseudodementia Dementia Onset can often be dated precisely Onset can be dated only within broad limits Symptoms usually of short duration before seeking help Symptoms usually of long duration before medical help is sought Rapid progression of symptoms after onset Slow progression of symptoms throughout course Patients complain actively of the cognitive impairment Patients often complain little of their cognitive difficulties (may even conceal disability and appear unconcerned) Nocturnal accentuation of dysfunction uncommon Nocturnal accentuation of dysfunction common Attention and concentration often well preserved Attention and concentration usually faulty On  direct  testing  ‘Don'ʹt  know’  answers  are  typical  (the   patient is not trying hard) Near-miss answers are frequent in cognitive tests (the patient is trying but not efficient) Memory loss for remote events may be more severe than for recent ones Memory loss for current events usually more severe than for remote events (Adapted from Kaplan & Sadock - Synopsis of psychiatry-10th edition) Dementia  in  Alzheimer’s  disease  (diagnostic  criteria) x Global deterioration in intellectual capacity and disturbance in higher cortical functions like memory, thinking, orientation, comprehension, calculation, language, learning DSM-5 AND CATATONIA Presence of three catatonic symptoms from a total of 12 is required to diagnose catatonia. In DSM-5, catatonia may be diagnosed as a specifier for depressive, bipolar, and psychotic disorders; as a separate diagnosis in the context of another medical condition; or as another specified diagnosis. © SPMM Course abilities and judgement, an appreciable decline in intellectual functioning and some interference with personal activities of daily living. x Insidious onset with slow deterioration x The absence of clinical evidence or findings from individual investigations suggestive of organic brain disease or other systemic abnormalities. x Absence of sudden onset or physical/neurological signs Remember 5As x Amnesia-Impaired ability to learn new information and to recall previously learned information x Aphasia-Problems with language (receptive and expressive) x Agnosia-Failure of recognition, especially people x Apraxia-Inability to carry out purposeful movements, even though, there is no sensory or motor impairment x Associated disturbance-behavioural changes, delusions, hallucinations Some patients exhibit mild cognitive impairment before the onset of full-blown dementia. A significant proportion of those with MCI does not develop dementia: if they convert to dementia, the most common dementia to develop is Alzheimer’s  dementia. Vascular dementia x Presence of a dementia syndrome, defined by cognitive decline from a previously higher level of functioning and manifested by impairment of memory and of two or more cognitive domains (orientation, attention, language, Visuospatial functions, executive functions, motor control and praxis) and deficits should be severe enough to interfere with activities of daily living not due to physical effects of stroke alone. (NINDS AIREN criteria) x Onset may usually follow a cerebrovascular event and is more acute x The course is usually stepwise, with periods of intervening stability. x Focal neurological signs & symptoms or neurological evidence of cerebrovascular disease (CVD) judged etiologically related to the disturbance. CVD defined by the presence of focal signs on neurological examination, such as hemiparesis, lower facial weakness, Babinski sign, sensory deficit, hemianopia and dysarthria and evidence of relevant CVD by brain imaging (CT or MRI) x Emotional and personality changes are typically early, followed by cognitive deficits that are often fluctuating in severity. © SPMM Course x Symptoms are not occurring during the course of the delirium Dementia with Lewy Bodies x Spontaneous motor features of Parkinsonism x Fluctuating cognition with notable variation in attention + alertness x Recurrent visual hallucinations, which are typically well formed and detailed. x A progressive cognitive decline that is severe enough to interfere with normal social and occupational functioning and memory loss may not be an early feature, but it is usually evident with progression. x Supportive features: Neuroleptic sensitivity and history of falls Parkinson’s  disease  dementia: If the Parkinsonian symptoms have existed for more than 12 months  before  dementia  develops  then  a  diagnosis  of  Parkinson’s  disease  dementia  is given. If both motor symptoms and cognitive symptoms develop within 12 months, then it is conventional to give a diagnosis of Lewy body dementia. Frontotemporal dementia x Insidious onset and gradual progression x Early loss of personal and social awareness x Early emotional blunting, Early loss of insight x Behavioural features: Early signs of disinhibition, decline in personal hygiene & grooming, mental rigidity, inflexibility, hyperorality, stereotyped and perseverative behaviour x Speech disorder: Reduced output + signs such as stereotypy, echolalia, and perseveration x Affective symptoms: Anxiety, depression, and frequent mood changes, emotional indifference. x Physical signs: Incontinence, primitive reflexes, akinesia, rigidity and tremor. Notable features in other organic disorders x Most cases of delirium recover in 4 weeks; in chronic lung disease, subacute bacterial endocarditis and carcinoma delirium may last up to 6 months. x In organic hallucinosis, insight may be present. x Encephalitis and CO poisoning can cause organic catatonia. x Influenza can cause post-infective depression. # 09 - 4. Classification of psychosis # 4. Classification of psychosis # 10 - Schizophrenia # Schizophrenia # 11 - Earlier diagnostic criteria # Earlier diagnostic criteria © SPMM Course 4. Classification of psychosis Schizophrenia Schizophrenia usually manifests as a severe psychotic illness with onset in early childhood, characterised by bizarre (i.e. Schneiderian) delusions, auditory hallucinations, thought disorder, strange behaviour and progressive deterioration in personal, domestic, social and occupational functioning, all occurring in clear consciousness. Common symptoms: The International Pilot Study of Schizophrenia survey determined the commonest symptoms exhibited by 306 acute schizophrenia patients in 9 countries as follows: Lack of insight – 97% Auditory hallucinations - 74% Ideas of reference – 70% Suspiciousness – 66% Flatness of affect – 66% Second person hallucinations – 65% Delusional mood – 64% Delusions of persecution – 64% Thought alienation – 52% Echo De Pensee, Gedankenlautwerden- 50% Earlier diagnostic criteria Before DSM-IV and ICD-10, various criteria were put forward to diagnose schizophrenia. Some of these are MRCPsych favourites: St Louis or Feighner criteria (Feighner et al. 1972) or Washington University Criteria National Institute of Mental Health (NIMH) Research Diagnostic Criteria (RDC) predating DSM-III For a diagnosis of schizophrenia, A through C are required: A. Both of the following are necessary: o A chronic illness with at least six months of symptoms prior to the index evaluation without a return to the premorbid level of psychosocial adjustment. o The absence of a period of depressive or manic symptoms sufficient to qualify for affective disorder or probable affective disorder. B. The patient must have at least one of the following: o Delusions or hallucinations without significant perplexity or disorientation associated with them. o Verbal production that makes communication difficult because of a lack of logical or understandable organization. (In the presence of muteness the diagnostic decision must be deferred.) C. At least three of the following manifestations must be present for a diagnosis of "definite" schizophrenia, and two for a diagnosis of "probable" schizophrenia. o Single o Poor premorbid social adjustment or work history o Family history of schizophrenia o Absence of alcoholism or drug abuse within one year Includes a polythetic symptom criterion, a duration criterion and an exclusion criterion. The symptom criterion lists eight symptoms or groups of symptoms. The first seven symptom groups are Schneiderian first-rank symptoms and other delusions or hallucinations, the last one gives diagnostic value to formal thought disorder if accompanied by either blunted or inappropriate affect, delusions or hallucinations of any type or grossly disorganized behaviour. The duration criterion requires that signs of the illness have lasted at least 2 weeks from the onset of a noticeable change in the  subject’s  usual  condition. The exclusion criterion describes the differential diagnosis with affective disorders: at no time during the active period of illness being considered did the subject meet the full criteria for either probable or definite manic or depressive syndrome to such a degree that it was a prominent part of the illness. # 12 - ICD 10 schizophrenia # ICD-10 schizophrenia © SPMM Course of onset of psychosis o Onset of illness prior to age 40 ICD-10 schizophrenia ICD 10 description of schizophrenia is largely based on Schneider’s  first-rank symptoms. Kurt Schneider described a number of symptoms which he believed were of first-rank importance in differentiating schizophrenia from related illnesses. According to the International Pilot Study of Schizophrenia, 58% of patients with acute schizophrenia exhibited at least one first rank symptom. However, at least 20% of schizophrenic never exhibit a first rank symptom while almost 10% of non-schizophrenic patients exhibit them. Duration criteria in ICD: ICD10 rejects the assumption that schizophrenia is an illness of necessarily long duration. Accordingly, acute psychotic episodes are diagnosed for up to one month; if schizophrenic features are continuous, the diagnosis is reclassified as schizophrenia after a month. If not, a diagnosis of the acute psychotic episode is valid for up to 3 months, after which other diagnoses such as a persistent delusional disorder may be entertained. Prodromal symptoms of schizophrenia are not included in the 1-month criteria for schizophrenia. Subtypes of schizophrenia Subtype Most prominent symptoms Less prominent (may or may not be present) Paranoid (commonest, with onset usually at a later age compared to hebephrenia and catatonia) Delusions or auditory hallucinations Disorganized speech or behaviour Flat or inappropriate affect Catatonic behaviour Hebephrenic or disorganised (poorest prognosis) Disorganized speech or behaviour and flat or inappropriate affect. Markedly impaired social and occupational functioning; poor self-care, poor hygiene, extreme social behaviour and disorganised behaviour Catatonic behaviour Catatonic (more common in developing nations; usually acute onset with episodic course and complete symptom remission) x Motoric immobility (i.e., catalepsy or stupor) x Excessive motor activity x Extreme negativism or mutism x Posturing, or stereotypy, mannerisms, grimacing x Echolalia or echopraxia (Minimum 2 of the above needed) Oneiroid (dream like) state can occur, and patients may experience visual hallucination. Transient catatonic features can be seen in all schizophrenia types © SPMM Course Residual Evidence of full blown acute episode in the past Currently negative symptoms or attenuated forms of 2 or more generic symptoms (i.e. odd beliefs instead of delusions, unusual perceptual experience instead of fully formed hallucinations) Absence of delusions, hallucinations, disorganized speech or behaviour, catatonia Simple Insidious development of negative symptoms without evidence of positive symptoms.  Very  rare.  Appears  as  if  one’s  personality  is  gradually  deteriorating   with increasing emotional bluntness; Occasional brief psychotic episodes may support the diagnosis. Undifferentiated Generic symptoms but not falling in other categories ‘Chronic  schizophrenia.' Persistent disability for two years or longer (not a subtype but a descriptive term) Catatonic schizophrenia is characterised by marked disturbance of motor behaviour and can present in three clinical forms; (1) excited catatonia (2) stuporous catatonia and (3) catatonia alternating between excitement and stupor. Hebephrenic schizophrenia is characterised by marked thought disorder and severe loosening of associations, emotional disturbances described by inappropriate affect, blunted affect or senseless giggling, abnormal mannerisms like mirror gazing. ICD 10 recommends a period of 2-3 months of continuous observation for a confident diagnosis. Hypochondriacal complaints may be seen in some cases. Philosophical, religious and abstract preoccupations may be seen along with a preference for solitariness. The onset of hebephrenic schizophrenia is insidious, usually in the early second decade (15 to 25 years). The course in many patients is relentlessly downhill. Severe deterioration without remissions often occurs over time. The recovery from the episode classically never occurs. The term ‘disorganised schizophrenia’ is used to denote hebephrenia in DSM-IV. Simple schizophrenia is characterised by an early onset (usually in the second decade), very insidious and progressive course, and presence of characteristic negative symptoms like marked social withdrawal, loss of initiative and drive or shallow emotional response. People with this condition drift down the social ladder quickly, living shabbily and wandering aimlessly. Delusions and hallucinations are usually absent if present they are short lasting and poorly systematised. The prognosis is usually very poor. Note that for simple schizophrenia – duration criteria is one year, not one month (ICD-10). Residual schizophrenia consists of long-term but not necessarily irreversible negative symptoms. Delusions and hallucinations must have been minimally intense or reduced for at least one year period. The positive symptoms are gradually replaced by negative symptoms. According to the ICD 10 diagnosis “residual schizophrenia is characterised by the following features in additional to the general guidelines of schizophrenia which includes prominent negative schizophrenic symptoms, evidence in the past of at least one clear-cut psychotic episode meeting the diagnostic criteria for schizophrenia, a period of at least one year during which the intensity and frequency of # 13 - Contrasting DSM IV and ICD 10 # Contrasting DSM-IV and ICD-10 © SPMM Course florid symptoms such as delusions and hallucinations have been minimal or substantially reduced and absence of organic brain disease or disorder”. Post schizophrenic depression is classed under F20s. Some schizophrenic symptoms (mostly negative) must be present though not dominating the picture. The most recent episode of relapse must not be more than 12 months ago. If no current schizophrenic symptoms at all then depressive disorder can be diagnosed. If florid schizophrenia symptoms with minor affective disturbances noted, then relapse must be suspected. Contrasting DSM-IV and ICD-10 ICD 10 DSM IV Characteristic symptoms At least one of: 1. Thought echo, thought insertion/withdrawal/broadcast 2. Passivity, delusional perception 3. Third person auditory hallucination, running commentary 4. Persistent bizarre delusions OR two or more of: 1. Persistent hallucinations 2. Thought disorder 3. Catatonic behaviour 4. Negative symptoms 5. Significant  behaviour  change At least one of: 1. Bizarre delusions 2. Third person auditory hallucinations 3. Running commentary OR two or more of: 1. Delusions 2. Hallucinations 3. Disorganized speech 4. Grossly disorganized behaviour 5. Negative symptoms Duration More than 1 month 1 month of characteristic symptoms With 6 months of social/occupational dysfunction Subtypes Paranoid Catatonic Hebephrenic Residual Undifferentiated Simple Postschizophrenic depression Paranoid Catatonic Disorganized Residual Undifferentiated Chapters • F20 Schizophrenia • F21 Schizotypal disorder • F22 Persistent delusional disorder • F23 Acute and transient psychotic disorders • F24 Induced delusional disorders • F25 Schizoaffective disorder • F28 Other non-organic psychotic disorders • F29  Unspecified  non-organic psychosis • 295.x Schizophrenia • 295.4 Schizophreniform disorder • 295.7 Schizoaffective disorder • 297.1 Delusional disorder • 297.3 Shared psychotic disorder • 298.8 Brief psychotic disorder • 298.9 Psychotic disorder NOS © SPMM Course Other ‘schizophrenias’ in ICD-10 In acute and transient psychotic disorders (ICD-10), onset within two weeks is described as acute while the onset within 48 hours is called abrupt. Complete recovery within 2 to 3 months is the rule. It can be of polymorphic form or schizophrenia-like in it is presentation. In acute polymorphic psychosis, several hallucination and delusions changing in both type and intensity from day to day or even same day is noted. Schizotypal disorder is diagnosed in patients with eccentric manners, social withdrawal, magical thinking, suspiciousness, and obsessive ruminations but without resistance. The ruminations may have dysmorphophobic contents too. At least a 2-year history with schizophrenia being never diagnosed in the past is necessary for diagnosing schizotypal disorder. Schizotypal disorder includes older descriptions such as borderline schizophrenia, pseudo neurotic schizophrenia, etc. Is classified along with schizophrenia and related disorders in ICD-10 but along with Cluster A personality disorders in DSM-4. Schizotypy is more common in the other first-degree relatives of schizophrenic subjects than in the general population and the relatives of schizotypal subjects have an increased risk of schizophrenia. Persistent delusional disorders are characterised by a persistent, often life-long, typically  ‘non-bizarre’ delusion or a set of related delusions arising insidiously in mid-life or later. Transient auditory hallucinations may occur, but clear and persistent auditory hallucinations (voices), schizophrenic symptoms such as delusions of control and marked blunting of affect, and definite evidence of brain disease are incompatible with this diagnosis. However, the presence of occasional or transitory auditory hallucinations, particularly in elderly patients, does not rule out this diagnosis. The delusions need not be strictly monothematic though this is mostly the case. Affect, thought and behaviour are globally normal, but  patients’  attitudes   Schizophrenia Delusional Disorder Bizarre delusions are common Non-bizarre delusions (cannot be bizarre by ICD-10 definition) Daily functioning is significantly impaired Daily functioning is not significantly impaired Apart from delusions may have one or more of the following: x Hallucinations x Disorganized speech x Disorganized behaviour x Negative symptoms These symptoms are almost always absent (tactile or olfactory hallucinations if at all present, are entangled in the content of a delusional complex) DSM-5 AND SCHIZOPHRENIA Presence of bizarre delusions or hallucinations is no longer sufficient as a sole criterion A for diagnosing schizophrenia. 2  of  5  ‘criterion-A’  symptoms  required  for  a   diagnosis with at-least one being a core positive symptom (delusions, hallucinations or disorganized speech) Schizophrenia subtypes (paranoid, disorganized, catatonic, undifferentiated, and residual types) have been removed. A dimensional method of rating severity for the core symptoms of schizophrenia is included. This proposes 8 dimensions (delusions, hallucinations, depression, mania, abnormal cognition, abnormal psychomotor behavior, disorganized speech and negative symptoms) © SPMM Course and actions in response to these delusions are appropriate and may lead to dangerousness in some cases. Symptoms should have been present for at least 1 month (DSM-IV). ICD-10 specifies at least 3 months for delusional disorder. According to DSM-IV delusional disorder – ‘Apart from the impact of the delusion(s) or its ramifications, functioning is not markedly impaired, and behaviour  is  not  obviously  odd  or  bizarre’.  This   criterion is not explicit in ICD-10. DSM-IV subtypes of delusional disorders Type Description Erotomania (de Clerambault syndrome) An erotic conviction that a person with higher status is secretly in love with the patient Seen most often in women though forensic samples are mostly males; may be associated with stalking or assaultive behaviour Grandiosity Patients believe they fill some special role, have some special relationship, or possess some special abilities. They may be involved with social or religious organisations Jealousy (Othello syndrome) Characterised by a delusion of infidelity. Patients possess the fixed belief that their spouse or partner has been unfaithful. Often patients try to collect evidence and/or attempt to restrict their partner's activities. Contributes to both wife battering and homicide. Persecutory Most common form of the delusional disorder. Patients are often convinced that others are attempting to hurt or harm them. This leads to them trying to obtain legal recourse, and sometimes turning violent. Somatic Varying presentations including patients who have repeated medical consultations requesting several treatment to those that show delusional concerns about a bodily infestation, deformity (delusional dysmorphophobia) or odour. Mixed and unspecified types Please refer to delusional misidentification syndromes in Descriptive Psychopathology notes Induced delusional disorders are accepted as a distinct diagnostic category and coded as F24 in ICD-10. This is a rare delusional disorder characterised by sharing of delusions between usually 2 or occasionally more persons who often have tightly knit emotional bonds. Only one person has genuine delusions due to underlying psychiatric disorder, most often schizophrenia or delusional disorder. On separation, the dependent individual may give up his or her delusions and the patient with the genuine delusions should be treated appropriately. In induced delusional disorders, induced hallucinations can be present, and this DSM-5 AND DELUSIONAL DISORDERS There is no requirement for delusions to be non-bizarre anymore Delusional symptoms must not be better explained by conditions such as obsessivecompulsive or body dysmorphic disorder with absent insight/delusional beliefs. Shared delusional disorder is no longer a separate diagnosis. # 14 - Various atypical psychotic disorders # Various atypical psychotic disorders © SPMM Course does not negate diagnosis. It is also called symbiotic psychosis or folie a deux. It is more common in couples and often involves nonbizarre delusions. Schizoaffective disorder is placed with F20 (psychoses) not F30 (affective disorders). In schizoaffective illness, both schizophrenic and mood symptoms are seen simultaneously in approximately equal proportion. The presence of mood-incongruent delusions is suggestive but not in itself sufficient to diagnose schizoaffective disorder; at least one typical schizophrenic symptom must be present. (Note - Affect neutral delusions are also included as incongruent delusions). The aetiology is assumed to be intermediate to that of schizophrenia and affective disorder. There are 2 subtypes: schizoaffective manic or depressive subtypes. Schizodepressive episodes are associated with a family history of schizophrenia and are usually less florid. The response to treatment is variable and may develop chronic negative symptoms. The depressive symptoms are more likely to signal a chronic course compared to manic presentations. In manic variant symptoms are florid but recovery is within weeks. Schizomanic episodes are associated with a family history of affective disorders. These patients respond well to mood stabilisers and recover rapidly. Various atypical psychotic disorders These disorders are recognized but not categorised separately in ICD-10. Bouffée délirante: The classical description of bouffée délirante was given by Legrain. Psychosis  of  sudden  onset,  ‘like  a  bolt  from  the  blue’; Polymorphous delusions and hallucinations of any kind; Clouded consciousnesses associated with emotional instability; Absence of physical signs, i.e. the disorder is not caused by any organic mental disorder; Rapid return to the premorbid level of functioning; and Relapses may occur, but individual episodes are separated by symptom-free intervals. The episodes develop in a predisposed individual and are caused by psychosocial factors (which also determine the content and form of the disorder), have a greater tendency to recover and seem never to end in deterioration. Process schizophrenia: The concept of process schizophrenia was first described by Langfeldt (1939). Langfeldt differentiated between two groups of psychoses usually diagnosed as schizophrenia: a group with  poor  prognosis,  labelled  ‘genuine’  or  ‘process’  schizophrenia,  and  a  group  with  good  prognosis,   labelled    ‘schizophreniform’  psychosis. (But later studies  that  reclassified  Langfeldt’s  100  cases  concluded   that  most  of  the  ‘schizophreniform  psychoses’  turned  out  to  be  affective  disorders  with  psychotic  features). The  term  ‘cycloid  psychoses’ was coined by Leonhard (1957) to describe endogenous psychotic syndromes characterized by a sudden onset, an admixture of symptoms belonging to the affective DSM-5 AND SCHIZOAFFECTIVE DISORDER A major mood episode (not merely mood symptoms) must be present for a majority (not  merely  ‘substantial  duration’) of the disorder’s  total  duration  after  Criterion  A   has been met. Diagnosis takes a more longitudinal perspective compared to DSM-IV © SPMM Course disorders and of symptoms belonging to schizophrenia and phasic course. Leonhard subdivided the cycloid psychoses into three forms: motility psychoses, confusional psychoses and anxiety–blissfulness psychoses. Cycloid psychoses predominate in severe postpartum psychiatric disorders and are more common among women. Perris described the diagnosis as follows; psychotic episodes of sudden onset, mostly unrelated to stress, with good immediate outcome but with a high risk of recurrence, characterized by mood swings (from depression to elation) and at least two of the following: various degrees of perplexity or confusion; delusions  (of  reference,  influence  or  persecution)  and/or  hallucinations  not  congruent  with  mood; motility disturbances (hypo or hyperkinesia); occasional episodes of elation and states of overwhelming anxiety (pananxiety). # 15 - 5. Classification of mood disorders # 5. Classification of mood disorders # 16 - Depressive disorder # Depressive disorder # 17 - Bipolar affective disorder (BPAD) # Bipolar affective disorder (BPAD) © SPMM Course 5. Classification of mood disorders Depressive disorder DSM-IV Major Depressive Disorder ICD 10 Depressive disorder Duration: Most of the day, nearly every day for at least two weeks. Duration of at least two weeks is usually required for diagnosis for depressive episodes of all three grades of severity. Five or more of following symptoms; at least one symptom is either depressed mood or loss of interest or pleasure: (1) Depressed mood (2) Loss of interest (3) Significant weight loss* or gain or decrease or increase in appetite (4) Insomnia or hypersomnia (5) Psychomotor agitation or retardation (6) Fatigue or loss of energy (7) Feelings of worthlessness or excessive or inappropriate guilt (8) Diminished ability to think or concentrate or indecisiveness (9) Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or suicide attempt or a specific plan Criterion A: Depressed mood, loss of interest and enjoyment, and reduced energy leading to increased fatigability and diminished activity Criterion B: other common symptoms are: (1) Reduced concentration and attention (2) Reduced self-esteem and self-confidence (3) Ideas of guilt and unworthiness (4) Bleak and pessimistic views of the future (5) Ideas or acts of self-harm or suicide (6) Disturbed sleep (7) Diminished appetite *To qualify as a diagnostic criterion, this must be an unintentional weight loss of at least 5% weight in one month. Note that reduced self-confidence is not listed in DSM. The 4-6-8 rule for severity grading in ICD-10: For mild depressive episode at least 2 criterion A ‘core symptoms’ with four symptoms in total is required. For moderate depression, at least 2 criterion A with six symptoms in total is required. To diagnose a severe episode, at least 2 criterion A symptoms with eight symptoms in total is required. Both DSM and ICD-10 define recurrent major depressive disorder if there is more than one episode of depression. In ICD-10, this diagnosis can be given to a patient with depression if there has been at least one previous major depressive episode separated by the current episode by at least two months. Bipolar affective disorder (BPAD) BPAD is characterized by periods of prolonged and profound depression alternate with periods of excessively DSM-5 AND DEPRESSION In DSM-IV a diagnosis of depression cannot be given in the presence of bereavement for 2 months after the loss. This exclusion is now removed. A  specifier  “with  anxious  distress”  is added to rate the severity of bipolar or depressive disorders. This takes DSM closer  to  ICD’s  description  of  mixed   anxiety depression. © SPMM Course elevated and irritable mood, known as mania. ICD 10 needs at least two mood episodes before a bipolar diagnosis can be considered, with complete recovery in between the episodes. The depressive episode must be present at least for 2 weeks; mania for 7 days (fewer if hospitalized); hypomania for 4 days and mixed episodes for 2 weeks before they can be diagnosed using ICD 10. In DSM, bipolar disorder can be diagnosed even with a single manic episode. BPAD is divided into two main broad types; Type 1 is characterised by full-blown mania or mixed mania and depression. Type 2 is characterised by recurrent depression and hypomania without episodes of either mania or mixed states. Except in the elderly, the natural course of mood episodes suggests that mania lasts for 4 months while depression for 6 months. This becomes longer in the elderly who show shorter periods of inter episodic remissions and more frequent episodes, which are considerably longer than those seen in working age adults. ICD-10 bipolar affective disorder Current episode, hypomanic Current episode, manic without psychotic symptoms Current episode, manic with psychotic symptoms Current episode, mild or moderate depression Current episode, severe depression without psychotic symptoms Current episode, severe depression with psychotic symptoms Current episode, mixed Currently in remission Other bipolar affective disorders: Bipolar affective disorder, unspecified In line with the depressive episode, a manic mood episode is also operationally defined in ICD and DSM. According to ICD, mania/manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, with 3 (or more) characteristic symptoms of mania. By definition, the disturbance must be sufficiently severe to impair occupational and social functioning. Psychotic features may be present. © SPMM Course DSM IV Manic episode ICD 10 Manic episode Duration: at least 1 week or any duration if hospitalised Duration: Sustained for at least a week (unless it is severe enough to require hospital admission). Criterion A: Abnormally and persistently elevated, expansive, or irritable mood. Criterion B: During the same period three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: (1) Inflated self-esteem or grandiosity (2) Decreased need for sleep (3) More talkative than usual or pressure to talk (4) Flight of ideas or subjective racing of thoughts (5) Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) (6) Increase in goal-directed activity (either socially, at work or school or sexually) or psychomotor agitation (7) Excessive involvement in pleasurable activities that have a high potential for painful consequences A mood that is predominantly elevated, expansive or irritable and definitely abnormal for the individual concerned. At least three of the following must be present (four if the mood is merely irritable), leading to severe interference with personal functioning in daily living: (1) Increased activity or physical restlessness; (2) Increased talkativeness ('pressure of speech'); (3) Flight of ideas or the subjective experience of thoughts racing; (4) Loss of normal social inhibitions resulting in behaviour which is inappropriate to the circumstances; (5) Decreased need for sleep; (6) Inflated self-esteem or grandiosity; (7) Distractibility or constant changes in activity or plans; (8) Behaviour which is foolhardy or reckless and whose risks the subject does not recognize e.g. spending sprees, foolish enterprises, reckless driving; (9) Marked sexual energy or sexual indiscretions. Psychotic symptoms: In bipolar disorder, mood symptoms are prominent. However in its more severe form, mania may be associated with psychotic symptoms (usually mood-congruent, but may also be incongruent). Delusions and hallucinations are often  ‘changeable’  in  their  quality. Grandiose and persecutory delusions are common in psychotic mania. Auditory hallucinations are usually the second person in nature and are often consistent  with  the  patient’s  mood (e.g. religious revelations). Hypomania/hypomanic episode- ICD description of hypomania is a difficult concept. By definition, hypomania shares symptoms with mania, but these are evident to a lesser degree, not severe enough to interfere with social or occupational functioning or require admission to hospital, or include psychotic features. It includes mildly elevated, expansive, or irritable mood, increased energy and activity, increased self-esteem, talkativeness, over-familiarity, reduced need for sleep and difficulty in focusing on one task alone. Mixed states are cases where manic and depressive symptoms occur simultaneously. The occurrence of both manic/hypomanic and depressive symptoms in a single episode, present every day for at least 1 week (DSM-IV) or 2 weeks (ICD-10) DSM IV course specifiers for bipolar disorder: # 18 - Other affective disorders # Other affective disorders © SPMM Course o Rapid cycling: When at least four episodes of bipolar disorder occur within a period of one year, the condition is described  as  ‘rapid  cycling’.  Some  patients  with BPAD have more than 4 episodes per year; they are called rapid cyclers. 70-80% of rapid cyclers are women. Some of the factors associated with the rapid cycling include the use of tricyclic anti-depressant, low thyroxine level, being a female patient, Bipolar type 2 pattern of illness and the presence of neurological disease. Ultra-rapid cycling refers to the situation when fluctuations are over days or even hours. o Postpartum onset refers to the onset of mania, hypomania or depression with 4 weeks of childbirth. o Seasonal pattern refers to recurrences over several years with most episodes typically start (and end) at the same time each year. Secondary Mania: This can occur as a result of misuse of alcohol or illicit drugs and can also occur with some prescribed drugs such as Levodopa and corticosteroids. The drug induced state wanes with the clearance of the drug responsible. It can also occur in certain organic conditions such as thyroid disease, multiple sclerosis and lesions involving cortical and or subcortical areas of the brain. Bipolar 3 is a variant used to describe minimal depression complicated by antidepressant-induced hypomania – these patients fall into bipolar spectrum (in ICD: this is coded as unspecified type). Other affective disorders Persistent affective disorders: This includes dysthymia and cyclothymia respectively for unipolar and bipolar patterns of symptoms that fail to meet criteria for severity but which are of long duration and sufficient to cause impairment. Dysthymia (ICD-10)/dysthymic disorder (DSM-IV): Chronic, mildly depressed mood and diminished enjoyment, not severe enough to be considered a depressive illness. Clinical features include depressed mood (< 2yrs), Reduced/increased appetite, Insomnia/hypersomnia, reduced energy/fatigue, Low self-esteem, Poor concentration and thoughts of hopelessness. Double Depression describes episodes of major depression superimposed on Dysthymia; the prognosis and treatment response may be worse. Cyclothymia:  There  is  also  a  subclinical  presentation  ”cyclothymia”  in  which  an individual may experience oscillating high and low moods, without ever having a significant manic or depressive episode (numerous periods of mild depression and mild elation) and not sufficiently severe or DSM-5 AND BIPOLAR DISORDER Criterion A for manic and hypomanic episodes now includes an emphasis on changes in activity and energy as well as mood Separate description of mixed episode has  been  removed.  A  new  specifier  “with   mixed  features”  has  been  added:  to   qualify for this specifier, there is no need to simultaneously fulfill criteria for both mania and major depressive episode. Presence of some features of the opposite pole of mood disturbance is sufficient. © SPMM Course prolonged to fulfill the criteria for bipolar affective disorder or recurrent depressive disorder. An individual usually perceives these mood swings as being unrelated to life events. Seasonal Affective Disorder (SAD) is included in ICD-10 in the Annex. Many patients exhibit a seasonal pattern for their affective illness. The classical presentation is depression with reversed biological features in winter. These do not constitute SAD. To diagnose SAD, ICD-10 specifies that 3 or more affective episodes must occur, with onset within the same 90 day period of the year, for 3 or more consecutive years. Remissions should occur within a defined 90-day period of the year. Seasonal episodes substantially outnumber any non-seasonal episodes that may occur. The affective episode is most commonly depressive in nature. Atypical features like hypersomnia, increased appetite, carbohydrate craving and weight gain are common. Most commonly, the onset is in autumn/winter (when daylight is less), and resolution is in spring/summer (when daylight is more). Phototherapy is a treatment that is popular in SAD. Bright light (10,000 lux) is considered to be superior to dim light. Daily exposure is usually for 1 to 2 hours. The benefit may become apparent within a few days. Maintenance treatment is given for the next few months until the usual time of remission. DSM-5 AND DYSTHYMIA Dysthymia of DSM-IV is now reclassified as persistent depressive disorder, a diagnosis that includes both chronic major depressive disorder and the previous dysthymic disorder. # 19 - 6. Classification of Neurotic Disorders # 6. Classification of Neurotic Disorders # 20 - Generalised anxiety disorder (GAD) # Generalised anxiety disorder (GAD) © SPMM Course 6. Classification of Neurotic Disorders Though the term ‘neurotic’  is retained, neurosis is not a major organising principle for classification in ICD10. DSM abandoned the name completely in 1994. In ICD-10, ‘Neurotic, Stress related and Somatoform disorders’ have been categorized under seven headings; phobic anxiety disorders, anxiety disorders (including panic disorder and generalized anxiety), obsessive compulsive disorders, reaction to severe stress and adjustment disorders, dissociative disorders (conversion) disorders, somatoform disorders and other neurotic disorders. In ICD-10, obsessive-compulsive disorder has a separate place in the classification but in DSM-4 it is classified as one of the anxiety disorders. ICD-10 contains a category of mixed anxiety and depressive disorder, but DSM-4 does not. In DSM-4, 12 distinct anxiety disorders are listed. Anxiety disorders include various combinations of psychological and physical symptoms not attributable to real danger and occurs as a persisting state (generalised anxiety disorder) or occurring either in attacks (panic disorder) Generalised anxiety disorder (GAD) GAD is characterised by prominent tension, excessive worry with generalised free-floating persistent anxiety and feelings of apprehension about everyday events leading to significant stress and functional impairment. To diagnose generalised anxiety disorder, ICD-10 requires duration of at least 6 months and the symptoms should have been present on most days during 6 months. The ICD-10 list contains 22 physical symptoms of anxiety whilst there are only 6 in the DSM-4 list. To diagnose GAD in ICD-10, at least 4 (with at least 1 from  ‘autonomic  arousal) of the following should be present: 1. Symptoms of autonomic arousal: palpitations/tachycardia; sweating; trembling/shaking; dry mouth. 2. ‘Physical’  symptoms:  breathing  difficulties;  choking  sensation;  chest  pain/discomfort;   nausea/abdominal distress. 3. Mental state symptoms: feeling dizzy, unsteady, faint or lightheaded; derealisation/depersonalisation; fear of losing control, going crazy, passing out, dying. 4. General symptoms: hot flushes/cold chills; numbness or tingling sensations. 5. Symptoms of tension: muscle tension/aches and pains; restlessness/ inability to relax; feeling keyed up, on edge, or mentally tense; a sensation of a lump in the throat or difficulty swallowing. # 21 - Panic disorder # Panic disorder © SPMM Course 6. Other: exaggerated responses to minor surprises/being startled; concentration difficulties/mind going blank due to worry or anxiety; persistent irritability; difficulty getting to sleep due to worrying (List adapted from Oxford Handbook of Psychiatry- edition 2; pg. 357) Panic disorder A panic attack is a discrete episode of intense anxiety. It starts abruptly, reaches a peak within few minutes (10 minutes) and then starts to subside within 20-30 minutes. The attacks usually tend to occur spontaneously with no obvious precipitants. DSMIV specifies 13 physical symptoms of which at least 4 must be present to define a panic attack. It also specifies different types of panic attacks: i.e., situationally bound/cued, situationally predisposed, and unexpected/uncued panic. Panic disorder is characterised by recurrent panic attacks, which are not secondary to substance misuse, medical conditions, or another psychiatric disorder. Frequency of occurrence may vary from many attacks a day to only a few in a year. It is usually accompanied by persistent worry about having another attack, phobic avoidance of places or situations and significant behavioural changes related to the attack. Symptoms must be present for at least one-month duration to diagnose panic disorder. In ICD-10, panic disorder is graded as severe if there are more than 4 attacks per week in a 4-week period. According to ICD-10, for a definite diagnosis of panic disorder, several severe panic attacks should have occurred within a period of about 1 month: (1) In circumstances where there is no objective danger; (2) Without being confined to known or predictable situations; and (3) With comparative freedom from anxiety symptoms between attacks (although anticipatory anxiety is common) According to DSM-IV at least one of the panic attacks, must be followed by at least one of the following three features for 1 month or more: (1) Anticipation of further attacks (2) Worry about implications or (3) Avoidance behaviour. Panic disorder can present either alone or with agoraphobia. In DSM–IV agoraphobia is not a distinct diagnostic entity; it can be only diagnosed along with panic disorder. In ICD-10, agoraphobia is held as a DSM-5 AND PANIC DISORDER Panic disorder and agoraphobia are separated in DSM-5. The controversial issue of the primacy of panic over phobic symptoms is now closed with the introduction of two distinct diagnoses, panic disorder and agoraphobia, each with separate criteria. Comorbid diagnosis is still possible. Only 2 types of panic attacks are recognised: unexpected and expected panic attacks. # 22 - Phobic anxiety disorders # Phobic anxiety disorders © SPMM Course primary diagnosis, with panic disorder being a qualifier for subcategorisation, in addition to being a diagnostic entity on its own but to be used only when no phobic disorder is notable. Phobic anxiety disorders According to Marks, the cardinal features of phobia include  the  ‘fear’  which  (1) Is out of proportion to the situation (2) Cannot be explained or reasoned away (3) Is beyond voluntary control (4) Leads to avoidance. Phobic anxiety is subjectively and behaviourally indistinguishable from other anxieties. Anticipatory anxiety is an important feature. Note that the phobic object is almost always external and not ‘currently dangerous’ for the patient. Internal phobic objects are noted in conditions such as nosophobia and dysmorphophobia; these conditions are classified under hypochondriasis. The circumstances provoking anxiety include situations (for example crowded places), objects like cockroaches and natural phenomena like thunder. The common types of phobic syndromes are agoraphobia, social phobia and specific (simple) phobias. Agoraphobia Agoraphobia is the commonest phobic disorder seen by psychiatrists. Agoraphobia is considered to be the most incapacitating of all phobias, with a lifetime prevalence of about 6-10% (Weismann and Merikangas 1986). It is more common in women between the age group of 15-35 and most cases begin in the early or midtwenties, though there is a further period of high onset in the mid-thirties. In later life, agoraphobic symptoms may develop secondary to physical frailty, with the associated fear of exacerbating medical problems or having an accident. The first episode typically occurs when a person (often a woman) is waiting for public transport or shopping in a crowded supermarket. Lack of immediately available escape route or exit is the main cognitive basis for the anxiety seen in agoraphobia. The three common themes that provoke anxiety and avoidance are of distance from home, crowding and confinement. Anticipatory anxiety can start even hours before the patient enters the feared situation. Avoidance of crowds, public places, or travelling away from home or being alone is a common feature. . Patients remain symptoms free if avoidance is successful. Symptoms usually fluctuate. It is not uncommon for agoraphobics to become totally housebound and, therefore, is sometimes called as housebound housewife syndrome, although not all patients with this condition are necessarily housewives. Agoraphobia may be accompanied by panic attacks, whether in response to environmental stimuli or arising spontaneously. © SPMM Course As highlighted earlier, ICD-10 considers agoraphobia as the primary disorder with panic attacks being secondary and indicate severity of agoraphobia. The opposite is true in DSM-IV (but this issue has been resolved in DSM-V: see the box above). In cases where depression starts earlier, a diagnosis of depressive disorder should suffice, especially in late onset agoraphobia. Social Phobias Social phobia occurs more in small group settings where close scrutiny is possible. Two types of social phobia are noted in ICD-10 - (1) discrete type – anxiety manifested seen in specific occasions e.g. shy bladder (when using a public toilet) or fear of public speaking or (2) diffuse type – seen with exposure to any generic social task. Fear of vomiting in public is seen in some with social phobia. Blushing is also more common in social phobia than other anxiety disorders. The condition usually begins between the ages of 17 and 30. The first episode occurs in a public place, usually without any apparent reason. DSM describes social phobia as a marked and persistent fear of one or more social or performance situations where one gets exposed to unfamiliar people or to possible scrutiny by others. DSM also specifies the fear of humiliating or embarrassing oneself as an important feature, which helps to differentiate it from the anxiety seen in social situations when someone is paranoid. In addition, DSM stipulates that the sufferer must also recognize that the fear is excessive or unreasonable. DSM-IV specifies that in children, difficult social situations should involve interactions with peer, but an appreciation of the unreasonable or excessive nature of the fear is not required. A duration criteria of 6 months is also specified only for children, not adults. Specific phobias The age of onset of most specific phobias is in childhood; phobia of animals at average age of 7, blood phobia at 9, dental phobia at 12 (Ost, 1987) and claustrophobia -20yrs. It is more common among women. DSM-IV distinguishes 5 subtypes of phobias: animals, aspects of the natural environment, blood/injection/injury, situational, and other provoking agents. Specific phobia does not usually fluctuate and remain constant. Disease phobia related to situations where disease can be acquired and so avoided is still a specific phobia (nosophobia) and not hypochondriasis. Blood injury injection phobia is different from other phobias in that the response to exposure is not tachycardia and sympathetically driven heart rate, etc. Instead, a fainting response occurs where the DSM-5 AND SPECIFIC PHOBIAS In adults, there is no requirement for a subjective recognition that the fear is excessive or unreasonable. For all ages, duration of 6 months or more is applied. # 23 - Obsessive compulsive disorder # Obsessive-compulsive disorder © SPMM Course patient may drop fainting with low BP and bradycardia. There is a high prevalence of the condition among first-degree relatives of affected people (Marks 1988) About 5% of adults have a fear of the dental procedures. It can become so severe that all dental treatment is avoided, and dangerous caries develops (Gale and Ayer 1969). DSM-IV specifies that in adults, but not children, an appreciation of the unreasonable or excessive nature of the fear to diagnose specific phobias. The duration criteria of 6 months is specified only for children, not adults; as many irrational fears in children may be transient and developmental (this is changed in DSM-V, see the box above). Obsessive-compulsive disorder OCD is characterised by obsessional thinking, compulsive behaviour and often associated with marked anxiety and depression. Diagnosis according to ICD10 obsessions (thoughts, images, or ideas) and compulsions share the following features, all of which must be present: (1) Acknowledged as originating in the mind of the patient (2) Repetitive and unpleasant; at least one recognised as excessive or unreasonable (3) At least one must be unsuccessfully resisted (although resistance may be minimal in some cases) (4) Carrying out the obsessive thought or compulsive act is not intrinsically pleasurable Obsessions can occur in several forms such as thoughts, ruminations, doubts, impulses and phobias. Obsessional slowness can occur as a result of Obsessional doubts or compulsive rituals. According to ICD-10, either obsessions or compulsions (or both) present on most days for a period of at least two successive weeks. Common symptoms: Checking (63%), washing (50%), fear of contamination (45%), doubting (42%), bodily fears (36%), counting (36%), insistence on symmetry (31%), aggressive thoughts (28%) (Data from OxfordHandbook of Psychiatry) Compulsive hoarding may be a neurobiologically distinct form of obsessive-compulsive disorder. Hoarding is notoriously difficult to treat by either psychological or pharmacological means. Symmetry obsessions tend to be chronic and treatment resistant. DSM-5 AND OCD A new exclusive chapter has been created to describe obsessive-compulsive and related disorders (not clubbed with anxiety disorders anymore). 2 new diagnoses are included in this chapter. 1. Hoarding Disorder with core symptom being the inability (or persistent difficulty) to discard or give up possessions, regardless of their actual value. 2. Excoriation Disorder (dermatillomania) with core symptom of compulsively  picking  one’s  own  skin  for   no apparent reason. # 24 - Reactions to severe stress # Reactions to severe stress # 25 - Acute stress reaction # Acute stress reaction # 26 - Adjustment disorder # Adjustment disorder © SPMM Course DSM-IV describes OCD as an anxiety disorder along with GAD and PTSD. A change has been made in DSM-V (see the accompanying box) Reactions to severe stress Acute stress reaction Acute stress reaction (ICD) usually starts in an hour; resolution begins within 8 hours (if the stress is hit and run) or 48 hours if it is prolonged. The presence of physical exhaustion, organic factors or disease states increases the risk. The stressor is usually one that poses a serious threat to security, integrity and social position. The patient may initially be dazed with narrowed attention; disorientation is not uncommon as a result. Sometimes agitation and overactivity are seen. Partial or complete amnesia for the acute stress reaction is not unheard of. Dissociative symptoms seem to predominate in some. Having a history of previous psychiatric disorder does NOT negate a diagnosis of acute stress reaction. Acute stress disorder is a DSM concept similar to acute stress reaction. It is defined as starting while experiencing or after experiencing the distressing event, and lasting at least two days to at most four weeks. The emphasis is on dissociation, with onset specified to be within four weeks with symptoms lasting up to 4 weeks. In DSM-4, the diagnosis of acute stress disorder requires marked symptoms of anxiety and 3 from a list of 5 dissociative symptoms- depersonalization, derealisation, a sense of numbing or detachment, reduced awareness of the surrounding and dissociative amnesia. It also specifies that the response should involve intense fear, helplessness or horror. Debriefing is used widely for treatment but with little evidence that it is effective; in some cases it may even be counterproductive. Adjustment disorder Adjustment disorder is a diagnosis in both ICD-10 and DSM-IV. In DSM-IV, it is seen as a residual category for individuals with clinically significant distress without meeting criteria for a more discrete disorder such as depression or PTSD. It is a condition that refers to the psychological reactions arising in relation to adapting to new circumstances and occurs in someone who has been exposed to a psychosocial stressor like DSM-5 AND ADJUSTMENT DISORDER Reconceptualized as a heterogeneous array of stress-response syndromes that occur after exposure to a distressing (traumatic or nontraumatic) event. No longer a residual category for other anxiety disorders DSM-5 AND ACUTE STRESS DISORDER The stressor criterion requires being explicit as to whether qualifying traumatic events were experienced directly, witnessed, or experienced indirectly. The need for subjective response with intense fear, helplessness, or horror is removed now. © SPMM Course divorce, separation etc., which is not catastrophic in nature. The usual presentations include anxiety, depression, poor concentration, irritability, anger, etc. with physical symptoms caused by autonomic arousals such as tremor and palpitations. Individual vulnerability plays a greater role in adjustment disorder than any other neurotic disorder. In adjustment disorder, patients may feel vulnerable to become violent though they rarely are violent. Conduct problems may be a presentation of adjustment disorder in adolescence; regressive phenomenon may be seen in children. The onset is more gradual than that of acute stress reaction, and the course is more prolonged. Social functioning is usually impaired. Onset must be within one month in ICD-10 and three months according to DSM-IV. Duration of adjustment disorder cannot exceed six months except in the subtype of prolonged depressive reaction, which can last up to 2 years. Brief depressive reaction subtype can last only up to a month. Also, the DSM-IV  Criterion  A2  regarding  the  subjective  reaction  to  the  traumatic  event  (e.g.,  “the  person’s   response involved intense fear, helplessness, or horror”)  has  been  eliminated. Bereavement and grief reaction Patients who experienced bereavement within last three months cannot be diagnosed to have an adjustment disorder. Normal bereavement is not coded in ICD 10 Chapter V, but in Chapter XXI. Normal grief: The classical symptoms experienced after bereavement which would include disbelief, shock, numbness, and feelings of unreality; anger; feelings of guilt; sadness and tearfulness; pining or searching, preoccupation with the deceased; disturbed sleep and appetite and, occasionally, weight loss; seeing or hearing the voice of the deceased (hallucinations of widowhood) Usually these symptoms gradually reduce in intensity, with the acceptance of the loss and readjustment (see the table below for the normal phases). A typical grief reaction lasts up to 12 months with an average duration of 6 months. © SPMM Course Irrespective of age, a third of those who lose a spouse meet criteria for major depression in the first month after the death, and half of these remain clinically depressed one year later. However, in normal grief reactions substantial improvement is expected within two months to 6 months, and those who continue to meet criteria for major depression after this period should receive antidepressant or psychotherapy. Abnormal grief: It is also called as morbid or pathological or complicated grief. It is a grief reaction that is very intense, prolonged, delayed (or absent), or where symptoms outside the normal range are seen: e.g. preoccupation with feelings of worthlessness, thoughts of self-harm or suicide, excessive guilt, marked slowing of thoughts and movements, a prolonged period of lack of ability to function, hallucinatory experiences (other than the image or voice of the deceased) In ICD-10, abnormal grief reactions are coded as adjustment disorders. Abnormal grief includes Inhibited grief: Absence of expected grief symptoms at any stage Delayed grief: Avoidance of painful symptoms within two weeks of loss Chronic grief: Continued significant grief-related symptoms six months after loss ( Working with grieving adults | BJPsych Advances, http://apt.rcpsych.org/content/10/3/164_br (accessed March 31, 2015). Likely causes of abnormal grief include sudden and unexpected death of the deceased; insecure survivor; dependent or ambivalent relationship with the deceased; presence of dependent children and so cannot show grief easily; presence of previous psychiatric disorder in the survivor. Phase I Shock and protest includes numbness, disbelief and acute dysphoria Phase II Preoccupation includes yearning, searching and anger Phase III Disorganisation includes despair and acceptance of loss Phase IV Resolution gradual return to normality # 27 - Posttraumatic stress disorder # Posttraumatic stress disorder # 28 - Dissociative (conversion) disorders # Dissociative (conversion) disorders © SPMM Course Posttraumatic stress disorder The term PTSD denotes an intense prolonged and sometimes delayed reaction to an intensely stressful event. The essential features are hyperarousal, re-experiencing of aspects of the stressful event and avoidance of reminders. The principal symptoms of PTSD include Hyperarousal o Persistent anxiety o Irritability o Insomnia o Poor concentration Hypervigilance due to re-experiencing and enhanced startle response o Intrusions o Recurrent distressing dreams o Intensive intrusive imagery (flashbacks, vivid memories) o Difficulty in recalling stressful events at will Avoidance o Avoidance of reminders of the events- Efforts to avoid thoughts, feelings, or conversations associated with the trauma. Efforts to avoid activities, places, or people that arouse recollections of the trauma o Detachment-Feeling of detachment or estrangement from others o Emotional numbness o Diminished interest in activities (anhedonia) Both ICD-10 and DSM-IV require 2 or more persistent symptoms of increased psychological sensitivity and arousal (not present before exposure to the stressor) to diagnose PTSD. PTSD should start within six months of the trauma. In a small number of patients the onset is delayed i.e. after six months – termed  as  ‘probable PTSD’; in others the course may be chronic > 6 months. Enduring personality changes are also reported following such trauma. In DSM-IV, a 3-months threshold is used to define chronic PTSD. Type 1 trauma refers to a single sudden catastrophic event e.g. accidents or rape. Type 2 trauma refers to a chronic repetitive insult against which the individual has no defence e.g. sexual abuse. Dissociative (conversion) disorders Under this chapter in ICD-10 dissociative amnesia, fugue, trance/possession and disorders of movement/sensation (motor disorders, convulsions, anaesthesia/sensory loss) are included. DSM-5 AND PTSD The stressor criterion requires being explicit as to whether qualifying traumatic events were experienced directly, witnessed, or experienced indirectly. The need for subjective response with intense fear, helplessness, or horror is removed now. Along with the symptom clusters of reexperiencing and hyperarousal, the avoidance/numbing cluster is split into two. So now there are 4 clusters. Irritable, reckless or self-destructive behaviour is added to the description of arousal symptoms. Diagnostic threshold is lowered for children. In addition, a separate PTSD criterion has been added for children less than age 6. © SPMM Course Dissociation is referred to as loss of integration among memories, identity, sensations and movements. It occurs closely in time with trauma. Theoretical concepts such as unconscious motivation or secondary gain are not used to describe this condition in ICD 10. Dissociation starts suddenly and terminated abruptly within weeks to months, Treatment is difficult in patients in whom it remains chronic (i.e. nearly a year). The concept of dissociative amnesia is centered on the loss of memory for important recent events, which is partial, patchy and selective. The characters of dissociative amnesia are o Episodic memory loss: retrograde only – no anterograde deficits. o Amnesia is for events that happened in a discrete period of minutes to years o The problem is not vague or inefficient retrieval but the strikingly complete unavailability of memories which were generally formed and were previously accessible. These events are traumatic or stressful. Amnesia can occur as a part of a dissociative fugue as well. In fugue purposeful journey away from home or   one’s   usual   base occurs. Self-care is usually maintained despite   ‘getting   lost’. Sometimes new identity can be assumed, and amnesia is present for past identity during the fugue; on recovery amnesia may be present for the fugue episode itself. As there is no cognitive impairment, the behaviour is usually normal. Perplexity and la belle indifference are frequent. Trance is a dissociative state where narrowed consciousness and limited but repeated movements are seen. Diagnosis of trance is made only if it is involuntary and not a culturally appropriate, intended practice. In addition, the trance states must be intrusive on activities of life and occur outside culturally sanctioned situations. Note that Temporal Lobe Epilepsy and head injury can also cause ‘organic’  trance. Conversion / hysterical disorder is called a dissociative disorder of motor movement and sensations. The degree of disability in this disorder is very variable. La belle indifference is not universal, but common in conversion disorder. Close friends or relatives might have had the actual organic illness whose symptoms are present in a subject with conversion disorder. A milder and transient variety is seen in adolescent girls. Both Ganser syndrome and twilight states are included in dissociative states according to ICD-10. In DSM-IV, under dissociative disorders, only amnesia, fugue, dissociative identity disorder (multiple personalities), and depersonalization disorder are included. Conversion disorders and DSM-5 AND DISSOCIATIVE DISORDERS Depersonalisation disorder is now renamed as depersonalization/derealization disorder. Fugue is now a specifier for amnesia; not a separate diagnosis Dissociative identity disorder now includes pathological possession syndromes seen in some cultures. Both observed and reported changes in personality are considered in the # 29 - Somatoform disorders # Somatoform disorders © SPMM Course pain disorder are classified along with the somatoform disorder. In other words, all motor/sensory presentations are classed as conversion while memory/personality presentations are retained in dissociation category. Somnambulism is listed as a nonspecific dissociation in DSM-IV. Seizures vs. pseudoseizures: At times it may be difficult to distinguish epilepsy from pseudoseizures (conversion). The following features are taken to be more suggestive of pseudoseizures: Seizures vs. pseudoseizures Avoidance behaviour during seizures (to prevent serious injuries) Change in symptomatology of  seizure  patterns  e.g.  progression  or  ‘march’  that  is  inconsistent  with  cortical organization, asynchronous limb movements. Closing eyes during seizures, especially resisting opening of eyelids when attempted Dystonic posturing (this can happen in frontal seizures though rare) Emotional or situational trigger for the seizures and seizures provoked by suggestion Gradual onset and cessation of seizures (true seizures have a rapid crescendo and decrescendo) Tongue biting is rare and if present, usually the tip (not the side) of the tongue is bitten. Pelvic movements (especially forward thrusting) and side-to-side head movements Prolonged seizures (duration of 2 to 3 minutes); High seizure frequency but no history of injury from seizures. Lack of concern or an excessive or exaggerated emotional response Multiple unexplained physical symptoms Non response to antiepileptic drugs or a paradoxical increase in seizures with drug treatment Seizures that occur only in the presence of others or only when the patient is alone Adapted from Elger RM. Psychogenic nonepileptic seizures: review and update. Epilepsy Behav 2003;4:207. Somatoform disorders Under this chapter in ICD-10, somatization disorder, hypochondriacal disorder, somatoform pain syndromes, autonomic dysfunction and undifferentiated somatoform disorder are included. All somatoform disorders are characterized by the lack of a psychological appraisal on the patient’s  part  along   with a resistance to consider presenting problems  as  one  of  ‘mental’  origin. Dissociative trance Possession trance x Altered narrow consciousness x Lost personal identity x No replacement with another identity x Stereotypic movements / utterances x Amnesia seen x Altered narrow consciousness x Lost personal identity x Replaced with another identity x Stereotypic movements / utterances x Amnesia seen © SPMM Course Somatization disorder is characterized by (a) at least 2 years of multiple and variable physical symptoms for which no adequate physical explanation has been found; (b) persistent refusal to accept the advice and reassurance of several doctors regarding the absence of a physical illness; (c) notable impairment of social and family functioning due to the symptoms and the illness behaviour. The term Briquet Syndrome or St. Louis Hysteria is sometimes applied to denote somatisation disorder. Family history of alcohol use and antisocial personality are common in women with somatisation disorder. Hypochondriacal disorder is characterized by 2 conditions (1) persistent belief of harboring atleast one serious physical illness even though repeated investigations and examinations have identified none or a persistent preoccupation with a presumed deformity or disfigurement (body dysmorphic type); (2) persistent refusal to accept the advice and reassurance of several doctors regarding the absence of a physical illness. Both nosophobia and nondelusional dysmorphophobia are classified as hypochondriasis in ICD-10. A 6 months duration criteria is specified in ICD-Diagnostic Criteria for Research (not in the regular diagnostic guidelines). Note that in DSM-IV, body dysmorphic disorder (dysmorphophobia) is considered as a separate diagnostic entity, within the chapter on somatoform disorders. It is described as a ‘subjective  description  of  ugliness  and  physical  defect  which  the   patient  feels  is  noticeable  to  others’.  It  is  an  excessive  concern   (overvalued idea) about trivial or non-existent physical abnormalities, which are perceived to be deformities. Beliefs about deformity that are of delusional intensity are classified under delusional disorders. With delusional intensity, the patient is constantly pre-occupied, convinced and tormented by abnormal belief that some part of his/her body is too large, too small or misshapen, which to other people, the appearance is normal or there is a trivial abnormality. The common complaints are about the nose, ears, eyes, mouth, buttocks, penis, breasts, but any part of the body may be involved. The affected person might think that other people notice and talk about his deformity and, therefore, would get involved in time consuming behaviours such as re-examining, repeated checking, involve in elaborated grooming rituals to hide the perceived defect and avoidance behaviour. This condition usually DSM-5 AND SOMATICSYMPTOMS In DSM-5, somatoform disorders are referred to as Somatic Symptom Disorders (SSD). Diagnosis of Somatization, Hypochondriasis, Pain Disorder and Undifferentiated Somatoform disorders are now eliminated. SSD can be diagnosed even if there is a medical disorder that explains the presenting symptoms. The emphasis is shifted from the actual physical symptoms to the maladaptive thoughts and feelings that surround these symptoms  (‘positive  features’). Individuals with high health anxiety but no somatic symptoms will be diagnosed to  have  ‘illness  anxiety  disorder’ Factitious disorder is placed under somatic symptom and related disorders. Body Dysmorphic Disorder has been moved from somatoform chapter to OCD & related disorders. A  “with  muscle   dysmorphia”  specifier  has  been  added  the description of body dysmorphic disorder. # 30 - Other neurotic disorders # Other neurotic disorders © SPMM Course begins in adolescence and is chronic with some fluctuations over time. It can occur as part of other psychiatric disorders such as depression or schizophrenia, or may be associated with social phobia or personality disorders Men and women are equally affected by hypochondriasis. In hypochondriasis patient looks for diagnosis, not symptom relief; he/she names the suspected disorder and may be more or less convinced about having the disorder. Somatoform autonomic syndrome refers to recurrent symptoms of autonomic arousal, such as palpitations, sweating, tremor, flushing, which often occur alongside other subjective symptoms referred to a specific organ or system despite having no evidence of structural or functional deficit in these systems. Patients refuse to be reassured regarding the absence of a physical illness despite the reassurances of different doctors. In somatoform pain syndrome, the major complaint is of persistent, severe, and distressing pain that is not explained by a physiological process or a physical disorder. Globus hystericus, psychogenic pruritus, psychogenic torticollis, teeth grinding (bruxism) and psychogenic dysmenorrhea are also included as  ‘other  somatoform  disorders’. Other neurotic disorders Neurasthenia, depersonalization-derealisation syndrome and other specified neurotic disorders (most of the culture-bound syndromes such as latah, dhat, koro) are included here. Psychogenic syncope and writer’s  cramp  are also described in this category. Neurasthenia is classified in F48 of ICD-10 as a neurotic disorder with either persistent and distressing complaints of increased fatigue after mental effort or persistent and distressing complaints of bodily weakness and exhaustion after minimal effort. This must be accompanied by at least two of the following features: 
- feelings of muscular aches and pains, dizziness
, tension headaches, 
 sleep disturbance, inability to relax, irritability
, dyspepsia. The diagnosis can only be made if other disorders classified in F40-47 section or depression cannot account for the presenting symptoms. Neurasthenia is the closest ICD-10 equivalent of Chronic Fatigue Syndrome. Depersonalization-derealization syndrome is diagnosed when either depersonalization or derealization symptoms are present in the presence of full insight (i.e. an acceptance of the subjective and spontaneous nature of the symptoms) and a clear sensorium. Depersonalization refers  to  the  perception  that  one’s feelings and/or experiences are detached, distant, not his or her own, lost (as if phenomenon). Derealization refers to the perception that objects, people, and/or surroundings seem unreal, distant, artificial, colourless or lifeless. Note that DSM classifies this condition as a dissociation disorder. © SPMM Course Comparing and contrasting various disorders with somatic features Dissociation 1. Mental effects of a conflict 2. E.g. Amnesia, Loss of identity, alter personality Conversion 1. Physical effects of a conflict 2. Paralysis, blindness, ataxia, anaesthesia, aphonia, seizures Somatoform/somatisation 1. Production of a symptom (positive) 2. Pain, vomiting, etc. 3. GIT and Musculoskeletal 4. Polysymptomatic Conversion 1. Loss of function (negative) 2. Paralysis, blindness, loss of balance, etc. 3. Neurological 4. Monosymptomati Hypochondriasis 1. Preoccupied with diagnosis 2. Concern: ‘One  dreadful  disease.' 3. Gastrointestinal features most common Somatisation 1. Preoccupied with symptoms 2. Concern: ‘One  excellent cure.' 3. Musculo-skeletal symptoms most common Malingering 1. Clearly intentional 2. Often monetary benefits 3. Military, compensation claims, etc. Factitious 1. ‘Truly puzzling’  with  ‘no  cause.' 2. Only gain is sick role 3. Seen in paramedical professionals 4. Munchaussen is severe form – wide doctor shopping is seen Factitious Disorders and Malingering DSM-IV considered factitious disorder and malingering in a separate chapter. In ICD-10, factitious disorders are considered along with personality disorders (F68). Malingering is not an ICD 10 mental disorder category but is coded in Z76.5. Munchausen by proxy is not coded in Chapter V of ICD10 but is discussed in T74.8. # 31 - 7. Disturbances of behaviour and body physiol # 7. Disturbances of behaviour and body physiology # 32 - Eating Disorders # Eating Disorders © SPMM Course 7. Disturbances of behaviour and body physiology This  includes  various  disturbances  in  ‘behaviour’  and  abnormalities  across  a  mixture  of  ‘physiological   systems’  such  as  weight,  libido,  pregnancy, etc. It also includes non-dependence producing substance abuse such as analgesic abuse; antidepressant use; laxative use and steroid abuse. Eating Disorders The ICD-10 diagnostic criteria for Anorexia Nervosa describes the presence of low body weight as being 15% or more below the expected norm and BMI as 17.5 or less. Other features include x Self-induced weight loss, avoidance of fattening foods, vomiting, purging, excessive exercise, use of appetite suppressants. x Body image distortion, dread of fatness: overvalued idea, imposed low weight threshold. x Endocrine disturbances due to HPA axis dysfunction (Hypothalamic- pituitary-gonadal axis) manifesting as amenorrhoea, reduced sexual interest, raised GH levels, increased cortisol, altered Thyroid tests, abnormal insulin secretion. x Delayed/arrested puberty- if onset pre-pubertal. While diagnosing anorexia, Quetelet’s  body mass index is applicable only if age is more than 16. In DSM-IV, amenorrhea is defined as at least three consecutive cycles being absent. DSM-IV also specifies two types: x Binge-eating/purging type: regularly engaged in bingeeating or purging behavior (such as self-induced vomiting or the use of laxatives, diuretics, or enemas). x Restricting type: no binge-eating or purging behavior In atypical anorexia nervosa, one or more of these essential features may be absent, or all are present but to a lesser degree. Atypical anorexia nervosa is described as “ a disorder that fulfills some of the features of anorexia nervosa but in which the overall clinical picture does not justify that diagnosis. For instance, one of the key symptoms, such as amenorrhoea or marked dread of being fat, may be absent in the presence of marked weight loss and weight-reducing behaviour. This diagnosis should not be made in the presence of known physical disorders associated with  weight  loss.” (ICD-10) x Several features are noted in patients with atypical anorexia when compared to those with typical anorexia. x Older age at onset and presentation x Recurring bouts of depression DSM-5 AND EATING DISORDERS Anorexia Nervosa: The requirement of amenorrhea as a condition for diagnosis has been removed. Bulimia Nervosa: The required minimum average frequency of binge eating/compensatory behaviour is changed from twice to once weekly. © SPMM Course x Numerous somatic complaints x Unmet dependency needs, and x Little evidence of distortion in body image is seen. Differential Diagnoses for Anorexia Nervosa Physical Disorders Hyperthyroidism; other endocrine disorders; GI disorders resulting in vomiting, loss of appetite and/or malabsorption; Malignancy; Chronic infection. Hypothyroidism can also produce amenorrhea. Psychiatric disorders Depression, OCD with eating abnormalities, delusional behaviour concerning food, vomiting secondary to conversion (cyclical vomiting) Adapted from Focus. Fall 2004, Vol. II, No. 4 (p 528) The ICD-10 diagnostic criteria for Bulimia Nervosa includes the following: x Persistent preoccupation with eating x Irresistible craving for food x Binges- episodes of overeating x Attempts to counter the fattening effects of food (self-induced vomiting, abuse of purgatives, periods of starvation, use of drugs e.g. appetite suppressants, thyroxine, diuretics) x Morbid dread of fatness, with imposed -low weight threshold In atypical cases of bulimia, one or more of these features may be absent. Neglecting insulin treatment is a weight reduction strategy seen in diabetics with bulimia. In DSM-IV, two types are specified: Purging and non-purging type. Obesity is not coded under eating disorders in ICD-10, but in chapter E66, which is not a mental disorder. Similarly  ‘loss  of  appetite’  is  not  considered  as  anorexia  even  if  it  is  ‘psychogenic’. EDNOS- Eating disorder not otherwise specified is the most common eating disorder in the outpatient setting and is widely used by clinicians using DSM-IV. Binge eating disorder (BED) is also increasingly recognised, but in ICD-10 this falls under atypical bulimia and in DSM-IV under EDNOS. Binge eating disorder is characterized by recurrent episodes of binge eating in the absence of extreme weight-control behaviour. This is often seen in a background of a general tendency to overeat. BED is associated with obesity; 5–10% of those seeking treatment for obesity have BED. Patients typically present in 40s. More males compared to other eating disorders, but only 25% of all binge-eating population is male. There is a high degree of spontaneous remission noted and stressed associated overeating is a common phenomenon. Self-help, behavioural weight loss programmes and CBT/IPT can help. # 33 - Sleep disorders # Sleep disorders © SPMM Course Sleep disorders ICD-10 chapter V (mental health) recognises only non-organic sleep disorders in which emotional causes are considered to be a primary factor. These are conditions that include dyssomnias (abnormalities in amount, quality, or timing of sleep) and parasomnias (abnormal episodic events occurring during sleep). Various chapters where sleep disorders are described in ICD-10 Hypersomnia, sleep-walking, sleep-terrors, nightmares, nonorganic sleep-wake disorder ICD-10 Chapter V, F51 Kleine-Levin syndrome, Narcolepsy, Disorders of the sleep - wake schedule, Sleep apnoea Chapter VI of ICD-10 Episodic movement disorders which include nocturnal myoclonus Chapter II Enuresis Chapter V, F98 (Childhood disorders) Primary nocturnal enuresis (considered to be due to delay in bladder development) Chapter XVIII Sleep walking and sleep terrors are mostly childhood disorders and if adult onset or adult persistence is seen then significant psychological disturbance must be suspected; these are sometimes seen in early stages of dementia especially REM disorders in Lewy body dementia. In sleep terrors, several minutes of disorientation is noted on waking, and some perseverative behaviour may also be noted; recall if at all possible may be limited to fragmentary mental images. In contrast nightmares are well recalled; they may be associated with benzodiazepine, tricyclic or thioridazine use. Kleine-Levin syndrome is characterised by periodic episodes of hypersomnolence and hyperphagia. Associated features include a lack of concentration, mood changes, sometimes hypersexuality and anxiety. Laboratory tests may show some nonspecific changes in the electroencephalogram. However, clinical presentation and laboratory tests are normal during asymptomatic intervals. It most often presents in adolescent males, with complete recovery by the 3rd to 4th decade of life. Possible precipitating factors include excessive workload, febrile illness, and respiratory infections. Narcolepsy is characterised by excessive daytime drowsiness accompanied by a sudden onset of REM sleep (sleep seizure or narco lepsy) and sudden loss of muscle tone, provoked by strong emotions (cataplexy). Sleep paralysis and hynagogic hallucinations may also occur (between wakefulness and sleep) but are less common. Sleep paralysis is an episode of inability to move occuring between wakefulness and sleep. These attacks usually occur during adolescence and persist through life. Hypnagogic hallucinations are usually auditory in nature but may be visual or tactile, occur in about 25% of patients. Narcolepsy is virtually always familial, and 99.5 % of patients have the HLA Antigen DR-2 (DR15/DQ6). There is usually no structural brain lesion present in these patients. # 34 - Sexual disorders # Sexual disorders © SPMM Course A more commonly used classification system for sleep disorders is the International Classification of Sleep Disorders ICSD system. DSM closely resembles ICSD. Classification of sleep disorders as per this system is shown below: Dyssomnias x Primary insomnia x Primary hypersomnia x Circadian sleep disorders x Narcolepsy x Breathing related sleep disorders x Sleep state misperception Parasomnias (subdivided according to the phase of sleep with which they are associated) Arousal disorders (arising from NREM sleep) x Confusional arousals x Sleepwalking x Sleep terrors Sleep– wake transition disorders x Sleep starts x Sleep talking REM sleep parasomnias x REM behavioural disorder x Nightmares x Sleep paralysis Other parasomnias x Sleep bruxism x Sleep enuresis Sexual disorders Sexual dysfunctions are coded in F52 group. These disorders include the lack or loss of sexual desire (sexual aversion disorder, failure of genital response, orgasmic dysfunction, premature ejaculation, nonorganic vaginismus, nonorganic dyspareunia and excessive sexual drive). According to DSM-IV, they can be classified into Sexual desire disorders (sexual aversion, hypoactive sexual desire) Sexual arousal disorder (female sexual arousal disorder, male erectile disorder) Orgasmic disorders (female and male orgasmic disorder, premature ejaculation) Sexual pain disorder (Dyspareunia, vaginismus) Others (including those due to general medical or substance use disorders) # 35 - Other physiological disorders # Other physiological disorders © SPMM Course Other physiological disorders Puerperal disorders: F53 codes mild and severe puerperal mental disorders instead of classifying postnatal  disorders  as  ‘depression’  vs.  ‘psychosis’.  This  is  because,  it  is  well  recognised  that  separating   postnatal psychosis from depression is often difficult in practice. Non dependence abuse: F55 codes for the abuse of a wide variety of medicaments, proprietary drugs, and folk remedies and psychotropic drugs that do not produce dependence, such as antidepressants; laxatives; and analgesics DSM-5 AND SEXUAL DISORDERS Genito-Pelvic Pain/Penetration Disorder is a new category that merges vaginismus and dyspareunia. The diagnosis of sexual aversion disorder has been removed. # 36 - 8. Disorders of adult personality and behavio # 8. Disorders of adult personality and behaviour # 37 - Personality disorders # Personality disorders © SPMM Course 8. Disorders of adult personality and behaviour Personality disorders x According to ICD-10, a diagnosis of personality disorders cannot be made in individuals younger than age 16 or 17. x Unlike other psychiatric disorders, personal distress is not a criterion for diagnosing personality disorders but this may be a feature seen during the course of a personality disorder. x At least three traits must be present from the list for diagnosing antisocial and borderline personality; the rest of the disorders requires at least four from the lists provided by ICD-10 diagnostic guidelines. x There are not many differences between ICD-10 and DSM-IV in the description of personality disorders. The notable exceptions are listed below. x Passive-Aggressive personality disorder and Depressive personality disorder are placed in an appendix of DSM-IV for research purposes. Passive aggressive is discussed with other personality disorders category in ICD10. DSM-IV ICD-10 Personality disorders are grouped into 3 clusters No clustering of personality disorders Schizotypal disorder is a personality disorder Not a personality disorder, but described as a variant of psychosis under the chapter on Schizophrenia Only single entity of borderline personality disorder Emotionally unstable personality disorder can be of impulsive or borderline type Features of Cluster A (odd, eccentric) personality disorders © SPMM Course Features of Cluster B (dramatic, erratic) personality disorders •Suspicious of other people and their motives. •Hold longstanding grudges against people, •Believe others are not trustworthy, •Emotionally detached •Feel other people are deceiving, threatening, or making plans against them. Paranoid personality disorder Paranoid personality disorder •Have difficulties in expressing emotions, particularly around warmth or tenderness. •Prefer loneliness •Aloof or remote, •Have difficulty in developing or maintaining social relationships •Remain unaware of social trends •Unresponsive to praise or criticism Schizoid personality disorder Schizoid personality disorder •Appear odd or eccentric; •May have illusions, magical thinking •Obsessions without resistance •May be members of quasi-cultural groups •Thought disorders and paranoia. •May believe in ESP, clairvoyance etc. •May have transient psychotic features Schizotypal personality disorder Schizotypal personality disorder © SPMM Course •Lack of regard for the rights and feelings of other people. •Lack of remorse for actions that may hurt others. •Ignore social norms about acceptable behaviour, •May disregard rules and break the law. •Make relations easily but break them equally easily •A small proportion may be psychopathic Antisocial personality disorder Antisocial personality disorder •Poor self-image, •Unstable personal relationships, •Impulsive behaviour in areas such as personal safety and substance misuse. •May self-harm, feel suicidal and act on these feelings, •Experience instability of mood, •Have episodes of micro-psychosis. •Feelings of chronic emptiness •Fears of abandonment – rejection sensitivity hence form intense but short lasting relations Borderline personality disorder Borderline personality disorder •Extreme or over-dramatic behaviour. •May form relationships quickly, but be demanding •Attention-seeking. •May appear to others as being self-centred with shallow emotions •Being inappropriately sexually provocative. Histrionic personality disorder Histrionic personality disorder •Exaggerated sense of own importance. •Frequently self-centred •Intolerant of other people. •Grandiose plans and ideas •Cravings for attention and admiration. •Fear of dependency is the core conflictual theme. •Narcissistic injuries to pride lead to rage reactions. Narcissistic personality disorder Narcissistic personality disorder © SPMM Course Features of cluster C (anxious, inhibited) personality disorders DSM IV ICD 10 equivalent Cluster A (odd or eccentric disorders) Paranoid personality disorder Paranoid personality disorder Schizoid personality disorder Schizoid personality disorder Schizotypal personality disorder NONE - classified as a type of schizophrenia like disorder in ICD Cluster B (dramatic, emotional, or erratic disorders) Antisocial personality disorder Dissocial personality disorder Borderline personality disorder Emotionally unstable: 1. Impulsive 2. Borderline subtypes Histrionic personality disorder Histrionic personality disorder Narcissistic personality disorder NONE; mentioned in other personality disorders category Cluster C (anxious or fearful disorders) Avoidant personality disorder Anxious (avoidant) personality disorder Dependent personality disorder Dependent personality disorder Obsessive-compulsive personality disorder Anankastic personality disorder •Fears being judged negatively by other people •Feelings of discomfort in group or social settings. •May come across as being socially withdrawn •Have low self-esteem. •May crave affection but fears of rejection overwhelming. Avoidant personality disorder Avoidant personality disorder •Assumes a position of passivity, •Allowing others to assume responsibility for most areas of their daily life. •Lack self-confidence, •Feel unable to function independently of another person, •Feels own needs are of secondary importance. Dependent personality disorder Dependent personality disorder •Difficulties in expressing warm or tender emotions to others. •Frequently perfectionists •Often lack clarity in seeing other perspectives or ways of doing things, •Rigid attention to detail may prevent them from completing tasks. •Some may be hoarders, scrupulous with money •May not be able to delegate tasks; workaholics. Obsessive-Compulsive personality disorder Obsessive-Compulsive personality disorder # 38 - Habit and impulse disorders # Habit and impulse disorders # 39 - Gender identity disorders # Gender identity disorders © SPMM Course Habit and impulse disorders Impulse control disorders (DSM-IV) or habit and impulse disorders (ICD 10 –chapter F 63) include the following: Kleptomania, Pyromania, Trichotillomania, Intermittent explosive disorder (not in ICD-10, but present in DSM-IV) & Pathological gambling. These disorders are typified by recurrent behaviours that appear irrational and result in harming the patient's own and others interests. This definition excludes the habitual excessive use of alcohol or drugs or sexual (F65.-) or eating (F52.-) related compulsive acts. A repeated failure  to  resist  impulses  (to  set  fire,  steal,  pull  one’s  own  hair  etc.)  is  a  common  theme. Gender identity disorders ICD-10 recognises three disorders: transsexualism, dual role transvestism and gender identity disorders of childhood. Gender identity is established  by  3  years;  it  is  an  individual’s  self  perception  of  being  male  or  female  and   depends on reared sex more than biological sex. It is resistant to change once established firmly. Gender dysphoria refers  to  feeling  of  incongruence  between  one’s  gender  identity  (I’m  a  man, or  I’m  a   woman)  and  one’s  phenotypic  appearance  (I  appear  like  a  man  or  woman). Various degrees of gender dysphoria exist. One mild form is recognized in ICD and DSM as dual role transvestism. Individuals with dual role transvestism wear clothes of the opposite sex in order to experience temporary membership in the opposite sex. The individual experiences a sense of appropriateness by wearing clothes of the other gender. There is no sexual motivation for the cross-dressing. The individual has no desire for a permanent change to the opposite sex. Dual role transvestism must be differentiated from fetishistic transvestism where cross-dressing results in sexual arousal often associated with masturbation or sexual activity. This is classified as a paraphilia (see below). A severe form of gender dysphoria is recognised as transsexualism in ICD and DSM. Transsexualism has the following criteria: x Persistent discomfort with his/her sex or sense of inappropriateness in the gender role of the sex x Strong and persistent cross-gender identification (not merely a desire for any perceived cultural advantages of being the other sex). This may be associated with the wish to  make  one’s  body  as  congruent   as possible with the preferred sex through surgery and hormone treatment. x The disturbance is not concurrent with a physical intersex condition and not due to other functional psychiatric disorders x The disturbance causes clinically significant distress or impairment in social, occupational or other important areas of functioning x The transsexual identity has been present persistently for at least two years. # 40 - Paraphilias (Disorders of sexual preference) # Paraphilias (Disorders of sexual preference) © SPMM Course Most adult transsexuals, in fact, have origins of symptoms in childhood itself. Gender identity disorders of childhood can also be present in adolescents and children. A duration criteria of 6 months is appreciated for the pre-pubertal group. It is important to rule out chromosomal and endocrine problems in this group. In children, the large element of management is promoting the young person's tolerance of uncertainty and resisting pressures for quick solutions for the gender dysphoria. Surgical intervention is not justified until adulthood. Rarely some patients may have a form of body dysmorphic disorder where there is a persistent preoccupation with castration or penectomy without a desire to acquire the characteristics of the other sex. This may be classed as Gender identity disorder - NOS (not otherwise specified) or body dysmorphophobia. But this is not transsexualism. A transsexual person need not necessarily be homosexual – In other words, gender identity must be differentiated from sexual orientation. In gender dysphoria of childhood, 1/3rd to 2/3rd boys later appear homosexually oriented but very few persist as adult transsexuals. GIDs, at any age, are more common in males. Cross-dressing behaviour can also be transient in some associated with stressful times. Also, some individuals with mild gender dysphoria (to a degree that does not cause undue distress while in a mentally healthy state) may experience a marked intensification of a low-grade gender dysphoria when experiencing depressive episodes. Paraphilias (Disorders of sexual preference) Paraphilias, impulsive disorders and other habitual problems are coded under F60. In paraphilias, egosyntonic urges of sexual deviancy are seen (except in some cases of exhibitionism where the urges are reported as ego-alien). Klismaphilia is not a separate entity but is related to use of enemas to achieve sexual arousal. Necrophilia is  also  an  ‘other  paraphilia’  in  ICD-10. This refers to achieving sexual arousal by using dead bodies or other death related objects for sexual arousal. Paraphilias described in ICD-10 & DSM-IV Exhibitionism Expose genitals to achieve arousal Fetishism Use of inanimate objects to achieve arousal Paedophilia Sex with prepubescent child (<13) Sexual masochism Real, not simulated act of being humiliated, beaten or bound to achieve arousal Sexual sadism Real, not simulated act of inflicting psychological or physical suffering including humiliation of victim to achieve arousal DSM-5 AND PARAPHILIC DISORDERS All Paraphilic Disorders now include two new specifiers: In a Controlled Environment and In Remission. © SPMM Course Fetishistic transvestism Crossdressing in heterosexual male to achieve arousal Voyeurism ‘Peeping-toms.' Frotteurism Touching and rubbing against non-consenting individual Frotteurism  is  coded  as  ‘other  paraphilias’  in  ICD-10, but separate disorder in DSM-IV. Fetishistic transvestism is termed transvestic fetishism in DSM-IV. # 41 - 9. Mental retardation # 9. Mental retardation © SPMM Course 9. Mental retardation ICD-10 specifies 4 degrees of mental retardation but advises that the IQ levels for grading severity of mental retardation be only for guidance and should not be applied rigidly in view of the problems of cross-cultural validity. Instead, the severity must be graded primarily by functioning ability. Degree of mental retardation defined using activities of daily life Profound: a minimal capacity for functioning, needs nursing care; constant aid and supervision required. IQ<20 Severe: Speech minimal; Can talk or learn to communicate. No profit from training in self-help. May contribute partially to self-maintenance under complete supervision later in life; IQ 20-34 Moderate: Profits from training in self-help; can be managed with moderate supervision. IQ 35-49 Mild: Can develop social and communication skills; minimal retardation and can be guided toward social conformity. IQ 50-69 The  term  ‘Mental  Retardation’  in DSM-IV is now replaced by  the  term  ‘Intellectual  Disability’ in DSM-V. Statement of Special Educational Needs (SEN): In England & Wales, following a statutory assessment by local  authority,  a  ‘statement  of  SEN’  will  be  prepared  to    set  out  what  special  help  the  child  needs,  and  to   consider the views and wishes of the child and their parents. The SEN statements consist of 6 essential parts as outlined below. The local educational board usually arranges for statutory assessments and initially issues a proposed statement, upon which the parents are invited to comment. The final statement has a legally binding effect on the board. It is possible to ask for reassessmeents to amend the statements. © SPMM Course •Demographics details •List of reports gathered when preparing the statement Part 1 Part 1 •Description of nature and complexity of learning difficulties •The needs listed here will determine the care provided by the state. Part 2 Part 2 •List of arrangements and provisions proposed to be offered by the local authority/education board •Must also include monitoring arrangements •The outlined provisions MUST be met by the board Part 3 Part 3 •Details of school placement Part 4 Part 4 •Non-educational (health and social) needs •NOT legally binding on the local authority Part 5 Part 5 •Describes processes in place to meet noneducational needs Part 6 Part 6 # 42 - 10. Disorders of psychological development # 10. Disorders of psychological development © SPMM Course 10. Disorders of psychological development In ICD-10 these include specific developmental disorders of speech and language (expressive, receptive language disorders, acquired aphasia with epilepsy), scholastic skills (reading, spelling, arithmetical skills), motor skills and pervasive developmental disorders. In non-pervasive disorders, the domain showing a deficit in development often improves with age. For example, in specific reading disorders of childhood, reading improves significantly though spelling difficulties persist longer. Pervasive developmental disorders include childhood autism, Asperger’s  syndrome,  Rett’s  syndrome,  atypical  autism  and   other childhood disintegrative disorder. Autism is defined by the presence of abnormal and/or impaired development evident before the age of 3 years, with abnormal functioning in all three areas of social interaction, communication, and restricted, repetitive behaviour. Unlike children with autism, children with Asperger’s  syndrome have normal language functions before the age of 3. Though language development is affected in autism, the children do not remain mute in most cases. Though not a diagnostic criteria, the presence of persistent gaze avoidance is strongly suggestive of pervasive  developmental  disorder  such  as  autism  /  Asperger’s.   Atypical autism is diagnosed if autistic features are seen but either of the age of onset is not satisfied or a failure to fulfill all three sets of diagnostic criteria is noted. Rett’s  syndrome is  seen  only  in  girls  in  whom  “apparently  normal  or  near-normal early development is followed by partial or complete loss of acquired hand skills and of speech, together with deceleration in head  growth,  usually  with  an  onset  between  7  and  24  months  of  age”  (ICD-10). Children also show handwringing stereotypies, hyperventilation and loss of purposive hand movements. During later ages, trunk ataxia and apraxia, associated with scoliosis along with choreoathetoid movements are seen. Epilepsy is also a common feature. Heller's syndrome or childhood disintegrative disorder is said to resemble dementia that occurs in childhood. Apparently normal development up to 2 years is followed by a loss of previously acquired skills and abnormal social functioning. DSM-5 AND AUTISM Autism Spectrum Disorder is a new description that will now include autism,  Asperger’s, Childhood Disintegrative Disorder, and Pervasive Developmental Disorder (not otherwise specified) in a single category. ASD is characterized by 1) deficits in social communication and social interaction and 2) restricted repetitive behaviors, interests, and activities (RRBs). If no RRBs are seen, then social communication disorder is diagnosed. © SPMM Course Acquired Aphasia with Epilepsy is also called Landau-Kleffner syndrome. It is a disorder in which the child, despite the previous normal progress in language development, loses both receptive and expressive language skills (starting from age 3 – 7) but retains general intelligence. Epilepsy with paroxysmal abnormalities on the EEG is noted; these almost always originate from the temporal lobes bilaterally. # 43 - 11. Disorders with childhood onset # 11. Disorders with childhood onset © SPMM Course 11. Disorders with childhood onset Major ICD-10 categories in this chapter are highlighted in the table below: Divisions Subdivisions Hyperkinetic disorders (HKD) Rarely used (Attention and overactivity, hyperkinetic conduct disorder) Conduct disorders Conduct disorder & oppositional defiant disorder Emotional disorders specific to childhood Separation anxiety, phobias, social anxiety, sibling rivalry Social functioning disorders Elective Mutism, reactive attachment disorder Tic disorders Transient  tics,  Tourette’s  syndrome  (chronic  combined  motor   and vocal) Other behavioural and emotional disorders Enuresis, Encopresis, Pica, Stuttering The hyperkinetic disorder is the ADHD equivalent in ICD-10. For ADHD/HKD, the diagnostic criteria are considered  to  be  more  ‘relaxed’  in  DSM  but  stricter  in  ICD-10. According to DSM-IV criteria, to meet the diagnosis of ADHD, some symptoms must be present before the age of 7 years, although ADHD is not diagnosed in many children until they are older than 7 years when their behaviours cause problems in school and other places. To confirm a diagnosis of ADHD, impairment from inattention and/or hyperactivity-impulsivity must be observable in at least 2 settings and interfere with developmentally appropriate functioning socially, academically, or in extracurricular activities and should persist for at least six months. ADHD is not diagnosed when symptoms occur in a child, adolescent, or adult with a pervasive developmental disorder, schizophrenia, or another psychotic disorder. Conduct disorder is an enduring set of antisocial and aggressive behaviours that evolves over time, usually characterized by aggression and violation of the rights of others. Diagnostic criteria: Children with conduct disorder are likely to demonstrate behaviours in the following four categories x Physical aggression or threats of harm to people, cruelty to people and animals x Destruction of their own property or that of others x Theft or acts of deceit x Frequent and serious violation of age-appropriate rules. (Like truanting or running away) © SPMM Course Other features would include early sexual behaviour, lack of empathy, low self-esteem, and gang involvement. Usually, the features must be present for a substantial duration of minimum six months before entertaining the diagnosis. According to DSM-IV criteria, these behaviours should begin before the age of 13. [Childhood onset type – symptoms present before age 10, Adolescent onset type – symptoms develop after age 10] Oppositional Defiant Disorder: An enduring pattern of negative, hostile, disobedient and defiant behaviour, without serious violations of societal norms or the rights of others. Symptoms must be persistent and evident for at least 6 months. In oppositional defiant disorder, a child's temper outbursts, active refusal to comply with rules, tendency to blame others, spiteful and annoying behaviours exceed expectations for these behaviours for children of the same age. Oppositional Disorder is seen as a limited form of conduct disorder. According to ICD10, the oppositional disorder is a subtype of conduct disorder. DSM-IV excludes oppositional disorder if a conduct disorder is present. Separation anxiety disorder (SAD) is defined as developmentally inappropriate and excessive anxiety concerning separation from home or from those to whom the individual is attached. This anxiety will interfere with normal age appropriate functioning. The essential clinical feature of separation anxiety is excessive worry about losing or being permanently separated from a major attachment figure. Reactive attachment disorder: This disorder, occurring in infants and young children is characterised by persistent  abnormalities  in  the  child’s  pattern  of  social  relationships, which are associated with emotional disturbance and reactive to changes in environmental circumstances. Elective Mutism is a disorder characterized by a persistent failure to speak in specific settings (school) despite the full use of language at home or with family, may be found in younger children with social phobia. A child with selective mutism may remain completely silent or near silent, in some cases whispering instead of speaking out loud. Fear of strangers is a normal phenomenon in the second half of the first year of life. A degree of social apprehension is normal in early childhood in socially threatening/novel situations. Social anxiety disorder of childhood is a diagnosis that can be used before the age of 6 years, but only when the anxiety is unusual in degree and accompanied by problems in social functioning. ©"SPMM"Course" 57" Sibling!rivalry!disorder"is"characterized"by"“the"combination"of:"(a)"evidence"of"sibling"rivalry"and/or" jealousy;"(b)onset"during"the"months"following"the"birth"of"the"younger"(usually"immediately"younger)" sibling;"(c)emotional"disturbance"that"is"abnormal"in"degree"and/or"persistence"and"associated"with" psychosocial"problems”"(ICDL10)." " " " " " " " " " " " " " " " " " " DSM%5!AND!ADHD!! For'ADHD'the'onset'criterion'has'been' changed'from'“symptoms'that'caused' impairment'were'present'before'age'7' years”'to'“several'inattentive'or' hyperactive-impulsive'symptoms'were' present'prior'to'age'12”' Subtypes'have'been'replaced'with' presentation'specifiers'that'map'directly' to'the'prior'subtypes' A'comorbid'diagnosis'with'autism' spectrum'disorder'is'now'allowed' The'symptom'threshold'has'been' changed'for'adults'with'a'cutoff'for' ADHD'of'five'symptoms,'instead'of'six' required'for'younger'persons,'both'for' inattention'and'for'hyperactivity'and' impulsivity.' DSM%5!AND!CHIDHOOD!ONSET! DISORDERS!! A'new'diagnosis'“Disruptive'Mood' Dysregulation'Disorder”'has'been'added' to'reduce'the'misdiagnosis'of'Bipolar' Disorder'in'children.'Features'of' DMDD'include'a'persistent,'irritable' mood'and'frequent,'major'anger' outbursts'or'tantrums'three'or'more' times'a'week'for'more'than'a'year.' Separation'Anxiety'Disorder'and' Selective'Mutism'have'been'moved'from'' “Disorders'Usually'First'Diagnosed'in' Infancy,'Childhood,'or'Adolescence,”'to' “'Anxiety'Disorders”.' © SPMM Course Notes produced using excerpts from: Cooper, J. E. (Ed.). (1994). Pocket Guide to the ICD-10 Classification of Mental and Behavioural Disorders: With Glossary and Diagnostic Criteria for Research: ICD-10/DCR-10. American Psychiatric Pub. American Psychiatric Association. (2013). DSM 5. American Psychiatric Association. First, M. B. (1994). Diagnostic and statistical manual of mental disorders. DSM IV-4th edition. APA. p, 97-327. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 16 - 52_Clinical_Examination # 01 - 1. History Taking & Interview Skills # 1. History Taking & Interview Skills © SPMM Course 1. History Taking & Interview Skills The four tasks of a psychiatric interview are 1. Build a therapeutic alliance. 2. Obtain the demographic information required. 3. Interview for diagnosis. 4. Negotiate a treatment plan. Basic concepts on approaching threatening topics: 1.Use normalizing questions to decrease a patient's sense of embarrassment about a feeling or behaviour. 2. Use symptom expectation and reduction of guilt to defuse the admission of embarrassing behaviour. 3. Use symptom exaggeration to determine the actual frequency of a sensitive or shameful behaviour. 4.Use familiar language when asking about behaviours. Nondirective techniques Use Example Comments Open-ended Qs The opening stage of the interview, to allow free narration. Non-directive technique What brings you to the hospital? Preferable when highly suggestible; not very useful to focus if overtalkative or extremely poor historian. Usually starts with ‘tell me’, ‘describe’, etc. Repetition Repeating the exact words of the patient Pt: I was having bad dreams last night. Dr: So, you were having bad dreams last night. Helps patient to feel that doctor is listening actively Restatement Similar to repetition but phrases rearranged Pt: I was having bad dreams last night. Dr: So, you are getting disturbed by the dreams you have. Helps patient to feel that doctor is listening actively Summation Brief summarisation of what the patient has said up to a point in the interview ‘So from what you have told so far, you are worried for last 4 months and not sleeping well, and your job is at risk. Right?’ Helps patient to check if he has said what he intended to say. Helps the doctor to form an idea of the narration so far. Clarification Doctor tries to get details from patients about what the patient has already said. ‘You said you are feeling depressed ever since you can remember. When do you feel most depressed?’฀ Helps in avoiding misconceptions by the clinician. Also shows clinician’s interest in knowing more. Facilitation Helping patients continue the interview by providing both verbal and nonverbal encouragement. Approval nods, leaning forward slightly to express interest, ‘Yes. And then?’, ‘yeah, go on…’ ‘Uh-huh’ etc. Helps patient to feel that doctor is listening actively. Encourages flow of information. © SPMM Course Techniques when changing topics: 1. Use smooth transitions to hint at something the patient just said. 2. Use referred transitions to hint for something said earlier in the interview. 3. Use introduced transitions to pull a new topic from thin air. 1. Non-directive techniques: These techniques are employed without focussing on a particular answer. 2. Directive techniques: These are focussed on seeking a particular answer or driven by other motives of the doctor. Note that these are not necessarily detrimental but must be used judiciously. Directive techniques Use Example Comments Closed questions When, where, how many, which and what questions. Answers can only be ‘yes or no’, in most occasions. When clubbed with non-facilitative gestures, can be detrimental to interview process. Stating a presumption followed by tags can be very directive. Did you sleep well last night? You have lost weight. Haven’t you? Better avoided in early parts of the interview as they can produce prescribed answers lacking in detail. Also avoid in highly suggestible patients. Good technique is to start with open; move to closed by the end of the interview. Useful to rule out less likely symptoms. Question rephrasing Persisting with a question to seek an answer; so, restating the question in different terms for a second time. Often used when patient digresses from the topic of discussion. The motive is to collect the specific information. Redirection Gently reorienting patient towards the topic of discussion. Pt: ‘It is not good if one’s parents are divorced even before one goes to school.’ Doc: ‘I’d like to hear more about your parents, but first let me get a picture of what’s happening to you of late’. The motive is to keep the patient on track. Transition Moving from one to another topic – this is a special skill and preferably must be done as smoothly as possible to keep the patient interested. ‘You mentioned that your mother is a medical secretary. What about yourself? What job do you do?’ Smooth transitions – uses the cue off something the patient just said. Referred transitions – uses the cue off something said earlier in the interview. introduced transitions -uses a new topic to proceed. © SPMM Course Limit setting Useful to manage time pressure, especially in garrulous patients. ‘I am going to interrupt you as there are few important things we need to cover today’. To be used cautiously, overuse may detach patient from the doctor. The motive is to use time effectively. © SPMM Course Other methods to elicit information: Technique Description Example Comments Confrontation Point out to a patient something to which the doctor thinks the patient is missing or denying. ‘You seem not to have gained any weight in last 6 months. Is it possible that your eating has been poor again?’ Must be done in a respectful way. The aim is to help patients face a difficult aspect rather than dismissing patients by showing a negative aspect. Interpretation Clarifying certain associations or relationships that the patient may not see. You seem very anxious when talking about your job. Are you having any problems at workplace? Sophisticated technique and should generally be used only after the doctor has established some rapport. Should be stated as a hypothesis after sufficient collection of evidence from the interview. Self-revelation Limited, discreet selfdisclosure by physicians ‘Do you like Shakespeare? I was a mad fan when I was at school.’ Helps physician feel atease sometimes. Excessive self-revelation is a boundary violation. Silence Silence can be used either to facilitate discourse or to indicate disapproval or disinterest. Sometimes useful and allows free emotional expression. Relieves patient’s pressure and he/she may fell relaxed that not every moment must be spent talking. Symptom expectation Without a formal admission from the patient, asking about details of problem behaviour. Doctor assumes (rightly) that the patient is involved in the act. What sorts of drugs do you usually use when you're drinking? (Assuming that the patient uses drugs) Defuse the admission of embarrassing behaviour. May help in reduction of guilt. But must be used with experience and according to the context. Symptom exaggeration When deception or minimisation is expected, overstating a guessed frequency in order to elicit a true answer. How many times have you taken overdoses since your last hospitalization? Four? Five? Also helpful in reducing guilt to certain extent as the patient feels that the doctor has expected a higher amount of problem that what she/he actually has brought. © SPMM Course Supportive techniques – not aimed at eliciting information: Supportive technique Use Example Reassurance Used to instil positive hope and avoid or reduce despair. Must not be falsely reassuring. ‘The depression may be very difficult for you. I think it is very likely with the proper treatment you can get back to your job’. Advice Many patients seek advice directly; it is acceptable to provide advice but based on sound understanding of the context. Premature advice can be obstructive than facilitative. ‘I think it is best for you to consider ECT at this time. If I am you, I will give this a serious thought.' Postponement Conscious and deliberate postponement of delicate issues; but must be opened at an appropriate time. ‘I can see that you are uneasy to tell me about your relationships. That’s OK, we can come back to this when you feel ready to discuss with me.’ Validation / normalisation Helps to decrease a patient's sense of embarrassment about a feeling or behaviour. Generally done by quoting how it is normal for people to have different emotions/ reactions/ behaviours, etc. ‘Sometimes when people are very depressed, they think of hurting themselves. Has this been true for you?’ Acknowledgement of affect Making a remark about patient’s affect can facilitate disclosure. I can see that you look anxious when talking about those voices. Positive reinforcement Gently uplifting self-esteem by statements of praise (but at a realistic extent) ‘I've never been good at expressing my problems’. ‘Well, I think you've described the situation in a way that helped me understand what you have been going through’. Statement of respect Affirmative statements (must be genuine and appropriate) indicating respect and dignity along with positive reinforcement “You have been through a lot.” “I’m impressed at how you have hung in there.” “You must be a very strong person.” Partnering The interviewer encourages the patient to ask questions and to express any concerns, encouraging team working “I’m here to help.” “Let’s plan on working on this together.” © SPMM Course Obstructive techniques that may hamper the progress of information sharing: Obstructive techniques Use Example Suggestive questions Answers are contained in the question itself. Misleads both the patient and the doctor. The patient is left with little choice. These voices are not from your head. Am I right? Why questions These questions ask the patient to discover their own problems, in a way. Not useful when used to elicit information from a distressed patient. Why do you keep waking up so early in the morning? Compound questions Adding two or more questions in a single statement. This confuses the patient and will lead to either a vague response or non-response. Do you take a vacation every year, and are you able to relax? Negative Nonverbal gestures Facial expression, body posture, and behaviour that indicate lack of interest or inattentiveness, The doctor is yawning or repeatedly checking his/her watch, other repetitive gestures like tapping the table, etc. Disapproval Expressing unhappiness with a topic that the patient wants to discuss; may lead to withdrawal and not revealing the important problem faced b y the patient. ‘Over the last month I have had trouble with sex’. ฀ ‘Dr: We are here to talk about your sleep.' Setting traps Tricking the patient using his own words. Often seen as doctor’s attempt to negate patient’s problems. You wanted to see me as nothing had gone well for you, but you just said that you have got a new job and keeping a good shape. Adapted from Kay J & Tasman A. Essentials of Psychiatry, 2nd edition, 2006. John Wiley & Sons, Ltd. © SPMM Course Open-Ended vs. Closed-Ended Questions Open-Ended Questions Closed-Ended Questions Highly informative answers They produce spontaneous formulations. Low yield answers They lead the patient. Low reliability of answers. Non-reproducible at a later date, or by a different doctor. High reliability. Low precision – do not focus on target symptoms. The intent of the question is clear, and so precise, focused answers elicited. Not very time efficient. My lead to circumstantial elaborations. High time efficiency. Low diagnostic coverage as patient selects the content revealed. Good diagnostic coverage as doctor selects interested content. Adapted from Othmer E, Othmer SC. The Clinical Interview Using DSM-IV. Washington, DC: American Psychiatric Press; 1994. Techniques for a poor historian  Use open-ended questions and commands to increase the flow of information.  Use continuation techniques to keep the flow coming.  The Shift to the neutral ground when necessary.  Schedule a second interview when all else fails. Techniques for over-talkative garrulous historian  Use closed-ended and multiple-choice questions to limit the flow.  Perfect the art of the gentle interruption.  Educate the patient about the need to move along in the interview. Ancillary methods of gathering information: Behavioural observation methods:  Observing and recording behavioural events, to study mental state or plan intervention. Often used when patients are in seclusion.  Event sampling: e.g. every fifth or tenth event is coded in detail  Time sampling: observations may be made only every 5 or 10 mins  ‘Functional analysis' refers to attempts to explain and predict the functions of a phenomenon by examining any relationships to the outcome. It is a special variant of behavioural observation methods, where the sequence of antecedent environmental events, target behaviour and concurrent events and consequent outcomes are observed. This is also called ABC analysis. Often used in LD setting, dementia care, and challenging behaviour services. © SPMM Course Using an interpreter:  Explain the goals of the interview to the interpreter  Explain structure and content of interview  Explain the need for literal translation – not interpreted translation in the Mental Status Examination  Ask for feedback when something is hard to translate  Offer to debrief the interpreter to address any of their own emotional concerns following the interpretation  Ask interpreter about the patient’s degree of openness or disclosure  Preferably work with same interpreter/culture-broker for the same case whenever possible # 02 - 2. Laboratory assessment of physical factors # 2. Laboratory assessment of physical factors © SPMM Course 2. Laboratory assessment of physical factors Depression Depression is a clinical diagnosis. A physical examination is always required to rule out several common medical disorders that can present with depression (especially endocrine disorders). Laboratory tests are required if medical causes are suspected and to assess baseline fitness before starting antidepressants. Several chronic medical disorders are associated with depression (e.g. Coronary artery disease, Diabetes mellitus, End-stage renal disease, HIV infection, various malignancies, degenerative neurological disorders and stroke) but these do not ‘present’ with depressive features and as such for a patient presenting with depression, there is no need to exclude all of these medical disorders before diagnosis depression. TEST WHY DO WE DO IT? Full blood count Rule out infectious and inflammatory pathology Thyroid-stimulating hormone (TSH) Rule out hypothyroidism Vitamin B-12 Deficiency can mimic depression HIV test & Syphilis (rapid plasma reagin) In suspected cases of sexually transmitted infections Electrolytes, including calcium, phosphate, and magnesium levels Deficiency can contribute to fatigue and mimic depression GFR and creatinine In preparation for antidepressant use and to rule out renal insufficiency contributing to depression Liver function tests (LFTs) In preparation for antidepressant use and to rule out alcohol-related liver damage in suspected cases Blood and urine toxicology screen In suspected cases of drug abuse 24-hour urinary free cortisol In suspected cases of Cushing disease; will require additional confirmation, as this can be positive in a large number of patients with depression. ACTH stimulation test Addison’s disease can also mimic depression The following table displays some common abnormalities. Please note that none of the tests below are required routinely during a workup for depression. LAB ABNORMALITIES INTERPRETATION Dexamethasone Suppression Test DST nonsuppression (DST-positive result) is seen in many disorders associated with depression e.g. grief reactions (10%), dysthymic disorders (23%), major depressive disorder (44%), melancholia/somatic syndrome (50%), psychotic affective disorders (69%), and in depression with serious suicidality (78%). DST-positive patients respond more favorably to biological interventions. DST nonsuppression is nonspecific; can be seen in chronic pain, patients with anorexia or bulimia, alcoholism, obsessive-compulsive disorder, or anxiety disorders. Corticotropin-Releasing Hormone Test HPA axis abnormality in major depression results in blunted ACTH response to CRH. © SPMM Course Serum Thyroxine Concentrations 1% and 4% of depressed patients, esp. women show evidence of overt hypothyroidism; 4% to 40% have subclinical hypothyroidism, contributing to treatment failure. Serum T4 reductions may accompany treatment with antidepressants, lithium, sleep deprivation, or ECT, especially in responders. Thyrotropin-Releasing Hormone Test ~ 30% of depressed patients show blunted TSH response during depression Anxiety and other neuroses A number of medical disorders can directly contribute to anxiety and panic attacks, but in practice, patients seeking clinical consultations seldom require specific investigations to diagnose these conditions. Diagnostic possibilities for panic attacks include paroxysmal atrial tachycardia, pulmonary embolus, seizure disorder, Meniere's disease, transient ischemic attack, carcinoid syndrome, Cushing's disease, hyperthyroidism, hypoglycemia, and pheochromocytoma. A physical examination is warranted for all first presentations; extensive medical evaluation for these disorders is indicated only when other features suggest physical disease. Lactate infusion: Nearly 72% patients with panic disorder have a panic attack when administered IV injections of sodium lactate. Therefore, lactate provocation is used to confirm a diagnosis of panic disorder. Hyperventilation and CO2 inhalation have been used. Panic attacks triggered by sodium lactate are not inhibited by peripherally acting beta-blockers but are inhibited by benzodiazepines and tricyclic drugs. Narcoanalysis: Interviews with amobarbital are very rarely used in current clinical practice for diagnostic and therapeutic indications. These are sometimes helpful in differentiating nonorganic and organic conditions, particularly in patients with symptoms of catatonia, stupor, and muteness. Organic conditions tend to worsen with infusions of amobarbital, but nonorganic or psychogenic conditions tend to get better because of disinhibition, decreased anxiety, or increased relaxation. Therapeutically, amobarbital interviews are useful in disorders of repression and dissociation such as amnesia and fugue. Benzodiazepines can be substituted for amobarbital. Psychosis Differential diagnoses to be considered in the history of presenting illness: head trauma (subdural haematoma), seizures, new-onset headaches, focal neurological deficits, abnormal body movements, memory loss, and tremor especially in older patients, recreational drug use, dietary history (deficiencies of vitamin B12, folate, thiamine, and niacin can all cause psychosis). Physical examination: vital signs, level of consciousness, evidence of malnutrition, signs of hypoor hyperthyroidism or cushingoid features, rashes associated with autoimmune disorders, © SPMM Course dysmorphic facial features (genetic syndromes e.g velocardiofacial), focal neurological signs and examination for signs of raised intracranial pressure Initial tests TESTS WHY DO WE DO IT? Full blood count Rule out infectious and inflammatory pathology; the baseline for starting haemotoxic antipsychotics such as olanzapine, clozapine. Thyroid profile (TSH, free T4) Rule out hypo or hyperthyroidism. If abnormal carry out free T3 level and thyroid autoantibodies ELISA for anti-thyroid peroxidase Blood glucose, lipid profile, ECG Baseline for antipsychotic therapy; metabolic syndrome is common among patients with psychotic disorders Prolactin levels Baseline for antipsychotic therapy In suspected cases of sexually transmitted infections Electrolytes, including calcium, phosphate, and magnesium levels May be abnormal if there is an underlying metabolic or endocrine disturbance GFR and creatinine In preparation for antidepressant use and to rule out renal insufficiency contributing to depression Liver function tests (LFTs) In preparation for antipsychotic use; to rule out chronic alcohol abuse and Wilson's disease in suspected cases Blood and urine toxicology screen Acute toxic drug effects the most common cause of psychosis; screen for amphetamines, cocaine, cannabis, and benzodiazepines SUSPECTED CONDITION TESTS REQUIRED Delirium with psychosis Blood glucose, Blood alcohol, Urine microscopy and culture, Blood culture, Chest X-ray. Suspected STDs HIV test & Syphilis (rapid plasma reagin) Screen for autoimmune disorders in suspected cases Anti-Nuclear Antibodies, CRP and ESR Suspected encephalitis syndrome NMDA receptor (NMDAR) and voltage-gated potassium channel receptor (VGKC) auto-antibodies (IgG) Cushing's syndrome 24-hour urinary free cortisol test followed by DST and ACTH challenge, evening salivary cortisol, and the dexamethasone-corticotropin-releasing hormone test Porphyria Spot urine sample for porphobilinogen during acute attack, and 24-hour urine for porphyrins, porphobilinogen, and delta-aminolevulinic acid Hyperparathyroidism Serum calcium and serum parathyroid hormone test Wilson's disease Serum ceruloplasmin, 24-h copper excretion test Lysosomal storage diseases Skin biopsy, genetic tests, and the detection of serum alpha-galactosidase enzyme Homocystinuria Homocysteine in urine and blood and molecular genetic testing Metachromatic leukodystrophy Arylsulfatase A enzyme activity in WBCs or in cultured skin fibroblasts Malnourishment Serum homocysteine and foalte (folate deficiency) , vitamin B12, niacin, tryptophan, nicotinamide adenine dinucleotide (NAD) and NADP CNS lesions MRI or CT scan; EEG if TLE is suspected Porphyrias: Acute intermittent porphyria (AIP) is one of the groups of disorders of haem © SPMM Course metabolism, characterised by neurological and psychiatric manifestations without obvious cutaneous markers. AIP manifests itself by abdomen pain, neuropathies, and constipation, but, unlike most types of porphyria, patients with AIP do not have a rash. It is an autosomal dominant disorder with the presentation starting between ages 18 and 40. It is episodic in nature, and the episodes are often triggered by certain medications including estrogens, barbiturates and benzodiazepines. Diclofenac can precipitate an episode. Psychiatric manifestations include depression, anxiety, delirium and psychosis. Most important lab test is demonstrating increased urinary porphobilinogen during acute attacks. Treatment is aimed at reducing haem synthesis by administering haemin. Autoimmune encephalitis presenting as psychosis: Autoimmune disorders with antibodies produced against crucial neurotransmitter receptors can present with psychosis. Several anecdotal reports have pinpointed the following receptors as most vulnerable in this regard.  Voltage Gated Potassium Channel complex (LGI1, CASPR2, contactin-2)  N-Methyl-D-aspartate receptor (NMDA)  AMPA receptor  GABA-B  Glycine receptor Some studies have estimated that 6.3% of first onset psychosis patients have pathogenic antibodies against brain receptors (Zandi et al., 2011). The most well known of these syndromes is the anti-NMDA receptor (NMDAR) encephalitis.  Anti-NMDAR antibodies result in the titre-dependent destruction of synaptic NMDAR through crosslinking and internalisation.  Around 4% of patients with anti-NMDAR present with isolated psychiatric symptoms.  It is more common in females (80%) than males  ~50% of women with anti-NMDAR have an underlying ovarian teratoma.  75% of patients first present to a psychiatrist with acute psychosis and/or mania.  Psychosis associated with anti-NMDAR encephalitis usually presents with a prodromal illness (fever, headaches, malaise). In suspected cases, the following investigations are appropriate o Serum NMDAR and VGKC antibodies o Test for ANA, CRP, ESR, FBC, U+E (low sodium is seen in those with anti-VGKC antibodies) o If there is a strong suspicion EEG (look for encephalopathy with disorganized © SPMM Course delta/theta activity) and MRI brain (look for medial temporal hyperintensity, usually seen in T2 or FLAIR sequences in the hippocampi, frontobasal and insular regions and basal ganglia; normal in ~50%). o Confirmatory diagnosis requires CSF analysis: Lymphocytic pleocytosis, elevated protein and oligoclonal bands are seen in ~60% of cases; almost all have intrathecal anti-NMDAR antibodies. Note that patients who are cured of anti-NMDAR encephalitis may continue having detectable antibodies in serum and/or CSF. CSF antibodies rise during each relapse o Elevated creatine kinase is a non-specific feature of the anti-NMDAR illness. o In females with anti-NMDAR, ask for ultrasound or CT pelvis. Anti-NMDAR encephalitis usually responds to 3 days of methylprednisolone orally or intravenous followed by oral prednisolone, in association with 5 days of plasma exchange. The remission thus achieved can be maintained by either (1) steroids alone; (2) steroids with a steroid-sparing agent, such as azathioprine or mycophenolate mofetil or (3) rituximab. Regular benzodiazepines may be required. AVOID ANTIPSYCHOTICS as dystonic reactions and NMS-like syndrome with rigidity, hyperthermia, and autonomic instability might occur on the use of antipsychotics in patients with anti-NMDAR antibodies. Dementia Patients presenting with memory difficulties always require a thorough physical examination to look for signs of neurological disorders. In addition, several nutritional and metabolic factors can produce what is called ‘reversible’ dementia – cognitive impairment with no progressive, degenerative pathology. Laboratory investigations required for initial dementia workup are shown below. TEST WHY DO WE DO IT? Full blood count Rule out infectious and inflammatory pathology; the baseline for starting antidementia medications. Thyroid profile (TSH, free T4) Low T4 can cause cognitive impairment Blood glucose, lipid profile, ECG Baseline before starting antidementia medications; metabolic syndrome is common among patients with vascular dementia Thiamine, folate levels Thiamine deficiency can result in memory impairment esp. in alcoholics Tests for syphilis or HIV HIV is associated with cognitive impairment that can worsen with opportunistic infections. Electrolytes, including calcium, phosphate, and magnesium levels May be abnormal if there is an underlying metabolic or endocrine disturbance causing cognitive impairment GFR and creatinine In preparation for antidementia medications Liver function tests (LFTs) In preparation for antidementia medications CT or MRI brain This is becoming a routine practice though the diagnostic yield of routine imaging is low in senile dementia of Alzheimer’s type. Recommended when suspecting vascular dementia, subdural hematoma or tumours. # 03 - Anorexia # Anorexia © SPMM Course EEG No need for routine EEG. But rapid onset dementia may suggest CJD for which EEG and MRI are warranted. Anorexia Several abnormalities are expected in physical investigation in anorexic subjects: (The list below is adapted from Fairburn & Harrison, 2003) Endocrine  Low concentrations of luteinising hormone, follicle stimulating hormone, and oestradiol  Low T3, T4 in low normal range, normal concentrations of thyroid stimulating hormone (low T3 syndrome)  Mild increase in plasma cortisol  Raised growth hormone concentration  Severe hypoglycaemia (rare)  Low leptin (but possibly higher than would be expected for bodyweight) Cardiovascular  ECG abnormalities (especially in those with electrolyte disturbance): conduction defects, especially prolongation of the Q-T interval, of major concern Gastrointestinal  Delayed gastric emptying  Decreased colonic motility (secondary to chronic laxative misuse)  Acute gastric dilatation (rare, secondary to binge eating or excessive re-feeding) Haematological  Moderate normocytic normochromic anaemia  Mild leucopenia with relative lymphocytosis  Thrombocytopenia Other metabolic abnormalities  Hypercholesterolaemia  Raised serum carotene  Hypophosphataemia (exaggerated during refeeding)  Dehydration  Electrolyte disturbance o Varied in form; present in those who frequently vomit or misuse large quantities of laxatives or diuretics o Vomiting results in metabolic alkalosis and hypokalaemia. o In repetitive vomiting, loss of hydrochloric acid from gastric juices leads to metabolic alkalosis (loss of acid – alkalosis). o Laxative misuse results in metabolic acidosis, hyponatraemia, hypokalemia # 04 - Alcohol use disorders # Alcohol use disorders © SPMM Course o During laxative induced diarrhoea, a large amount of bicarbonate may be lost in the stool. With normal kidneys, the lost bicarbonate is replaced effectively and a serious base deficit does not develop. When there is poor renal blood flow due to hypovolemia/starvation, base deficit and acidosis develop rapidly. o Acidosis also results from excessive production of lactic acid when patients have severe diarrhoea. Other abnormalities  Osteopenia and osteoporosis (with heightened fracture risk)  Enlarged cerebral ventricles and external cerebrospinal fluid spaces (pseudo atrophy) Calculating BMI: BMI = Weight in kg / (height in meters)2. e.g. if weight = 50kg and height is 165cm, then BMI = 50 / (1.65) (1.65) = 50 / 2.7225 = 18.36. BMI categories: Underweight = <18.5; Normal weight = 18.5-24.9; Overweight = 25-29.9; Obesity = BMI of 30 or greater Alcohol use disorders No single lab test can dependably diagnose alcohol abuse. Of available tests such as GGT (a liver enzyme), Mean Corpuscular Volume, Breathalyzer and Carbohydrate Deficient Transferrin (CDT), the CDT is the single most specific and sensitive test for detecting heavy alcohol use over last 10 days. But due to a high degree of intersubject variability it is best to compare CDT levels with patient’s own baseline. In primary care, AUDIT is often considered to be the best screening tool. As alcohol abuse is associated with systemic complications, several other lab tests may be required when these complications are suspected. System involved Complications Neurological Seizures (intoxication or withdrawal), Wernicke's encephalopathy, Korsakoff's dementia, polyneuropathy, coma, amnesia, alcoholic dementia, cerebellar degeneration, damage to corpus callosum (Marchiafava syndrome) Gastrointestinal GI bleeds, peptic ulcer, malnutrition (esp. thiamine), Mallory-Weiss tears, esophageal strictures, fatty liver, hepatic cirrhosis, portal hypertension, pancreatitis and hypoglycaemia Cardiovascular Cardiomyopathy, hypertension, hyperlipidemia Hematologic Pancytopenia, folic acid and B12 deficiency resulting in MCV changes and anaemia, clotting disorders due to liver failure, immune compromise Respiratory Lung cancer, pneumonia due to aspiration under intoxication Musculoskeletal Muscle wasting, osteoporosis Renal Renal failure, hepatorenal syndrome, hyponatremia and other electrolyte imbalances Endocrine Testicular atrophy, sexual disorders, menstrual irregularities Pregnancy Low birth weight, foetal alcohol syndrome, developmental delays, neural tube # 05 - Specific investigations # Specific investigations © SPMM Course defects due to maternal malnourishment. Specific investigations ELECTROCARDIOGRAM:  The major use of ECG in a psychiatric ward, apart from emergency needs, is to measure QT interval when treating patients using antipsychotics.  Prolonged QT can predispose to fatal ventricular arrhythmias such as torsades de pointes (polymorphic ventricular tachycardia).  QTc is QT corrected for heart rate. While valuable for classifying risk groups, it is not a precise predictor of torsade de pointes as it has low positive predictive value.  There are different methods to arrive at QTc from QT – these give markedly different values.  As a clinical measure, the risk is said to increase if QTc is beyond normal limits (440 ms for men; 470 ms for women) – anything more than 500 ms is clearly an increased risk.  QT varies with gender, time of day, food intake, alcohol intake, menstrual cycle, ECG lead used.  Risk factors for prolonged QTc include • Congenital long Q-T syndrome, • Underlying heart disease, bradycardia, heart failure, and ischemic disease • Female gender, • Extremes of age, • Presence of liver disease, • Electrolyte abnormalities (hypokalemia, hypocalcemia and hypomagnesemia), • Illicit drug use (principally stimulants), • Starvation or anorexia, • High physical exertion (agitation), • High dosages of the drug contributing to the lengthened Q-T interval, and • Rapid infusion of torsadogenic drugs. URINALYSIS:  Testing for drugs: This is one of the most frequently used lab investigations in psychiatry. When a patient repeatedly gives negative urine samples despite strong suspicions, a cheap and quick way of checking the sample is by testing specific gravity – this will reveal any adulteration of urine with tap water. The following table will help answering some recurrent questions on this theme. © SPMM Course Substance Time present in urine Alcohol Up to 12 hrs Amphetamine Up to 48 hours Benzodiazepine 3 days (depending on t1/2) Cannabis Occasional use – up to 3 days. High daily use for long time – up to 4 weeks. Cocaine 6 – 8 hrs; metabolites up to 2 - 4 days Codeine 48 hours Heroin 1 to 3 days Methadone 3 days or more Morphine 2 to 3 days Phencyclidine (PCP) 8 days Data from Oxford Handbook of Psychiatry & Rudolph’s Paediatrics 21e. p 230  Renal disturbances in IV drug users: Renal disease in cocaine and heroin abusers has been associated with the nephrotic syndrome, acute glomerulonephritis, amyloidosis, interstitial nephritis, and rhabdomyolysis. In a heroin user with a puffy face, hypertension and weight gain – suspect heroin-related nephropathy. Infective endocarditis, HIV, and HBV and HBC infections are associated with renal pathologic patterns similar to those that can be caused by the drug itself. In Black patients, focal segmental glomerulosclerosis is often seen while in Whites mostly membranoproliferative glomerulonephritis is noted.  SIADH: Urine analysis may be important with regard to SIADH induced by antidepressants or antipsychotics/Psychogenic polydipsia where excessive water consumption occurs without obvious organic illness and Diabetes insipidus due to lithium (nephrogenic) or head injury (central). As a rough guide use the following tables. Plasma osmolality Urine osmolali Diagnosis High (>295mosm/kg) Low Diabetes Insipidus (Central / nephrogenic) Low (<280 mosm/Kg) Low Psychogenic polydipsia Low High SIADH - hyponatraemia Psychogenic / Primary polydipsia Diabetes Insipidus Gradual onset Acute or sudden Nocturia is rare Nocturia is common Plasma osmolality normal/low Elevated plasma osmolality Urine osmolality normal/low Low urine osmolality © SPMM Course Plasma ADH levels normal compared to osmolalit Low in central type NOTE - polydipsia and polyuria are not features of SIADH or hyponatraemia per se.  The clinical features of SIADH are attributed to water retention, hyponatraemia, and hypo-osmolality of the serum. Most hyponatraemic patients have no symptoms or signs until the serum sodium concentration falls below 125 mmol/L. Initially, the symptoms include lethargy, muscle cramps, anorexia, nausea, and vomiting. When hyponatraemia develops more rapidly or more profoundly, coma, convulsions, and death may occur. On longer term hyponatraemia can cause neurologic signs and symptoms such as altered levels of consciousness, headache, impaired memory and confusion. If the serum sodium concentration drops below 110-115 mmol/L, seizures and irreversible brain damage can occur. # 06 - 3. Physical examination of a psychiatric pati # 3. Physical examination of a psychiatric patient # 07 - General examination # General examination © SPMM Course 3. Physical examination of a psychiatric patient General examination SIGNS Relevant conditions Argyll-Robertson pupil Neurosyphilis; the more common cause is diabetes. Checker-board abdomen Multiple surgical scars in factitious disorder. Constricted pupils Opiate intoxication, Horner’s syndrome Dilated pupils Stimulant abuse or opiate withdrawal, anxiety states Kayser Fleischer ring Golden Brown pigment around cornea in Wilson’s disease Generalised lymph node enlargement HIV illness, Lymphomas. Goitre Thyroid disease, very small number related to lithium use Gynaecomastia Hyperprolactinaemia, cirrhosis, androgen or steroid abuse Jaundice Heavy alcohol use. Lanugo hair Anorexia nervosa Lemon stick appearance, central obesity Cushing’s syndrome Lid lag, lid retraction, exophthalmia, and proptosis Hyperthyroid state Mask like face Extrapyramidal affect is seen in Lewy body dementia, Parkinsonism, and in psychomotor retardation of depression Parotid swelling Bulimia, mumps Piloerection Opiate withdrawal Rapid/irregular pulse Anxiety, delirium states, Drug/alcohol withdrawal and Hyperthyroidism Russell's sign Bulimia nervosa – calluses at knuckles Sialorrhoea Clozapine treatment; parkinsonism; facial palsy of Bell’s, stroke involving cranial nerves Splinter haemorrhages, Osler’s nodes, and Janeway lesions Due to infectious endocarditis in IV drug users. Xanthelasma Lipid accumulation, related to Olanzapine or another antipsychotic treatment. Patients with acute hyperventilation (often in the context of panic attack in a psychiatric clinic) may present with agitation, increased breathing rate with shallow breaths (tachypnoea), chest pain, dizziness, palpitations, tetanic cramps (carpopedal spasm), paresthesias, generalized weakness, and syncope. Paresthesias are due to acid-base imbalance, and occur more commonly in the upper extremity and are usually bilateral. Unilateral paresthesias are left-sided in approximately 80% of cases. Perioral numbness is very common. Minor Physical Anomalies (MPAs) are often observed in a range of developmental disorders. MPAs are also more frequent in patients and siblings of patients with schizophrenia than in healthy controls, supporting neurodevelopmental aetiology. MPAs can be rated using Lane Scale # 08 - Neurological examination in psychiatry # Neurological examination in psychiatry © SPMM Course Neurological examination in psychiatry Cranial nerves examination: No. Name Main clinical examination technique I Olfactory Smell – each side separately II Optic Test visual acuity using Snellen’s charts (near and distance), colour using Ishihara charts, field by confrontation/perimetry and pupillary reflexes. III Oculomotor Eyelid elevation, eye elevation, adduction, depression in abduction, pupillary reflex for efferent fibres IV Trochlear Eye intorsion, depression in adduction V Trigeminal Facial and corneal sensation, muscles of mastication VI Abducens Eye abduction VII Facial Facial movement, taste fibres VIII Vestibular Balance – Romberg / Caloric test Minor Physical Anomalies in putative developmental disorders  Preauricular tag  Preauricular pits  Lip pit  Bifid uvula  Supernumerary nipples:  Partial syndactyly (generally involving toes 2–3)  Pigmented naevi  Cafe-au-lait spots  Sacral haemangioma  Prominent or flat occiput  Prominent or flat forehead  Primitive shape of ears  Earlobe crease  Fine electric hair  Tongue with smooth and rough spots  Double antihelix  Simian crease [Instead of the two usual creases only a single uninterrupted palmar crease traverses the palm from the radial to the ulnar border. To be considered as an anomaly, the line should be uninterrupted].  Single flexion crease on 5th finger  Sole crease  Prominent heel  Double posterior hair whorl  Multiple buccal frenula  Furrowed tongue  Brushfield spots © SPMM Course Cochlear Hearing – Rinne, Weber tests. IX Glossopharyngeal Sensation - soft palate, taste fibres X Vagus Cough, palatal and vocal cord movements XI Accessory Head turning, shoulder shrugging XII Hypoglossal Tongue movement Adapted from Kumar & Clark Textbook of clinical medicine 6th edition Pg 1179  The auditory function is tested using 512 Hz – Weber’s test and Rinne’s test; vibration sense is tested for peripheral neuropathy using a 128Hz fork.  The Weber test involves holding a vibrating tuning fork against the forehead in the midline. The vibrations are normally perceived equally in both ears because bone conduction is equal. In conductive hearing loss, the sound is louder in the abnormal ear than in the normal ear. In sensorineural hearing loss, lateralization occurs to the normal ear.  In the Rinne test, the vibrating tuning fork is placed over the mastoid region until the sound is no longer heard. It is then held at the opening of the ear canal on the same side. A patient with normal hearing should continue to hear the sound. In conductive hearing loss, the patient does not continue to hear the sound since bone conduction, in that case, is better than air conduction. In sensorineural hearing loss, both air conduction and bone conduction are decreased to a similar extent.  The vestibular portion transmits information about linear and angular accelerations of the head from the utricle, saccule, and semicircular canals of the membranous labyrinth to the vestibular nucleus.  The Romberg test is performed to evaluate vestibular control of balance and movement. When standing with feet placed together, and eyes closed, the patient tends to fall toward the side of vestibular hypofunction. Results of the Romberg test may also be positive in patients with polyneuropathies, and diseases of the dorsal columns, but these individuals do not fall consistently to one side as do patients with vestibular dysfunction.  Provocative tests include caloric testing. Normally on cold water testing, nystagmus is noted to the opposite side; warm water elicits nystagmus towards the same side. (COWS – Cold Opposite, Warm Same, can be used as a mnemonic) Neurological soft signs: Neurological signs are often referred to as either “hard” or “soft” signs. The ‘hard signs’ refer to impairments of the basic motor and sensory functions that are localisable to the pyramidal, extrapyramidal or cranial nerve systems. © SPMM Course The soft signs are non-localisable neurological findings thought to reflect neurodevelopmental aberrations when seen in psychiatric disorders. These are seen in many psychiatric disorders including schizophrenia, autism, OCD and ADHD. However, this distinction between hard and soft signs is artificial, merely reflecting our inability to define the brain-behaviour relationship that underlies certain neurological abnormalities. There are three groups of symptoms collectively known as soft signs - abnormalities of motor coordination, sensory integration and signs of cortical disinhibition. In recent times, neuroimaging studies that parse finer details of the cortex have implicated several parts of the brain in ‘soft’ signs, further blurring their distinction from hard signs. Cerebellar signs The cerebellum provides an important feedback loop for coordination of muscle activity. Midline cerebellar dysfunction results in ataxia of gait, difficulty in maintenance of upright posture, and truncal ataxia. The following cerebellar signs are noted in various degrees in psychiatric disorders. The lateral cerebellar hemispheres (the neocerebellum) controls the movement of the ipsilateral limbs. The midline vermis is involved in the control of truncal tone, speech and eye movements. The flocculonodular lobe (also called archicerebellum) is involved in vestibular functions. Cerebellar signs Ataxia Difficulties in coordinating truncal and limb movements, often seen in midline damage. Tested using tandem walking (heel-to-toe walk) test. Hypotonia Reduced muscle tone resulting in loss of ‘checking’ effect when passively manipulated (leg swinging test results in pendular swinging of legs until passive inertia sets in) Intention tremor An oscillating tremor that accelerates in pace on approaching the target Dyssynergia (incoordination) Results in loss of smoothness of execution of a motor activity. Dysmetria (past pointing) Overshooting or undershooting of a target while attempting to reach an object Common soft neurological signs in psychosis Choreoathetosis (predating psychosis esp. in children) Abnormal gait Grimacing Abnormal reflexes Changes in muscle tone Abnormal saccades Frequent blinking Dysdiadochokinesia Astereognosis Poor left-right discrimination Anosognosia Apraxia Gaze impersistence Frontal release © SPMM Course Dysdiadochokinesis Inability to perform rapid alternating movements. Tested by asking the patient to tap 1 hand on the other repeatedly while simultaneously pronating and supinating the hand Dysrhythmia Inability to tap and keep a rhythm Dysarthria Staccato or scanning speech with poor modulation of the volume and pitch of the speech. Dyssynergia, dysmetria and tremor can be elicited by finger nose or heel shin test. Dysarthria is usually a sign of diffuse involvement of the cerebellum. Meningeal signs: These signs can be elicited in the presence of meningeal inflammation or irritation due to haemorrhage/trauma. Nuchal rigidity or neck stiffness:  The Brudzinski sign (Flexion of his knees and hips when you try to flex one’s neck constitutes a positive Brudzinski's sign.)  The Kernig sign (this is elicited by flexing one hip and knee and then extending the knee with the hip still flexed). Hamstring spasm may occur; if severe, opposite knee may flex during the test – positive Kernig’s) The Lasègue or straight-leg raising (SLR) sign is elicited by passively flexing the hip with the knee straight while the patient is in the supine position. Limitation of flexion due to hamstring spasm and/or pain indicates local irritation of the lower lumbar nerve roots. Reverse SLR sign is elicited by passively hyperextending the hip with the knee straight while the patient is in the prone position. Limitation of extension due to spasm and/or pain in the anterior thigh muscles indicates local irritation of the upper lumbar-nerve roots. Cortical sensory signs: The cortical sensory system includes the somatosensory cortex and its central connections. Functions include kinaesthetic sensation, stereognosis, graphesthesia and tactile localization and tactile 2-point discrimination on both sides of the body. Position sensation is tested with the subject’s eyes closed. The subject is then tested in the various directions of passively elicited distal joint movements. Movement abnormalities:  Fibrillations are not visible to the naked eye except when the tongue is affected. © SPMM Course  Fasciculations may be seen under the skin as quivering of the muscle. Although fasciculation is usually benign (e.g. can occur with fatigue); if widespread it can be associated with neuromuscular disease, including amyotrophic lateral sclerosis (ALS).  Asterixis can be elicited by having the patient extend both arms with the wrists dorsiflexed and palms facing forward, and eyes closed. Brief jerky downward movements of the wrist are considered a positive sign. Asterixis is commonly seen in metabolic encephalopathies. (Note pronator drift is elicited by having the patient extend both arms with the wrists supinated and palms facing upwards and eyes closed – slow unequal drift towards pronation indicates hemiparetic weakness)  Myoclonus is a brief <0.25 seconds muscle jerk; generalized and sometimes asymmetric. These occur alone or in association with various primarily generalized epilepsies; associated with CJD and also with severe Alzheimer’s.  In athetosis, the spasms have a slow writhing character and occur along the long axis of the limbs or the body itself; the patient may assume different and often peculiar postures.  The term chorea means dance. Quasi-purposeful (patient turn it to appear as if they are purposive) movements affect multiple joints with a distal preponderance. It is associated with caudate lesions.  Hemiballismus is a violent flinging movement of half of the body. It is associated with lesions of the subthalamic nucleus. Reflexes Primitive reflexes: These include the glabellar tap, rooting, snout, sucking, and palmomental reflexes. These are generally absent in adults. When present in the adult, these signs signify diffuse cerebral damage, particularly of the frontal lobes (hence the name frontal-release signs). Superficial reflexes: These are segmental reflex responses that indicate the integrity of cutaneous innervation and the corresponding motor outflow. These include corneal, conjunctival, abdominal, cremasteric and plantar (Babinski) reflexes.  Corneal and conjunctival reflexes – afferent is via 5th nerve while efferent is via 7th nerve.  Abdominal reflex can be elicited by drawing a line away from the umbilicus along the diagonals of the 4 abdominal quadrants. A normal reflex draws the umbilicus toward the direction of the line that is drawn.  The cremasteric reflex is elicited by scratching on the medial surface of the thigh to elicit scrotal contraction or lift in male subjects. A normal reflex results in elevation of the ipsilateral testis. © SPMM Course  The best known of this group of reflexes is the plantar reflex or Babinski reflex. The normal response is plantar flexion of the great toe. This normal response is considered an absent (negative) Babinski sign. Dorsiflexion of the great toe (Babinski sign present) suggests an upper motor neuron lesion and is referred to as a positive Babinski sign. Lack of either response may indicate the absence of cutaneous innervation in the S1 segment or loss of motor innervation in the L5 segment ipsilaterally. Deep tendon reflexes: Intact cutaneous innervation, motor supply, and cortical input to the corresponding spinal segment are required for normal deep tendon reflexes. Deep tendon reflexes include biceps, brachioradialis, triceps, patellar, and ankle jerks. These get exaggerated in UMN lesions and are absent in respective LMN lesions. Pseudobulbar palsy is a UMN lesion; exaggerated jaw jerk is noted in patients with this condition. Bulbar palsy is a result of LMN lesion and jaw jerk is absent in this case. Neurocutaneous system  Frontal baldness: Myotonic dystrophy  Dermatomal eruptions: Herpes Zoster  Ash leaf macules: Tuberous sclerosis  Ungual fibromas: Tuberous sclerosis  Dimples and large moles along the spine: spina bifida occulta  Cafe au lait spots: Neurofibromata, Tuberous sclerosis.  Axillary freckling: Neurofibroma Speech abnormalities Dysarthria Types Description Spastic dysarthria Strained and hoarse voice, hypernasality and slow, imprecise articulation related to bilateral UMN lesions. Often accompanied by swallowing and drooling difficulties (Palmer 2005). Flaccid dysarthria Isolated areas of involvement are depending on which motor neurone is affected. LMN type lesion. The tongue is usually small due to loss of tone if XII nerve is involved and lies flaccidly on the floor of the mouth. Could be of nasal quality if IX and X nerves are involved. Ataxic dysarthria Excess loudness, tremor and irregular articulatory breakdowns (scanning speech). Intonation, pitch and volume and also be affected, as well as difficulty with alternate tongue movements. The cerebellum is often involved. Hypokinetic dysarthria A breathy monotone voice with reduced loudness and articulation tends to be accelerated and imprecise. Associated with motor control circuit Muscle Spinal Roots Biceps C5, 6 Brachioradialis C6 Triceps C7 Patellar L2-4 Achilles S4 © SPMM Course damage. Hyperkinetic dysarthria Features strained hoarseness and voice arrests. Associated with basal ganglia damage. Mixed dysarthria Similar symptoms to spastic dysarthria, and tends to be accompanied by a wet sounding voice with rapid tremor, poor laryngeal and tongue movements and poor control of lips (Damage to more than one motor system). Hysterical aphonia The examination is usually normal. Sudden loss of voice, but preserved vocal cord activity is notable. Gait Gait is the motor attitude of a person in the upright position.  Hemiparetic gait: Seen in patients with stroke affecting the pyramidal system. Typically, clenched hand with extended knee and plantarflexed ankle. This makes the paralyzed leg appear longer (pole-like) than the other. The patient resorts to circling it around resulting in repeated circumduction of the affected leg while walking.  Ataxic gait: In mild cases this can only be elicited by or tandem walking tests. In severe cases, a staggering wide-based gait is seen. Unilateral (rather than midline) cerebellar lesions may result in the patient veering to the side of the lesion (resulting in sailor’s gait).  Shuffling gait: This is often seen in Parkinsonian patients. The patient takes very short steps and appears to shuffle legs away or apart rather than propelling them forward. Progressively short steps result from a tendency of the patient to accelerate (festinating gait).  Steppage gait: Here the patient takes high steps as if climbing a flight of stairs while walking on a level surface. Steppage gait is seen in chronic peripheral neuropathies e.g. drop foot and dorsal column disorders.  Waddling gait: It is seen in patients with proximal myopathy. Patients have a broad-based gait with a duck-like waddle resulting from the dropping of the pelvis to the side of the leg being raised. A compensatory forward curvature of the lumbar spine adds to the body swing. This is also be seen in patients with congenital hip dislocation and near term in pregnant women.  Scissoring gait: This is seen in patients with spastic paraplegia. Marked rigidity and excessive adduction of the swinging leg together with plantar flexion of the ankle and flexion at the knee due to contractures of all spastic muscles leads to forced tip-toe walking with knees rubbing together and crossing like scissors. # 09 - Other neurological signs # Other neurological signs © SPMM Course Other neurological signs  Absent ankle jerks, upgoing plantars: This is an odd combination - UMN lesion of corticospinal tracts is expected to cause exaggerated ankle reflex (i.e. clonus) with upgoing plantar normally. But in subacute combined degeneration cord, Syphilitic taboparesis and Friedrich's ataxia and MND we see absence of ankle jerk as spinal reflex pathway is affected (afferent) while UMN type damage still produces Babinski – upgoing plantar.  Anisocoria: This refers to pupillary asymmetry, which may result from sympathetic or parasympathetic dysfunction. Sympathetic dysfunction results in Horner syndrome, in which the pupil is small but reacts to light. Parasympathetic dysfunction results in the tonic pupil.  Argyll-Robertson pupil, seen in neurosyphilis, is irregular and small; it does not react to light, but does accommodate.  Anosognosia refers to the denial of illness and typically is seen in patients with right frontoparietal lesions, resulting in left hemiplegia that the patient denies.  Asterixis involves momentary loss of tone and flapping of the hand are seen when the patient extends his arms in front with the wrists dorsiflexed. This is seen in patients with metabolic encephalopathies GAIT Conditions Antalgic gait Trauma, Osteoarthritis Broad, unsteady gait (Drunken/sailor’s gait) Cerebellar lesions Festinating/shuffling gait Parkinson’s Gait apraxia (Magnetic gait or failed gait ignition) Hydrocephalus High stepping due to foot drop Neuropathic / polio / peripheral lesions in MS Lurching, chaotic gait Huntington’s disease Pigeon gait Torsional abnormalities seen in hip dysplasias Propulsive gait Carbon monoxide poisoning (stiff with head and neck bent) Stiff, scissoring gait UMN lesions, cerebral palsy, cortical lesions in MS or stroke Stomping gait Friedreich's ataxia Pernicious anaemia, Tabes Dorsalis (Syphilis) Trendelenburg gait Weakness of the abductor muscles of the lower limb, principally gluteus medius Waddling myopathic gait Pregnancy, proximal myopathy. © SPMM Course  Beevor sign is seen with bilateral lower abdominal paralysis that results in upward deviation of the umbilicus when the patient tries to raise his head and sit up from the supine, recumbent position.  Brown Sequard syndrome is due to hemisection of the spinal cord; the full syndrome is rare. Clinical features are related to various tracts that are severed.  Chvostek sign is seen in hypocalcemia. Tapping the cheek at the angle of the jaw precipitates tetanic facial contractions.  Doll 's eye maneuver: This refers to turning the head passively with the patient awake and fixated or when the patient is in a coma. In the former, the eyes remain fixated at the original focus when all gaze pathways are normal; in the latter, the eyes deviate in the opposite direction when the brainstem is intact.  Friedreich’s ataxia is an inherited neurological disease (trinucleotide repeat) with pes cavus, kyphoscoliosis, cerebellar signs, impaired joint position / vibration, cardiomyopathy, optic atrophy.  Gower sign: This sign, seen in severe myopathies, occurs when the patient attempts to stand up from the floor. Patients first sit up, then assume a quadruped position, and then climb up their own legs by using their arms to push themselves up.  Holmes-Adie syndrome - A benign form of the tonic pupil is seen in Holmes-Adie syndrome, i.e., a tonic pupil with absent patellar and Achilles reflexes.  Horner's syndrome: Remember PAMELA – Ptosis, Anhidrosis, Miosis, Enophtholmos and Loss of ciliospinAl reflex. This collection of signs indicates a lesion of the sympathetic pathway on the same side. Seen in cervical lesions –e.g. apical lung tumour affecting cervical sympathetic ganglion, carotid aneurysms.  Kayser-Fleischer ring: This is a brownish ring around the limbus of the cornea. It is best demonstrated by an ophthalmologic slit lamp examination.  Marcus-Gunn pupil: This sign requires a swinging flashlight test to assess. As the flashlight swings from 1 eye to the other, the abnormal pupil dilates as the light swings back from the normal side. No anisocoria is seen. The phenomenon is also called a paradoxical pupillary reflex and indicates an afferent (optic nerve) pupillary defect. Lateral corticospinal damage Lateral corticospinal damage •Ipsilateral spastic paralysis below the level of the lesion •Babinski sign ipsilateral to lesion •Abnormal reflexes (UMN type hyperreflexia) Posterior column damage Posterior column damage •Ipsilateral loss of tactile discrimination, vibratory, and position sensation below the level of the lesion Lateral spinothalamic damage Lateral spinothalamic damage •Contralateral loss of pain and temperature sensation. This usually occurs 2-3 segments below the level of the lesion. © SPMM Course  Mononeuritis multiplex: Painful asymmetric asynchronous sensory and motor peripheral neuropathy with isolated damage to at least 2 separate nerve areas. Causes: diabetes, vasculitis, amyloidosis, direct tumor involvement, autoimmune disorders paraneoplastic syndromes.  Milkmaid's grip: This refers to the inability to maintain a sustained grip commonly seen in patients with chorea.  Myerson sign: Patients with Parkinson disease, particularly those with bilateral frontal lobe dysfunction, continue to blink with repeated glabellar taps.  Optic neuritis: The classic triad of optic neuritis consists of (1) loss of vision, (2) eye pain, and (3) dyschromatopsia. 70% unilateral. Usually recover spontaneously (Multiple sclerosis) within 2-3 weeks. Movement- or sound-induced phosphenes are seen. Reduction in vision may worsen in bright light, a symptom that seems paradoxical. The Uhthoff symptom, described as exercise- or heat-induced vision loss is seen in 50% of patients. Afferent pupillary defect is noted on testing (i.e. direct light reflex absent; consensual present)  Subacute combined degeneration is due to vitamin B12 deficiency; causes peripheral neuropathy, posterior column signs with pyramidal signs below the waist.  Trombone tongue: This is seen in patients with chorea. It refers to the unsteadiness of the tongue when the patient tries to protrude it outside the mouth. Rigidity Hypertonia Exaggerated reflexes Mild atrophy (disuse) e.g. pseudobulbar palsy Atonia or hypotonia Loss of deep tendon reflexes Atrophic, wasted Fasciculatione.g. bulbar palsy UMN Lesion UMN Lesion LMN Lesion LMN Lesion # 10 - Bedside cognitive examination tools # Bedside cognitive examination tools © SPMM Course Bedside cognitive examination tools (This section is best read in conjunction with the section on neuropsychological tests in the Applied Neuroscience chapter and the chapter on Rating Scales) MMSE: The Mini-Mental State Examination (MMSE) is the standard screening instrument for dementia introduced by Folstein in 1976. It takes 5–10 minutes to administer and has a median positive Likelihood Ratio of 6.3 and a median Negative Likelihood Ratio of 0.19.  Brief tool for grading cognitive impairment in elderly and screening form dementia.  Not very sensitive to change, but used in anti-dementia drugs’ clinical trials.  ADAS-Cog may be better suited to detect change.  Practice effect may occur with MMSE.  It is a 30point scale  With less than 9 years of formal education, the cut off for suspecting dementia must be 21/22 and not the usual 23/24.  Insensitive to early decline.  Doesn’t pick up frontal executive defects Bulbar Palsy Bulbar Palsy •LMN weakness of 9-12 cranial nerves •Wasted, fasciculating tongue •Nasal speech •Lost jaw jerk and gag reflex •emotional lability not seen •MND, polio, botulism, myasthenia gravis, muscular dystrophies Pseudobulbar palsy Pseudobulbar palsy •bilateral supranuclear (UMN) lesions of lower cranial nerves •Stiff tongue; wasting seen only in later stages •Donald-duck speech •Exaggerated jaw jerk; preserved gag reflex •emotional lability (pathological emotionalism) •MND, multiple sclerosis, multiinfarch dementia and severe head injury. © SPMM Course ITEMS in MMSE o Orientation (10) o Registration (3) and recall (3) tasks (6 points total) o Attention task (5) o Multistep command (3) o Naming (2) o Repetition language (1) o Reading comprehension (close your eyes, 1 point) o Writing (1) o Visual construction (copy interlocking polygons, 1 point) Clinical interview with carers and patients is the best diagnostic tool for any disorder including dementia; overreliance on MMSE scores can be counterproductive. The clock drawing test: Clock drawing test requires verbal understanding (comprehension), short-term working memory to process the instruction and spatially coded knowledge in addition to constructive skills and planning (executive function). (It does not test orientation to time!)  Watson introduced a 7 scores screening method with a good degree of reliability. The placing of any three digits in a quadrant is considered to be correct. An error score of one is assigned to each of the first three quadrants containing any errors, and an error score of four is assigned for the fourth quadrant if it contains an error. Thus, a maximum error score of seven can be obtained. The normal range for the score is 0-3. A score of 4 or greater in this scoring system has a sensitivity of 87%, a specificity of 82% and a kappa value of 0.70 for identifying dementia (according to the NINCDS-ADRDA criteria for probable dementia).  The test has a high correlation with the MMSE and other tests of cognitive dysfunction.  It can also be used in diagnosing unilateral neglect and inattention.  Subjects of low education, advanced age and depression perform more poorly. There are many methods of administering and scoring.  Normal clock-drawing ability reasonably excludes cognitive impairment Addenbrooke’s cognitive examination (ACE-Revised):  ACE-R evaluates six cognitive domains (orientation, attention, memory, verbal fluency, language and visuospatial ability). It is useful for detecting dementia and mild cognitive impairment. © SPMM Course  Frontal tests such as verbal fluency are also included in the ACE, making it more sensitive to frontal types of dementia than MMSE. (Hodges R et al., 2000). It is also effective for differentiating the subtypes of dementia, such as Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, and other forms of dementia associated with parkinsonism (Rittman et al., 2013).  The normative data provided with ACE-R (revised version) states that there are two defined cut-offs (<88: sensitivity=0.94, specificity=0.89; <82: sensitivity=0.84, specificity=1.0). The likelihood ratio for a positive test of dementia at a cut-off of 82 is 100:1.  Language domain receives the major share of the scoring in ACE. # 11 - 4. Imaging of the nervous system # 4. Imaging of the nervous system © SPMM Course 4. Imaging of the nervous system Computed Tomography – CT  The most widely available scan in clinical practice  CT scanners effectively take a series of head X-ray pictures from 360 degrees around a patient's head.  The CT image contrast is determined by the degree to which tissues absorb X-rays.  Structures close to bone may appear obscured in a CT image e.g. brainstem  The difference in the attenuation between gray matter and white matter is not very high.  CT is limited to one plane of rotation – often axial.  Appreciation of tumours and areas of inflammation is possible by intravenous infusion of iodine-containing contrast agents. Iodinated compounds in the vascular compartment absorb much more irradiation than the brain tissue and so appear bright.  One feature that is better visualized on CT scanning is calcification, which may be invisible in MRI.  CT scans and MRI are the most common neuroimaging tools used in psychiatry. The CT is widely available with shorter scan duration at a low cost, but exposure to radiation is a disadvantage.  CT has poor sensitivity to early ischemia and has poor visualization capacity for posterior fossa lesions. Magnetic Resonance Imaging – MRI  MRI does not rely on the absorption of X-rays but is based on nuclear magnetic resonance (NMR) principle. MRI magnets are rated in Tesla (T) units of magnetic field strength.  The nuclei of all atoms spin about an axis that is randomly oriented in space. When atoms are placed in a magnetic field, the axes of all odd-numbered nuclei (H1 in particular) align with the magnetic field. This axis deviates away from the magnetic field when exposed to a pulse of radiofrequency electromagnetic radiation oriented at 90 or 180 degrees to the magnetic field. When the pulse terminates, the axis of the spinning nucleus realigns itself with the magnetic field, and during this realignment, it emits its own radiofrequency signal. MRI scanners collect these signal emissions.  The images can be in the axial, coronal, or sagittal planes.  The rate of the realignment of the H1 axis is determined by its immediate environment and the degree of water content.  Hydrogen nuclei within fat realign rapidly, and hydrogen nuclei within water realign slowly.  Routine MRI studies use 2 different radiofrequency (RF) pulse sequences: T1 and T2.  T1 images: © SPMM Course  The RF pulses are brief, and data collection is brief  Hydrophobic environments are emphasized i.e., fat is bright on T1, and CSF is dark.  The T1 image most closely resembles that of CT scans and is most useful for assessing overall brain structure.  T1 is also the only sequence that allows contrast enhancement with the contrast agent gadolinium-diethylenetriamine pentaacetic acid (gadolinium-DTPA).  On T1 images, gadolinium-enhanced structures appear white.  T2 images  This RF pulse lasts four times as long as T1 pulses, and the collection times are also extended.  Emphasizes signal from hydrophilic areas i.e. brain tissue is dark, and CSF is white on T2 images.  Areas of the brain tissue that have abnormally high water content, such as tumors, inflammation, or strokes, appear brighter on T2 images. T2 images reveal brain pathology most clearly.  The proton density sequence  A short radio pulse is followed by a prolonged period of data collection,  Useful to see periventricular structures  Fluid attenuated inversion recovery (FLAIR)  The T1 image is inverted and added to the T2 image to double the contrast between gray matter and white matter.  Very useful for detecting sclerosis of the hippocampus caused by temporal lobe epilepsy and for localizing areas of abnormal metabolism in degenerative neurological disorders.  MRI scans are contraindicated in patients with pacemakers or implants of ferromagnetic metals. Claustrophobia is a relative contraindication.  MRI is less useful in emergencies due to limited availability and longer scan duration, in addition to higher costs. But it involves no radiation and can use water soluble Gadolinium for contrast studies. It has good sensitivity for early ischemia with better posterior fossa visualization. Structures / pathology CT scan T1 image T2 image Infarct Dark Dark Bright Bleed (haemorrhage) Bright Bright (unless too old / too fresh) Bright (unless too old / too fresh) Tumour Dark Dark Bright MS plaque Dark Dark Bright # 12 - Functional Magnetic Resonance Imaging (fMRI) # Functional Magnetic Resonance Imaging (fMRI) © SPMM Course Magnetic Resonance Spectroscopy –MRS  MR spectroscopy can detect several biologically important nuclei with an odd number of protons and neutrons.  H-1 proton spectroscopy can be used to quantify Nacetyl aspartate (NAA), creatine, and cholinecontaining molecules.  GABA and glutamate can be detected using MRS but not dopamine as it is available in a very low concentration  Phosphorus-31 MRS can be used to determine the pH of brain regions and the concentrations of phosphorus-containing compounds (e.g., adenosine triphosphate [ATP] and guanosine triphosphate [GTP]) that are important in the metabolic activity of the brain.  Additional indications include the use of MRS to measure concentrations of psychotherapeutic drugs such as lithium in the brain. Some compounds, such as fluoxetine and trifluoperazine (Stelazine), contain fluorine-19, which can also be detected in the brain and measured by MRS. Functional Magnetic Resonance Imaging (fMRI)  Neuronal activity within the brain causes a local increase in oxygen consumption. Consequently the local concentration of deoxyhaemoglobin increases, relative to oxyhaemoglobin. While oxyhaemoglobin is diamagnetic (weak magnetic contrast), deoxyhemoglobin is paramagnetic, producing an MR signal that can be detected with the T2 (demyelinated) CSF Dark Dark Bright Bone Bright Bright Dark Air Dark Dark Dark Fat Dark Bright Bright Tissue Shades of grey Grey matter – grey White matter - white Shades of grey MR molecule Potential clinical uses 1H Magnetic resonance imaging (MRI), Analysis of metabolism – NAA, creatine and choline. 19F Measurement of pO2, Analysis of glucose metabolism Measurement of pH, Pharmacokinetics 7Li Pharmacokinetics 31P Analysis of bioenergetics Measurement of pH 14N Measurement of glutamate, urea, ammonia 13C Analysis of metabolite turnover rate Pharmacokinetics of labelled drugs 17O Measurement of metabolic rate # 13 - Single Photon Emission Computed Tomography SP # Single Photon Emission Computed Tomography - SPECT © SPMM Course sequence. This is called Blood Oxygen Level Dependent (BOLD) technique. This process is the basis for functional MRI.  fMRI is a proxy measure of tissue activity that depends on relative changes in perfusion; it does not measure the actual neuronal metabolism.  No radioactive isotopes are administered in fMRI; this is a significant advantage over PET and SPECT.  A subject can perform a variety of tasks, both experimental and control, in the same imaging session. In resting fMRI, the brain regions that have high levels of activity during rest are studied. These regions include the precuneus, lateral parietal regions and medial prefrontal cortex. A network of these regions showing higher baseline activity at rest is called default mode network or DMN. Single Photon Emission Computed Tomography - SPECT  SPECT uses radioactive compounds to study regional differences in cerebral blood flow within the brain. This records the pattern of photon emission from the bloodstream which varies according to the level of perfusion in different regions of the brain.  Similar to fMRI it does not measure neuronal metabolism directly.  SPECT uses compounds labeled with single photon-emitting isotopes: iodine-123, technetium-99m, and xenon-133.  Xenon-133 quickly enters the blood and is distributed to areas of the brain as a function of regional blood flow. Xenon-SPECT is thus referred to as the regional cerebral blood flow (rCBF) technique. Xenon-SPECT can measure blood flow only on the surface of the brain, which is an important limitation.  Assessment of blood flow to the whole brain with SPECT requires the injectable tracers such as technetium-99m-d,l-hexamethyl propylene amine oxime (HMPAO).  This is attached to highly lipophilic molecules that rapidly cross the blood-brain barrier to enter brain cells. Once inside the cell, the ligands are enzymatically converted to charged ions, which remain trapped in the cell. Thus, over time, the tracers are concentrated in areas of relatively higher blood flow. This is the ligand most commonly used in detecting perfusion changes in dementia.  In addition to studying perfusion, Iodine-123 (123I)-labeled ligands for the muscarinic, dopaminergic, and serotonergic receptors can be used to study the occupancy and distribution of these receptors. Iodobenzamide is used for D1/D2 receptors; iomazenil is used for GABA-A receptors; nor-β- CIT for dopamine and serotonin transporters; epidepride for D2/D3 receptors. © SPMM Course Positron Emission Tomography – PET  PET can be used to study blood flow, receptor distribution and metabolic activity of brain tissue.  A key difference between SPECT and PET is that in SPECT a single particle is emitted, whereas in PET two particles are emitted; the latter reaction gives a more precise location for the event and better resolution of the image.  The isotopes used in PET decay by emitting positrons, with the resolution closer to its theoretical minimum of 3 mm.  Relatively few PET scanners are available because they require an on-site cyclotron to make the isotopes.  The most commonly used isotopes in PET are fluorine-18, nitrogen-13, and oxygen-15. These isotopes are usually linked to another molecule, except in the case of oxygen-15 (15O).  The most commonly employed ligand is [18F]fluorodeoxyglucose (FDG). FDG gives direct information about neuronal metabolism. Other molecules are listed in the table below. Diffusion tensor imaging – DTI  DTI combines the principles of nuclear magnetic resonance and molecular diffusion.  Diffusion refers to the random translational motion of molecules, also called Brownian motion, that result from the energy carried by these molecules.  During their random, diffusion-driven displacements, molecules probe tissue structure at a microscopic scale well beyond the usual image resolution: the predominant direction of the molecular movement can help determine the integrity and trace white matter tracts.  In traditional diffusion weighted images only 3 gradient directions are applied; DTI – diffusion tensor allows multiple (e.g. 16) gradients .  From DTI, mathematical measures such as the Fractional Anisotropy (FA) can be calculated. This is an index of the integrity of white matter.  The principal direction of the diffusion tensor can be used in tractography to infer the whitematter connectivity of the brain. Purpose PET ligand Blood flow C15/H215O Glucose metabolism F18 deoxyglucose Dopamine D2 receptors 11C raclopride Dopamine neuron density 18F dopa; 18F metatyrosine GABA-A receptors 11C flumazenil 5HT2 receptors 18F altanserin; setoperone Striatal D2, cortical 5HT2 11C methylspiperone Serotonin synthesis rate 11C methyltryptophan Muscarinic receptors 11C scopolamine © SPMM Course Neuroimaging findings in psychiatry: Neuroimaging findings in depression Periventricular and deep WM hyperintensities Subcortical – thalamic and striatal hyperintensities Decreased frontal and basal ganglia volumes Decreased metabolism in prefrontal cortex, Anterior cingulate & amygdale Higher prefrontal metabolism (esp. anterior cingulate) predict better treatment response Higher 5HT2A receptor density – higher dysfunctional negative thoughts Increased MAO-A activity (especially women) Elevated D2 binding in untreated depression – psychomotor retardation Therapeutic dose of SSRIs- 80% 5HT transporters occupied Neuroimaging findings in schizophrenia Ventricular enlargement Loss of grey matter – especially insular cortex, anterior cingulate (medial prefrontal cortex) and medial temporal lobe Progressive loss of brain volume in first few years of diagnosis fMRI reveals poor DLPFC activation in executive tasks Decreased NAA (N-Acetyl aspartate) in PFC (neuronal loss) in MRS Widespread reduction in DTI (diffusion tensor) – fractional anisotropy: frontal and corpus callosum – more in chronic treated patients Neuroimaging findings in Alzheimer’s Ventricular enlargement Loss of temporal lobe volume – especially hippocampus Decreased parieto-temporal fMRI activation and SPECT blood flow Neuroimaging findings in OCD Both reduced and increased volumes of caudate nuclei reported. Higher caudate blood flow due to increased metabolism. This reduces after effective treatment of the OCD. (Adapted from Murray, R, et al. (ed) Essential Psychiatry, Cambridge Press) Neuroimaging findings in Childhood-Onset Schizophrenia: Summary of key grey matter structural changes reported from Childhood-Onset Schizophrenia samples (Rapoport & Gogtay, 2011). In addition to what is shown, a ventricular enlargement at baseline and slower growth rates of (especially right hemispheric) white matter are also noted. From Hollis & Palaniyappan, Rutter’s Child and Adolescent Psychiatry, Ed: Thapar et al...6e. Wiley & Sons. © SPMM Course Notes prepared using excerpts from:  Agrell & Dehun (1998). The clock-drawing test . Age and ageing 27:399  Lennox, B. Antibody-mediated encephalitis: a treatable cause of schizophrenia. Br J Psychiatry. 2012 Feb;200(2):92-4.  Barton, JJS. Prosopagnosia associated with a left occipitotemporal lesion. Neuropsychologia. 2008 46(8):221424  Carlat, DJ. The Psychiatric Interview: Practical Guides in Psychiatry, 2nd Edition, 2005. Lippincott Williams & Wilkins  Cartlidge, N. States related to or confused with coma. Neurol Neurosurg Psychiatry 2001; 71(Suppl 1):i18-i19  Fuller Neurological examination made easy Churchill Livingstone; 4 edition  Higgins, E S.& George, MS. Neuroscience of Clinical Psychiatry, The: The Pathophysiology of Behavior and Mental Illness, 1st Edition. Lippincott Williams & Wilkins 2007. Page 16  http://bestpractice.bmj.com/best-practice/monograph/1066/diagnosis.html  http://www.emedicine.com/EMERG/topic270.htm  http://www.emedicine.com/neuro/TOPIC632.HTM  Jaffe JA & Kimmel, PL. “Chronic Nephropathies of Cocaine and Heroin Abuse: A Critical Review,” Clin J Am Soc Nephrol 1, no. 4 (July 1, 2006): 655-667.  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007  Katz DI, Alexander MP. Traumatic brain injury: predicting course of recovery and outcome for patients admitted to rehabilitation. Arch Neurol 1994; 51: 661–70  Kay J & Tasman A. Essentials of Psychiatry, 2nd edition, 2006. John Wiley & Sons, Ltd.  Kayser MS and Dalmau J. Anti-NMDA Receptor Encephalitis in Psychiatry. Curr Psychiatry Rev. 2011; 7(3): 189–193.  Kipps & Hodges. J. Neurol. Neurosurg. Psychiatry 2005;76;22-30  Koyama T, Tamai K, Togashi K (2006) Current status of body MR imaging : fast MR imaging and diffusionweighted imaging. Int J Clin Oncol 11:278-285.  Lewis DA. Structure of the human prefrontal cortex. Am J Psychiatry. 2004; 161[8]: 1366  Moo et al. J Neurol Neurosurg Psychiatry 2003;74:530-532  Semple et al (Ed). The Oxford Handbook of Psychiatry 1st edition. Oxford University Press 2005.  Strub & Black. The Mental Status Examination in Neurology (2000) 4th ed. F. A. Davis Company.  Zadikoff C and Lang AE. (2005) Apraxia in movement disorders. Brain 128:1480–97 DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information. # 17 - 522_Descriptive_Psychopathology # 01 - 1. Mood and Affect # 1. Mood and Affect: # 02 - Aspects of Affect # Aspects of Affect: # 03 - Coexisting features of mood disturbance # Coexisting features of mood disturbance: © SPMM Course 1. Mood and Affect: The terms affective disorder and mood disorder are used interchangeably in clinical practice. The difference between mood and affect has been variously described. It is generally accepted that mood refers to a more pervasive emotional state than affect (as if climate = mood and weather = affect). Both mood and affect can have an objective and subjective components though one school of thought proposes to use the term mood for subjective and affect for objective components of emotional expression. Aspects of Affect: Descriptor Valence The quality of affect: i.e. happy, depressed, perplexed, anxious or angry Reactivity Responsiveness of affect to environmental cues - One expects affect to be reactive to cues in the environment; we laugh on hearing a joke, blush when embarrassed, etc. If the reactivity is conspicuously absent, then this is called blunted affect or parathymia, according to Bleuler. Bleuler proposed this feature as a primary schizophrenic symptom. Range of expression This may be restricted or constricted in depression and anxiety states. Congruence Incongruent affect may be seen in hebephrenic schizophrenia and learning disability. For example, a patient might maintain a silly, jocular affect in spite of receiving a bad news. Stability This refers to the reasonable maintenance of an affective state until a clear external stimulus demands a change in affect. The absence of such stability manifests as a sudden unprovoked change in affect; the patient may break down into tears for no reason or appear enlightened with apparently no environmental cues. This is called labile affect; it is seen in histrionic personality, borderline personality, and sometimes in PTSD. Control An extreme form of labile affect is termed as emotional incontinence; it is seen in organic states such as pseudo bulbar palsy where frontal lobe is damaged. Here the patient bursts out into laughter or tears within minutes with no control over these emotions – it appears as if the patient has developed an incontinence of the emotion filled ‘bladder’. He/she has little control over these expressions. Coexisting features of mood disturbance: Mania is characterized by extreme euphoria (disturbed emotion), pressured speech (disturbed thought) and too many ideas and plans to be carried out (disturbed will). It is not a pure mood or affective disorder in this sense. The terms euphoria, ecstasy and expansiveness, refer to various degrees of an elevated mood, but they do not include thought or will component. The same applies to the term ‘depression’ in clinical sense – it includes mood, will and thought components and not just sad affect. Melancholia is probably the oldest of terms used in psychopathology. It is defined as a quality of mood, which is distinct from grief, occurring in association with significant psychomotor retardation often with somatic symptoms of depression (as described in ICD-10). It is very characteristic of depression; patients often describe this as a deeply distressing affective state. # 04 - Pain symptoms # Pain symptoms: © SPMM Course Mixed states: It is long appreciated that between the extremes of mania and depression various mixed states exist. In fact, mixed states are commoner than pure mania or depression, according to the recent literature. s. no Type Mood Will Thought Manic stupor High Low Low Mania with poverty of thought High High Low Inhibited mania High Low High Depressive mania Low High High Excited depression Low High Low Depression with flight of ideas Low Low High Over the years, the six Kraepelinian mixed states have dwindled into just two varieties: 1. Dysphoric Mania (when predominant mania is present with some depressive symptoms) and 2. Depressive Mixed State (when full depression is present with some manic symptoms). Other terms such as agitated depression (full depression with psychomotor agitation), anxious depression (depression with marked anxiety), irritable depression (depression with marked irritability), and mixed hypomania (hypomania with some depressive symptoms) are used in this context but are better avoided. Pain symptoms: Pain is frequently associated with mood disturbances. It is difficult to distinguish organic and non-organic pain as often there are mixed elements of both in a pain syndrome. Nevertheless certain differences exist as listed below. Psychiatric vs. Organic pain: Organic pain Non-organic pain Less diffuse More diffuse More anatomical confinement Less anatomical Often fluctuant and remits during intervals Often constant and unremitting Usually characteristic quality Difficult to describe the quality Progression, if occurs, will have tissue boundaries Progresses without tissue confinement generally Anywhere in the body Head and neck, back are the most common Can wake patients from sleep Rarely wakes one from sleep Tenderness may be present Tenderness very rare May have typical postural changes e.g. intracranial pathology Usually no postural variation # 05 - Anhedonia & Alexithymia # Anhedonia & Alexithymia: # 06 - Mood and perception of time # Mood and perception of time: © SPMM Course For somatoform pain, head and neck are the most common sites. In somatisation disorder, musculoskeletal symptoms are the commonest. In hypochondriasis gastrointestinal symptoms predominate. Anhedonia & Alexithymia: Anhedonia was a term coined by Ribot; it refers to the inability to derive pleasure in life often leading to diminished interests in activities. It may be of two types: physical and social anhedonia. Physical anhedonia represents a defect in the ability to experience physical pleasures, such as pleasures of eating, touching etc., while social anhedonia represents a defect in the ability to experience interpersonal pleasure, such as pleasure of being with people, talking, etc. Anhedonia is common in melancholic depression with somatic syndrome where it is a core symptom. It is also observed as a part of the negative syndrome of schizophrenia. In schizophrenia, anhedonia is considered to be more social or interpersonal than a personal/physical deficit. Alexithymia was first described by Sifneos. A- Absence or defective + LEXI –words + THYMIA - emotion i.e. Difficulties in using words to express emotions. It is often accompanied by 1. Diminution of fantasy. 2. Reduced symbolic thinking 3. Literal thinking concerned with details 4. Difficulties in recognizing one's own feelings 5. Difficulties in differentiating body sensations and emotional states. 6. A ‘robot-like existence’ is suggested – but patients rarely complain in these terms. It is especially seen in psychosomatic illnesses, somatoform disorders, depression, PTSD, personality disorders and paraphilias. Note that in some cultures especially south Asian, somatic metaphors are used in describing emotions often. Mood and perception of time: This may be altered in patients with depression or mania. In a study of 32 acutely depressed, 30 acutely manic, and 31 control subjects, the experience of time was assessed both subjectively (with a visual analog scale) and objectively (with Chronotest software and the Trail Making Test (TMT)). Both manic and depressed subjects were slow in the TMT, but the subjective experience of time was slowed in the depressed, sped up in the manic, and unchanged in the control subjects (Bschor et al. 2004). An allied phenomenon seen in some patients with schizophrenia is the age disorientation. In chronic schizophrenia patients may lose the track of their age and may claim that they are of an age at least 5 years different from their actual age. Age disorientation is defined as misstating one's age by 5 or more years. It is observed in a substantial number of chronically ill, institutionalized schizophrenic patients. Prevalence estimates have been limited to data from surveys of hospitalized mental patients in chronic care facilities, where approximately 25% of patients are age disoriented. The majority of age-disoriented schizophrenic patients understate their age. In fact, an additional 10% of schizophrenic subjects report an incorrect subjective age that is within 5 years of their age at illness onset. Age-disoriented patients are generally older, have a longer current admission, and were younger at first admission than age-oriented patients. Age disorientation is associated with early onset and poor prognosis. # 07 - 2. Disorders of perception # 2. Disorders of perception © SPMM Course 2. Disorders of perception Perception consists of two parts – receiving information from a sensory modality (bottom up) and interpretation or processing of the sensation instantaneously using cognitive faculties (top down). Normally, any perceived object corresponds to the stimulus that elicited it. Perception occurs in visual, auditory, tactile, gustatory, olfactory, kinaesthetic or proprioceptive modalities – any distortions in perception could also occur in any of these domains. Perceptual errors can occur at different levels – Perceptual disorder Stimulus present? Corresponding object perceived? Error Perceptual distortions Yes Yes Object’s quality altered Illusions Yes No A different object is perceived Hallucinations No Yes Perception without a stimulus Negative hallucinations Yes No No object is perceived  If a stimulus is perceived as corresponding object but not accurately – changes in physical properties e.g. size, shape, intensity and colour - this is a perceptual distortion. In depression and hypoactive delirium there is dulled perception; intense perceptions can occur in mania, hyperactive delirium and drug-induced states (hallucinogens). Hyperacusis especially is seen in migraine and alcohol hangover.  Changes in the shape of objects especially with the loss of symmetry are called dysmegalopsia.  The objects can shrink in size – micropsia or enlarge - macropsia.  These are usually organic – could be ictal (parietal) or ocular (accommodation errors – paralysed accommodation can cause micropsia), rarely in acute schizophrenia. Hallucinogens (Mescalin) can also change the colour of perceived objects or make components of an object e.g. body parts – to be seen detached in space.  Stimulus is perceived as an object but not corresponding to the source – both stimulus and object are present, but different from each other – illusions.  There is no stimulus but perception occurs – hallucinations.  There is a stimulus but no perception occurs – negative hallucinations. # 08 - Imagery & Illusions # Imagery & Illusions © SPMM Course The above table has been pictorially represented below: Imagery & Illusions The imagery is not a perception because there is no stimulus involved and no object perceived; it is essentially a fantasy. Imagery refers to images produced voluntarily with complete insight that they are mental, not external phenomena. They also lack the objective quality of hallucinations and normal sense perceptions. One form of imagery called eidetic imagery is considered to be a special ability of memory wherein visual images are drawn from memory accurately at will and described as if being perceived currently. This is noted in children (2-15% school goers) and may be a part of religious experiences; no pathological association is noted consistently. Illusions may be difficult to differentiate from hallucinations if the source of stimulus is difficult to trace – e.g. ‘Did I see the devil on the wall or from the wallpaper pattern?’ But, fortunately, these are qualitatively different and so eliciting the description patiently can help. There are three major types of illusions: STIMULUS PERCEIVED OBJECT EXPERIENCE # 09 - Pseudohallucinations # Pseudohallucinations: © SPMM Course Type of illusion Context Quality Effect of concentration Example Affect illusion Prevailing emotional state leads to misperceptions Often fearful, emotion provoking. Disappears on focussing the object with extra concentration A depresse d patient reading ‘deed’ as ‘dead.' Pareidolic illusion Formed objects from ambiguous stimuli, coloured by prevailing emotion; not entirely due to inattention or affective change Often playful and whimsical. On paying extra effort, the object intensifies – does not disappear. Seeing cars in the cloud Completion illusion Stimulus that does not form a complete object might be perceived to be complete Due to inattention Disappearance on concentration is the rule. CCOK is read as COOK In pareidolia, fantasy and imagery play equal parts, apart from the actual sense perception. It is common in delirium especially in children when febrile, hallucinogen use. Pareidolia are under some degree of voluntary control and not characteristic of any psychotic illness. Pseudohallucinations: Though the distinction between these two is not always clinically relevant, presentation with consistent pseudo hallucinations with no other psychotic features should make one question the veracity of the psychopathology. Pseudohallucinations: There are two different definitions: o Involuntary hallucination-like experiences occurring in inner subjective space, with a vivid outline that are absolutely different from normal sense perceptions and hallucinations (Kandinsky, Jaspers & Sims). o Hallucinations that are recognized to be unreal and self-originating are pseudohallucinations according to Hare. European psychopathologists use the former definition more often. Pseudohallucinations are not pathognomonic of anything; they are not always pathological. # 10 - Hallucinations # Hallucinations © SPMM Course They are intermediate between fantasy (imagery) and hallucinations. Like fantasy they are in subjective space, lack quality of concrete reality, have quality of idea and so not sought in other modalities simultaneously (not searched for, no attempts to reach out etc.) and appreciated to be observer-dependent, self-originating. Like a hallucination, they have a clear outline, vivid, retained for the good length of time, cannot be dismissed at will and are behaviourally and emotionally relevant i.e. acted upon or felt for. The hallucinatory experiences of bereavement and in Ganser’s state are pseudohallucinations Hallucinations Hallucinations have several important qualities that are essential in differentiating from other mental phenomena: 1. They take place at the same time as other sensory perceptions – e.g. the voice is heard even when music is playing, or someone is talking to me. So they are different from dreams where no real component exists alongside the false perception. 2. They take place in the same space as other perceptions - angel is seen standing at the corner of my room. This is different from fantasy or imagery which takes place in subjective space. 3. They are experienced as sensations – not as thoughts – contrast from obsessional images. 4. The percept has all qualities of an object – i.e. it is believed that it can be experienced in other modalities too, like a real object which can be seen, felt, smelt and heard. This is why hallucinators search for the man behind the voice or try and reach out and touch visual percepts. 5. They are involuntary – appearance cannot be controlled; independent – will exist even when not perceived by the hallucinators; may lack the quality of publicness – not every one could hear and see them. Auditory Hallucinations:  Elementary, unstructured hallucinations are seen in acute organic states.  Musical hallucinations are similar to Charles Bonnet syndrome in visual domain – can occur in those with deafness, also in organic conditions. Formed auditions like voices – as in thought echo – cannot be elementary. Phonemes are any auditory hallucinations that occur as human voices. Schizophrenic phonemes are usually multiple, may or may not be recognizable, usually male with a different accent, speaking in one’s mother tongue and usually episodic - almost never continuous. When a same word is repeated continuously, normal subjects hear phonetically linked but different words. Hallucinating schizophrenia TRUE HALLUCINATION PSEUDO HALLUCINATION Objective, outside spatial location Absence of insight Sought in other modalities (see text) Often seen in psychosis Subjective spatial location The presence of insight, often. Not sought in other modalities usually. Often in personality disorders, following trauma, dissociative experiences. © SPMM Course subjects hear different words that have no phonetic connection to the original repeated word – this is called verbal transformation effect. Patients could be distracted away from their voices, but it is the attention paid to the external stimulus which is more important than the degree of external stimulus used to distract. Alcoholic hallucinosis initially starts as fragmented voices, later organised into clear voices. Visual hallucinations: Occipital lobe tumours, postconcussional states, epileptic twilight state, hepatic failure (any toxic delirium), dementia are some causes for visual hallucinations. 30% of old age psychiatric referrals have visual hallucinations. Solvent sniffing and hallucinogens can cause elementary visual hallucinations like light flashes. Simultaneous visual-verbal hallucinations – green man speaking to me – is seen in TLE. Visual hallucinations are very uncommon in schizophrenia (But Andreasen quotes 30% in a series observed with acute schizophrenia). Reports of “black patch” psychosis were frequent following simultaneous bilateral cataract surgery in the early era of the procedure, attributed to sensory deprivation, leading to the recommendation that only one eye be operated on at a time. It was subsequently recognized that “black patch” psychosis was a relatively uncommon postoperative delirium partly due to anticholinergic eye drops.* Charles Bonnet Syndrome: Elderly patients, with normal consciousness and no brain pathology, with reduced visual acuity due to ocular problems, experience vivid, distinct, usually well-coloured (in contrast to real sensation that is blurred due to eye disease) formed hallucinations – mostly humans, at times animals and cartoons. These objects usually show movement, and can be voluntarily controlled – disappear on closing the eyes; insight about unreality is usually preserved – though they may evoke emotions including fear and joy. About 1/3rd are elementary; usually the hallucinations are located in external space. Podoll's criteria for diagnosis include: Elderly person with normal consciousness with visual hallucinations; not in the presence of delirium, dementia, psychosis, intoxication or neurological disorder with lesions of central visual cortex; reduced vision resulting from eye disease (most commonly macular degeneration). The syndrome can occur in people with normal vision1,2 Lilliputian hallucinations can occur in visual or haptic mode – they usually involve seeing tiny people or animals (or feeling diminutive insects crawling if haptic) and are seen in delirium tremens and unlike other organic visual hallucinations, Lilliputian hallucinations can be accompanied by pleasure though often intermingled with terror. These are not the same as micropsia. Patients with DT often have a prodromal affect or pareidolic illusions before these hallucinations. Autoscopic hallucinations are the visual experience of seeing oneself. Males predominate 2:1, impaired consciousness is a common accompaniment and depression is the commonest psychiatric cause. They are also called phantom mirror images and may take the form of pseudohallucinations. Schizophrenia (usually pseudo), TLE, parietal lesions (organic states more likely to have true hallucinations) are also implicated. In negative autoscopy, one looks into a mirror and sees no image at all. Palinopsia: palin for "again" and opsia for "seeing". It is a visual disturbance that causes images to persist even after their corresponding stimulus has left. It is seen in LSD use, migraine, occipital epilepsy, head trauma. It is similar to afterimage, but colour inversion (usually shadows or distorted colours noted in afterimages) is conspicuously absent. © SPMM Course Somatic hallucinations: These can be divided into superficial, visceral and kinaesthetic. The superficial somatic hallucinations are tactile (haptic - touch), hygric (fluid – wetness etc.) and thermic (heat or cold). Visceral hallucinations are usually pain-like sensations arising from deep viscera like liver. These are sometimes termed as coenesthetic hallucinations and suggest schizophrenia. Kinaesthetic or proprioceptive hallucinations refer to joint or muscle sense, often linked to bizarre somatic delusions. They are also seen in benzodiazepine withdrawal and alcohol intoxication. Formication (formic acid – from ant) is a special type of haptic hallucination – unpleasant sensation of little animals or insects crawling under the skin, seen in DT and cocaine intoxication. Tactile hallucinations can be seen in parietal seizures. Superficial somatic hallucinations are almost never noted in TLE though the visceral sense of ‘raising epigastrium’ is seen. The common experience of the phantom limb is a body image disturbance and not a hallucination; though it is in external space, it does not satisfy other qualities of hallucination and patients are aware of unreality usually. It is a body image disturbance with a neurological basis. Somatic hallucinations may or may not be accompanied by passivity delusions. Without the passivity delusions, they cannot be classed as a First rank symptom. Olfactory hallucinations can occur in the aura of TLE – usually burning smell or urine smell. In depression, this can be an adjunct to nihilism. Gustatory hallucinations e.g., bitter taste of poison can give rise to delusions of persecution in schizophrenia. They are also seen in TLE. Extracampine hallucinations: Hallucinations that occur outside the normal field of perception e.g., images seen behind your back, under your sternum or hearing voices from Inverness, etc. They occur in schizophrenia, epilepsy and also in hypnagogic hallucinations of healthy people – so not diagnostically important. Both illusions and hallucinations are not necessarily pathological though they both are false perceptions, along with pseudohallucinations. For example hypnagogic hallucinations (hallucinations when going to sleep – go for gogic - usually auditory. Also seen in Narcolepsy-cataplexy. They can be visual or tactile too. First noted by Aristotle) and hypnopompic hallucinations (hallucinations when waking up) can occur in normal individuals. Hallucinations also occur in glue sniffing, post-infective depression, children with fevers and in phobic anxiety. Sensory deprivation in normal healthy people can also produce hallucinations. They are not more frequent in schizophrenia than other conditions. Functional hallucinations: An external stimulus provokes hallucination, and both hallucination and stimulus are in same modality but individually perceived. e.g. voices heard whenever the noise of water running through the tap is heard. They are not illusions – as the stimulus is perceived appropriately (noise of water), but, in addition, there is another perception (voices) without any appropriate object. HYPNAGOGIC HALLUCINATIONS 3 times more common than hypnopompic 37% normal adults experience at least once Hypnopompic is more specific for narcolepsy EEG shows alpha rhythm (subject not awake) Hearing one’s name called is the most common # 11 - Synaesthesia # Synaesthesia: © SPMM Course Reflex hallucinations: These are hallucinations in one modality provoked reflexively by a stimulus in another modality e.g. seeing an angel whenever listening to music. They are similar to functional hallucinations in that there is a stimulus, which is perceived normally, followed by a hallucinatory perception – only difference being the modality of stimulus and perception being same in functional while different in reflex hallucinations.It is important to differentiate synesthesia from reflex hallucinations in EMIs. In synesthesia it is the music that is seen – the stimulus and object of perception remain the same albeit in different modalities - the patient does not claim that she could see Jesus or angel. Also the perceptions are simple, unformed and non-bizarre in synesthesia e.g colours; in reflex hallucination these are formed voices, vivid images like angels etc. The stimulus –perception sequence is usually completed before hallucination occurs in reflex hallucination – ‘I heard the music and then came the angel’; in synesthesia music itself is seen as colour – the experiences are simultaneous. Synaesthesia: It was Francis Galton (1880) who first reported the condition called synaesthesia. He noticed that a certain number of people in the general population, who are otherwise completely normal, seemed to have a certain peculiarity: they experience sensations in multiple modalities in response to stimulation of one modality. The phenomenon of perceiving a stimulus of one modality in a different modality (may be single or multiple modalities) is called synesthesia. E.g. tasting the music, hearing colours and smelling voices. It is not a hallucination as the perceived object has an appropriate stimulus. The original stimulus is usually perceived in appropriate modality too when the cross modality perception occurs (syn – joint, simultaneous). It is common in females 4:1 to 6:1, runs in families and colour-number synesthesia is the most common form. It is thought to be due to extensive cross wiring between multimodal association regions in some people, probably due to failed selective pruning. Several pieces of evidence support the notion that indeed synesthetic experience has a neural basis: 1. There is a remarkable consistency of associations (e.g., sound–color associations) over time. For example, Baron-Cohen et al. found a consistency of 92% of color–sound associations after 1 year in 13 synesthetic subjects but only a 37% consistency (after 1 week) in a control group. 2. There is evidence that synesthesia can be acquired in the course of neurological illnesses such as multiple sclerosis, temporal arteritis, tumors to the sella region, and others. 3. Synesthetic experiences can be induced by ingestion of drugs such as mescaline. 4. There appear to be differences between nonsynesthetes and synesthetes in measures of cerebral blood flow. © SPMM Course # 12 - 3. Delusions # 3. Delusions © SPMM Course 3. Delusions DSM-IV defines a delusion as “A false belief … that is firmly sustained despite what almost everyone else believes and despite what constitutes incontrovertible and obvious proof or evidence to the contrary”. This definition, though very useful, conceals the multidimensionality of delusional experience, which is now well endorsed by cognitive psychologists, phenomenologists, philosophers as well as clinicians. Do delusions exist in a continuum? Some authors suggest that ‘delusions and hallucinations are commonplace in healthy populations, with prevalence up to approximately 25% depending on the definitional criteria, and so psychosis exists in a continuum model’. This claim is yet to be validated and established. (Lincoln, 2007). Using data based solely on self-report measures, Lincoln (2007) found that high distress associated with beliefs seems to be a relevant characteristic of delusions in persons with schizophrenia, compared to ‘delusion-like beliefs in common population’. The presence of hallucinatory experiences accompanying delusions did not differ between schizophrenia and ‘common’ population. Are delusions really persistent? Though classically defined as persistent belief, doubts have been cast on this of late. In a follow-up of nearly 1100 acutely hospitalized psychiatric patients who were re-interviewed at 10-week intervals for 1 year, it was demonstrated that most delusions exhibited a high degree of plasticity; in nearly one-third delusions completely subsided on follow-up (Applebaum et al. 2004). Delusional ideation is more likely to persist in never married, older patients, those with schizophrenia, and with delusions of thought broadcasting, those with higher degree of preoccupation and higher behavioural relevance, and those with more than one primary delusion. Even when delusional experience persists in certain patients, this does not mean that the same delusion will be maintained; considerable change in content was noted during the follow-up. What are the dimensions of delusions? Kendler (AJP, 1983) has listed the dimensions of delusional experiences. The dimensions of delusions include 1. Conviction: The extent to which the patient believes. 2. Extension: The extent to which the belief extends to various spheres of life. 3. Disorganisation (or organisation): the degree of internal consistency and systematisation of the belief. 4. Bizarreness: The implausible quality of the belief (especially in schizophrenia). 4%–8% of patients receive a diagnosis of schizophrenia because of the presence of Bizarre Delusions. Bizarreness is defined using the following notions: physical (or logical) impossibility and overall implausibility or © SPMM Course incomprehensibility with the lack of grounding in ordinary experience. Most bizarre delusions are Schneiderian (i.e. of FRS type). 5. Pressure: The extent to which the patient is preoccupied and distressed. 6. Acting on delusion: The extent to which the belief drives behaviour 7. Seeking evidence: The extent to which the patient questions the veracity of belief or seeks to strengthen the belief. Often patients with delusions, do not need any external proof or evidence, and despite showing evidence to contrary, will continue to hold their delusional beliefs. 8. Lack of insight. Primary delusions: These are defined in two different ways 1. Jaspers’ concept: primary delusions are the true, un-understandable beliefs that arrive fully formed and cannot be reduced further to any other mental experiences. This has been challenged recently. 2. Primary delusions are the first psychopathology to occur in the course of symptoms (temporal sequence). Often both are true i.e. they are irreducible and precede other mental phenomena. There are 4 types: 1. Autochthonous delusions or delusional intuitions or simply, primary/true delusions: These are ideas that occur de novo, or 'out of the blue' - takes form in an instant, without identifiable DELUSION Conviction Extension Disorganis ation Bizareness Distress Action Evidence Insight © SPMM Course preceding events, as if full awareness suddenly burst forth in an unexpected flash of insight, like a bolt from the blue. This can be a quite elaborate delusional system on arrival itself. Wernicke formulated the concept of autochthonous delusions. Autochthonous stands for ‘out of soil’, ‘aboriginal’. 2. In delusional perception, a normally perceived object is given a new meaning, usually in the sense of self-reference - the conclusion being entirely unwarranted, the perception is normal. Hence, it is a two-staged process – normal perception preceding the attachment of delusional significance; these two steps need not be simultaneous - might even be separated for years! The only type of delusion included in Schneider's first-rank symptoms is delusional perception. 3. Delusional mood or atmosphere refers to the sense of perplexity and uncertainty that exists during a prodrome of psychosis, usually ending in an autochthonous delusion which will make sense of the perplexity on arrival. Delusional mood/atmosphere can precede other primary delusions. It is the only psychiatric phenomenon that can directly precede and causally related to primary autochthonous delusion. Note that delusional mood is a specific affective experience – not thought content. 4. Delusional memory can be of two types. It can be a retrospective delusion where something that never happened and so false, irrational or bizarre is reported as if occurred in the past and recollected now. E.g.,. A male schizophrenia patient said I had a hysterectomy at age 3 and since then I became a man. Sometimes a normal memory might be delusionally elaborated – “My dad bought me a camera when I was seven, now I understand it is because he was homosexual”. It is difficult sometimes to say what is fact and what is not though the distinction between above two variants is more an academic exercise. More importantly delusional perception can mimic delusional memory when the first stage of normal perception is actually a ‘recollected’ normal perception from memory. But in spite of this delusional perception is a two stage process – e.g. “I saw an envelope yesterday (normal perception but recollected from memory), I realised my stomach is upturned”. Primary delusions do not carry any prognostic significance in schizophrenia though they have diagnostic relevance. While primary delusions can occur in epileptic psychoses, they are not generally associated with epilepsy when they occur in psychotic disorders. Primary delusional experiences occur more in acute stages of schizophrenia and are not seen in chronic schizophrenia, due to being mixed with secondary delusions, hallucinations, FTD, etc. Other delusions that follow a primary delusion or other mental phenomena like hallucinations, affective disturbances, etc. are termed as secondary delusions. © SPMM Course In delusional perception, the delusional judgment or belief that follows a perception will be unrelated to the prior perception Persecutory delusions: Primary delusions vary considerably in content and are not characteristically persecutory in nature. In contrast, most secondary delusions are often persecutory, making persecutory themes the commonest contents of delusions as a whole. Paranoid delusions: The term paranoid is very much misused in psychiatric practice. Paranoia stands for ‘besides mind’. In the strict sense, the term paranoid can be used only for self-referential delusions, irrespective of their content. For example, grandiose delusion ‘God is sending a messiah to help me’, persecutory delusion ‘mafia is after me’, referential delusion ‘those kids are talking about me, cameras are fixed to watch me’, hypochondriacal delusion or nihilistic delusion ‘my body is rotting away’ etc are all paranoid delusions. Monothematic delusions: These can occur as single delusions in various disorders though in their commonest form they occur in major psychotic illnesses like schizophrenia or affective psychosis. Delusion Example Content of monothematic delusions Capgras delusion "That's not my wife; it is an impostor who looks just like her." Cotard delusion "I am dead." Fregoli delusion "I am constantly being followed by people I know, but I can't recognize them because they are always in disguise." Mirrored-self misidentification "The person I see when I look in the mirror isn't me; it is some stranger who looks like me." Perception (factual) Judgement Delusional perception Perception (factual) Perception (factual) Judgement Judgement Delusional Misinterpretati on Delusional Misinterpretati on © SPMM Course De Clerambault's delusion (erotomania) "Person X is secretly in love with me" (Person X being some important or famous person who has never encouraged this idea) Othello syndrome (pathological jealousy) "My wife is having an affair." From Coltheart, M, et al. Schizophrenia and Monothematic Delusions. Schizophrenia Bulletin 2007 33(3):642-647 Morbid jealousy can occur in various forms – delusion, overvalued idea, in depression and in anxiety states; it is not a misidentification syndrome. It was first described by Ey. It is common in alcoholics. It has a potential of violence, especially against rival than a partner and can occur among cohabiters and homosexual couples too. De Clerambault’s syndrome is a type of delusion of love, in which a woman believes that an older man who is of higher social status is in love with her. It is not related to delusional misidentification. It is also called Old Maid's insanity where persecutory beliefs coexist. Cotard’s syndrome is severe depression with nihilistic and hypochondriacal delusions tinged with grandiosity and a negative attitude. It is not related to delusional misidentification. Cotards syndrome is seen in schizophrenia though more commonly in depressive psychosis. It is generally seen in the elderly, with hypochondriacal and nihilistic delusions with a tinge of grandiosity amidst nihilism (not grandiose delusions!).It is also reported in organic lesions and migraine. Hypochondriacal delusions: These are seen typically in psychotic depression especially in elderly, as a part of Cotard’s syndrome. A specific type described by Munro called monosymptomatic hypochondriacal psychosis consists of 1. Delusions of body odour and halitosis (olfactory delusions). Some of these may have olfactory reference syndrome – no olfactory experiences but only fixed belief about body order with anxiety reaction. Paranoid personality disorder is often associated with this syndrome. 2. Delusional infestation (Ekbom’s syndrome) It is a delusion of parasitic – macroscopic - infestation with classical matchbox sign: An old lady comes to clinic with a match box, of skin scrapings usually, as evidence for the parasite that infests her causing itching. This can predate the onset of dementia. It may or may not be associated with a somatic hallucination. 3. Dysmorphic delusions (misshaped nose, etc.). The various misidentification syndromes (Ellis, 2005) are 1. In Capgras syndrome, a person believes that a person usually close to him has been replaced by an exact double. Capgras syndrome is sometimes referred to as the illusion of doubles though it is a delusion. First reported by Kahlbaum (1866) but more extensively described by Capgras and colleagues (1923, 1924). The Capgras delusion is classified as a dangerous delusion and may be associated with violence. Capgras delusion is etiologically heterogeneous – at least 15 different causes are recorded. It is now thought to be mostly due to organic brain damage (>50%, Lishman) apart from being seen as a part of schizophrenia or isolated delusional disorder including brain © SPMM Course injury and schizophrenia. It is thought to be cognitively mediated by the combination of reduced affective responsivity to familiar faces plus impaired belief evaluation, and neuropsychologically it is believed to be due to the combination of the disconnection of the face recognition system of the brain from the autonomic nervous system plus damage to a specific region of right frontal lobe. 2. In Fregoli syndrome, there is the false identification of familiar persons in strangers. A familiar person is thought to be taking various disguises. First reported by Courbon and Fail (1927). They described a 27-year-old woman, a domestic servant with a passion for the theatre, who developed the delusion that the actresses Robin and Sarah Bernhardt were persecuting her in the guise of others. They suggested the term Frégoli delusion with reference to the celebrated Italian mimic Léopoldo Frégoli. The essential feature of this delusion is that there is no belief in actual physical change: instead the patient believes that his/her persecutors can invade the body of others. It is rare compared to Capgras. 3. In the syndrome of subjective doubles, the patient believes that another person has been physically transformed into his own self and the patient is convinced that exact doubles of him- or herself exist. 4. Intermetamorphosis - A becomes C, C becomes B etc. People keep transforming their physical and psychological identities. Courbon and Tusques (1932) described Sylvie G, a 49-year-old woman who claimed that objects and animals seemed altered. People could change gender as she looked at them. Many people looked like her son or her aunt. She could distinguish them from her true son only by examining their feet (his were large and were invariably shod in dirty shoes). Her husband might change appearance into that of a neighbour (all except his eye colour and missing finger). There were no further reports of intermetamorphosis for 46 years since when five cases have been described, including three by Young et al. (1990). Feature recognition (appearance) Affect recognition (warmth) RESPONSE SYNDROME Looks like my dad, but he is not my dad, probably an impostor Capgras syndrome My dad, but does not look like him… is he disguising himself? Fregoli syndrome Who is he? Prosopagnosia (Seen in neurological disorders) © SPMM Course 5. Paraprosopia: This is very rare, re-described by Ellis. Here, a face appears to transform within seconds into a grotesque mask, often described by patients as a "monster", "vampire" or "werewolf" [Krauss, 1852]. Most likely to be reported by schizophrenic children but also observed in adults (e.g. Daniel Paul Schreber, 1842-1911, President of the Court of Appeal in Dresden, saw two men "as devils with particularly red faces…"). The concept of misidentification is now being extended to misidentification of time, a place apart from the person (reduplication phenomenon). Other disturbances in thought content: Ideas of reference are seen in paranoid PD where the individual is unduly self-conscious and feels that people take notice of him or observe things about him that he would rather not be seen. It can also precede the development of full-blown schizophrenia where it is called sensitive ideas of reference or "sensitiver Beziehungswahn”! It is not characteristic of mania. Overvalued ideas: Overvalued ideas (Wernicke) are solitary abnormal beliefs that are neither delusional nor obsessional in nature, but which dominates a person’s life and his actions. They have a poor prognosis and tend to dominate the sufferer's life. Common conditions presenting with overvalued ideas are paranoid or anankastic personality disorder, Body Dysmorphophobia, anorexia nervosa, morbid jealousy & transsexualism. Folie a deux is a shared delusion, in which a psychotic person transfers his delusions to one or more people close to him. The non-psychotic victim usually exhibits dependent traits on the primary patient. Separation of the pair can result in remission. Doppelganger: This is also known as double phenomenon – it is the awareness of oneself as being both outside and inside oneself. It is a cognitive and ideational disturbance as opposed to autoscopy, which is a perceptual disturbance. It can occur in the absence of mental illness too. It is not a delusional misidentification syndrome; unlike doppelganger, the latter is the pathology of familiarity. How are delusions formed? 1. Attentional biases: People with persecutory delusions preferentially attend to threat-related stimuli and preferentially recall threatening episodes. (Blackwood, AJP 2001) 2. Attributional biases: An exaggeration of self-serving attribution bias is seen in psychosis. Patients excessively attribute hypothetical positive events to internal causes (stable and global – grandiose) and hypothetical negative events to external causes (stable and global- persecutory). The attribution bias in paranoid subjects shapes delusional content rather than form, as patients with non-persecutory delusions do not show this bias significantly. Paranoid patients specifically attribute negative self-referent events active malevolence on the part of the other person (external personal attribution) rather than circumstances or chance (external situational attribution). (Blackwood, AJP 2001). This might serve to preserve the self-esteem of paranoid patients, acting as a self-defence. © SPMM Course 3. Probabilistic reasoning bias: When deluded patients were shown sequences of black and white beads and were asked to decide which jar [jar A had majority black beads and B had majority white] the sequence was probably drawn from, they came to a conclusion with far lesser beads in a sequence than controls. They were also relatively overconfident about the accuracy of their judgement. This was hypothesized to be due to impaired probabilistic reasoning (generating hypothesis and testing statistical probability). But later studies showed that when allowed to see as many numbers of beads as controls generally do, patients reached similar correct conclusions – they were able to generate hypothesis and test the probability; the defect being deficient datagathering (less information before decision). This is called Jumping-to-conclusion style of reasoning. (JTC). 4. Mentalising deficits/bias: Persecutory delusions reflect false beliefs about the intentions and behavior of others that could arise from the theory of mind deficits. # 13 - 4. First Rank Symptoms # 4. First Rank Symptoms: © SPMM Course 4. First Rank Symptoms:  Kurt Schneider, a German psychiatrist and a pupil of Karl Jaspers, pointed out certain symptoms as being characteristic of schizophrenia and therefore exhibiting a "first-rank" status in the hierarchy of potentially diagnostic symptoms.  The "first-rank" symptoms (FRS) have played an extremely important role in the recent diagnostic systems: in the International Statistical Classification of Diseases, tenth Revision (ICD-10) as well as in Diagnostic and Statistical Manual of Mental Disorder, (DSM-III-IV), the presence of one FRS is symptomatically sufficient for the schizophrenia diagnosis but FRS are not essential to diagnose schizophrenia.  FRS may also be encountered in the nonschizophrenic conditions, and, therefore, they are not specific or diagnostic for schizophrenia (Palaniyappan, 2007).  Kurt Schneider proposed an empirical cluster of symptoms, one or more of which in the absence of evidence of organic processes, could be used as a positive evidence for schizophrenia. He did not claim that they are comprehensive – but they are clearly identifiable, frequently occurring and occur more often in schizophrenia than any other disorder.  FRS emphasizes on the form of the experience rather than content i.e. the feature that voices echo one’s thoughts is more important that what the voices actually said.  Disturbance of self-image (ego-boundary) is the predominant underlying feature of all FRS.  In a critical review of FRS studies published in English between 1970 and 2005, Nordgaard et al. (2008) report the following findings. The FRS are reported to occur in 22% to 29% of patients with affective disorders. Generally, the prevalence of FRS in schizophrenia is reported to range between 25% and 88%. This range remains equally high in the reports from western and developing countries and in studies of different ethnic groups.  In some studies, delusional perception is the most frequent FRS, whereas the same symptom is the least frequent in other studies. A number of studies find no single dominating type of FRS.  Assessment of the diagnostic weight of individual FRS is absent with the exception of Mellor and colleagues who suggest that "voices discussing" should be given less diagnostic weight than other FRS.  The majority of the reports conclude that FRS do not affect the outcome. No study finds that the outcome is related to the number of FRS observed in the individual patient. FRS are not of any prognostic importance at all. They do not specify any subgroups with the differential treatment response or heritability. © SPMM Course The First Rank Symptoms 3 hallucinations Audible thoughts (Thought echo) Voices heard arguing (3rd person) Voices heard commenting on one's actions (running commentary) 3 ‘Made’ phenomena Made affect (Someone controlling the mood/affect) Made volition (Someone controlling the action – usually a completed act) Made impulse (Someone controlling the desire to act –not completed act but the drive. If the action has been carried out, patient admits to ownership of act, not the impulse behind it) 3 Thought phenomena (Experiences themselves are more important than later explanations or how patient interprets them) Thought withdrawal Thought insertion (External agency inserting thoughts upon the patient) Thought broadcast (Also called thought diffusion – as if in television broadcast, everyone comes to know about the patient’s thinking as and when the patient thinks – refers to the loss of privacy of thoughts. Cf. referential delusion – ‘people act as if they know what I am thinking’) 2 isolated symptoms Delusional perception Experience of sensations on the body caused by external agency (somatic passivity) Totally (3X3) +2. What is NOT FRS? Command hallucinations are not first rank symptoms. Somatic hallucinations are also NOT first rank symptoms unless there is a delusional elaboration and attribution of the origin of sensations to an external agency (i.e. unless they are presenting as somatic passivity). Note that somatic passivity can follow a normal sensation like a headache, ascribed to a ‘Russian neurosurgeon who inserted a chip through my nose when I was sleeping’! Schneider described mood changes (depression or elation), emotional blunting, perplexity and sudden delusional ideas as symptoms of the second rank. Thought alienation: © SPMM Course The three thought phenomena described above are sometimes grouped together as thought alienation or delusions of thought control. These are related to a primary disturbance in the subjective control of thinking. This is a high yield topic for MCQs – please study the table below. Phenomenon Self – nonself difference Where is the thought now? Who owns the thought? Who influences the thought? NORMAL THOUGHTS Preserved (we know that our thoughts are private) Self (in our subjective space) Self (it is our own thought) Self (we can stop thinking when we want) Thought insertion Violated Self (with the patient) External agency External agency produced and influenced the thought Thought withdrawal Violated Taken away (may be delusionally elaborated) Self Originally self-produced, now external agency influences Thought broadcast Violated Diffused everywhere Self External agency influences it as soon as it originated from self Thought blocking Not violated Unknown Self Self Obsessions (this is not a thought alienation) Not violated Self Self Self but disturbed (the thoughts may be against one’s values – so egodystonic but not fully disowned) Thought alienation table is modified from Mullins, S. & Spence, S.A. Re-examining thought insertion. The British Journal of Psychiatry (2003) 182: 293-298 # 14 - 5. Psychopathology of speech # 5. Psychopathology of speech # 15 - Aspects of conversational speech # Aspects of conversational speech: # 16 - Disorders of phonationarticulation # Disorders of phonation/articulation: # 17 - Disturbed speech production # Disturbed speech production: # 18 - 1. Altered speed of speech # 1. Altered speed of speech: # 19 - 2. Altered amount of speech # 2. Altered amount of speech: © SPMM Course 5. Psychopathology of speech Aspects of conversational speech: 1. Spontaneity: Comments that are not just responses to questions is present in normal speech 2. Turn-taking: Responses and comments are made only when the other speaker completes his sentences, or when natural pauses occur during conversations. 3. Mutual topic: Content is focussed and related to the comments made by the other speaker 4. Animation: Accompanying non-verbal behaviours are almost always present in normal speech Disorders of phonation/articulation: Aphonia refers to the inability to vocalize. It refers to sound production (phonation) rather than sound manipulation (articulation) – disturbance of the latter being dysarthria. In aphonia, whispering occurs; it may be due to paralysed vocal cords or due to hysteria. Dysarthria refers to disorders of articulation; it may be due to lesions in the brain stem (bulbar), cortex (pseudo bulbar), cerebellum or extrapyramidal system. Dysarthria can also be drug induced in schizophrenia. Stammering: In stammering the normal flow of speech is interrupted by pauses or by the repetition of fragments of words or parts of words. Tics often accompany stammers. Boys stammer more often than girls; usually reduced in adulthood. Stuttering is difficulty in uttering speech sounds at the beginning of words. Utterances are repetitive, prolonged and pauses are common. Primary stuttering is seen in children, in adults new onset stutter may be related to stroke or extrapyramidal symptoms. Disturbed speech production: 1. Altered speed of speech: Quiet speech in low volume with poor intonation, reduced spontaneity and prolonged reaction time is seen in depression. The terms used here are bradyphasia (decelerated talking) while tachyphasia refers to accelerated talking seen in manic states. 2. Altered amount of speech: 2.1. Logorrhoea refers to increased quantity of speech, generally without the pressure of speech or formal thought disturbances (see below) and seen especially in early manic states. 2.2. Alogia is a term used to denote poverty of speech and a decrease in spontaneous talking; it occurs in depression and schizophrenia. This must be differentiated from the poverty of content of speech where the amount of speech is adequate but conveys little information. This is often related to schizophrenic formal thought disorder (see below). 2.3. Mutism: This denotes a complete lack of speech. Severe depression with psychomotor retardation may be associated with mutism though this is relatively rare in the absence of catatonia. Mutism is almost always present in a catatonic stupor. a. Elective mutism: Mostly seen in children who refuse to speak to certain people; for example, the child may not speak at school but speak at home. # 20 - 3. Repetitive speech # 3. Repetitive speech: # 21 - Disturbed Language processing # Disturbed Language processing: © SPMM Course b. Hysterical mutism: This is relatively rare, and the most common hysterical disorder of speech is aphonia. c. Akinetic mutism is associated with lesions of the upper midbrain or posterior diencephalons and Crutzfeld Jakob Dementia. Here the patient is mute but remains aware of the environment though cannot move or respond. 3. Repetitive speech: Verbigeration: Repetition of phrases or sentences. This occurs spontaneously and without any goal. This should not be confused with echolalia. This is not catatonia. Palilalia: Repetition of last uttered word, without any apparent purpose; seen in learning disabled, pervasive developmental disorders and in Tourette’s. Verbigeration is a closely associated phenomenon though neurologists prefer to use the term palilalia for both. Logoclonia: Repetition of last syllable of a word, seen in Parkinson’s. Disturbed Language processing: Sound received by ears is transmitted to Wernicke’s area and auditory association cortex, which processes the language component. Arcuate fasciculus connects Wernicke’s area to Broca’s area. Broca’s area is the higher motor area of language production. Signals from Broca’s area are relied on onto the motor area to coordinate the delivery of language via the tongue, lips and vocal cords. © SPMM Course Arcuate Fasciculus (conduction aphasia) Wernicke's area A Wernicke's area A Auditory association cortex Auditory association cortex Broca's area C Broca's area C Language association cortex Language association cortex Peripheral speech areas (tongue, lips) Peripheral speech areas (tongue, lips) Ears Ears # 22 - Components of Language production # Components of Language production: # 23 - Aphasia # Aphasia: # 24 - Disorders of reading and writing # Disorders of reading and writing: © SPMM Course Components of Language production: 1. Fluency: Production of meaningful words and sentences. Depends on intact Broca’s area and its forward connections. 2. Comprehension: Understanding words and sentences spoken by others. Depends on intact Wernicke’s area and its connection with association cortex and sensory input 3. Repetition: Repeating what others say. Requires no high-level processing; can take place if Broca's, Wernicke’s and arcuate fasciculus are intact. It does not need relay of higher association area to either Broca’s or Wernicke’s. 4. Naming: Ability to use nouns especially the names of objects. Naming defects (anomia) accompanies any aphasia but in various degrees. Aphasia: This refers to a higher level ‘language’ problem – not sound production or manipulation error but the problem of language reception, production and processing. Aphasia is almost always organic. Adapted from Harrison’s Textbook of internal medicine; 15 e In Broca's aphasia the speech is nonfluent; it often appears laboured with any interruptions and pauses. Function words (prepositions, conjunctions) are most affected though the good degree of meaningappropriate nouns and verbs are still produced. Abnormal word order and a characteristic agrammatism are noted. Speech is telegraphic. Harrison textbook quotes the following example: "I see...the dotor, dotor sent me...Bosson. Go to hospital. Dotor...kept me beside. Two, tee days, doctor send me home”. In Wernicke's aphasia, the comprehension is impaired for both spoken and written language. Language output is fluent but is highly paraphasic, sometimes with string of neologisms and circumlocutions. Hence, it is also termed as "jargon aphasia." The speech contains large numbers of function words (e.g., prepositions, conjunctions) but few substantive nouns or verbs that refer to specific actions. The output is, therefore, voluminous but uninformative. Disorders of reading and writing: As aphasia is a disturbance of language production, reading and writing difficulties too accompany all aphasias. In addition, some disorders of isolated reading/writing problems have been described. Type of aphasia Fluency Repetition Comprehension Naming Wernicke’s sensory aphasia Intact Lost Lost Lost Broca’s motor aphasia Lost Lost Intact Lost Conduction aphasia Intact Lost Intact Lost Transcortical sensory aphasia Intact Intact Lost Lost Transcortical motor aphasia Lost Intact Intact Lost © SPMM Course o Pure word blindness (alexia): Here the patient can speak normally and comprehend what is spoken; he can also write spontaneously and to dictation, but reading comprehension is impaired. o Pure agraphia: This is an isolated inability to write while other faculties of language are preserved. It is sometimes seen as a component of Gerstmann’s syndrome (parietal deficits) o Alexia with agraphia results in acquired illiteracy. o Pure word deafness: Patient can speak, read & write fluently, but comprehension is impaired only for spoken language. Bilateral (or left sided with disrupted connections to non-dominant circuit) damage to the superior temporal pole is suspected. o Pure word dumbness: Spoken language cannot be produced clearly, but the patient can comprehend language well, can read and write # 25 - 6. Disorders of Thought # 6. Disorders of Thought: # 26 - Elements of thought # Elements of thought: © SPMM Course 6. Disorders of Thought: Normal thinking: Normal thinking is of three types (or functions): 1. Fantasy/dereistic thinking or autistic thinking: There is no goal direction, unrealistic - daydreaming type. Predominant in cluster A personality, dissociation and pseudologia fantastica. 2. Imaginative thinking: Again fantasy elements but admixed with memory, involving abstract concepts but goal-directed and does not cross boundaries of possibility and realism. Determining the tendency of thoughts preserved e.g. lateral thinking. 3. Rational or conceptual thinking: based on factual reality and uses logic. Psychopathology of thought includes 1. Disorders of thought content (e.g. delusions) 2. Disorders of thought form (e.g. tangentiality) 3. Disorders of thought stream (e.g. pressure of speech) 4. Disorders of thought control (e.g. obsessions) Elements of thought: Normally every thought we have has the following four properties: 1. Form 2. Stream 3. Content 4. Control. As a student of psychopathology, one wonders why should the authors make a fuss about the stream, form and content of thought; what is the real difference among this three concepts? A simple way of understanding this is through an analogy of buying fruits in the supermarket. Element Supermarket Analogy Refers to Disturbances Content Apples, pears or oranges? ‘the material.' What is being thought about? Delusions of persecution, suicidal thoughts, etc. Form Bags, boxes, sold loose as single fruit? ‘the package.' In what manner is the thought present? Loosened associations, tangentiality Stream or flow Packed as a dozen, a score, just four only, half a dozen, etc. ‘the amount.' How is it being thought about? Fast, slow, etc. The poverty of thought, the pressure of speech and crowding of thoughts. Control of thought Mango is a produce of South Africa; tomatoes are from Spain, etc. ‘the origin.' Where is it from? To some extent obsessions can be considered here, passivity and first rank thought disturbances. Thought content could be deciphered from ones’ behaviour, but thought form and stream, unless extremely deranged, cannot be studied without being expressed as speech. Formal thought disorder (FTD) refers to disturbances in form and not content; it is wrong to say ‘someone is deluded so he has a formal # 27 - Formal thought disorders (FTD) # Formal thought disorders (FTD): © SPMM Course thought disorder’. But note that the term FTD increasingly includes both form and stream errors (not content errors) and scales that measure thought disorder do not differentiate stream from form anymore. Formal thought disorders (FTD): Note that various authors have used various terms to describe the FTD. Hence there is a significant overlap among the various terms – the following terms are not mutually exclusive of each other. Various terms denoting FTD: The term paralogia refers to positive FTD – i.e. symptoms of thought disorder that are identified as the presence/appearance of an abnormal element in thought processes (e.g. tangentiality). The term alogia is sometimes used to refer to negative FTD – symptoms considered due to the absence/disappearance of a normal element of thought/speech (e.g. poverty of speech content). Kraepelin used the term akataphasia for FTDs to convey the essence that speech disorders are a result of thought disorder. Blueler’s term ‘loosening of associations’ is often considered to indicate the presence of FTD. Classifications of FTD: Cameron proposed 4 characteristic formal thought disorders – Metonymy: imprecise approximate expressions used as substitute words. For example paperskate for a pen. Asyndesis: This refers to the lack of genuine causal links in speech. For example, ‘I got up at eight this morning as well as few birds of different colours on the painting, shrinking all the time to drop few coins. On the floor. All the time.’ Overinclusion: In overinclusive thinking ideas that are only remotely related to the concept under consideration become incorporated in the patient's thinking; Conceptual boundaries are lost. This is used to explain the thought disorders in schizophrenia and is different from the mechanism in the flight of ideas. Sorting tests can be used to test overinclusion. It occurs in nearly 50% of schizophrenia patients, especially when acutely ill. Interpenetration: Irrelevant thoughts penetrate ongoing stream of thoughts. Carl (not Kurt) Schneider proposed a different set of 5 elements of FTD Substitution: one thought – often inappropriate, fills the gap between other appropriate, more consistent thoughts. Omission: A chunk of thought goes missing from stream of conversation, patient being unaware – best analysed when written, Fusion: various thoughts fuse together, leading to loss of goal direction. Drivelling: disordered intermixture of constituent parts of one complex thought © SPMM Course Derailment (aka entgleisen); In derailment normally flowing track of thoughts suddenly change. The determining tendency is preserved but is misdirected. Schneider also described desultory thinking, sometimes considered along with driveling. In desultory thinking, speech is grammatically correct but sudden ideas force their way in from time to time. Each one of these ideas is a simple thought that, if used at the right time would be quite appropriate. Kleist proposed that semantic disturbance of language was more common than grammatical or syntactical errors in schizophrenia. The impact of semantic problems in speech could result in 1. Verbal paraphasia – where meaningful sentences produced in spite of the loss of appropriate words e.g. ‘food filling muscular carton’ for the stomach (a metonym). 2. In literal paraphasia, no one can make out the meaning of sentence spoken except the patient. Grammatical or syntactical disturbances include 1. Agrammatism refers to the loss of parts of speech – e.g. propositions leading to disordered word sequences. 2. In paragrammatism, individual phrases are well constructed and meaningful but they do not fit in with the goal of thought. The content delivered appears mixed up, though individually understandable. Various features of FTD: Neologism refers to making up a totally new word that is not in dictionary or using a known word with a completely different meaning e.g. ‘Inkur’ for pen (new) or ‘roast’ for pen (different). Stock words are either newly synthesized or already known words but used in an idiosyncratic way repeatedly, often with many meanings and in different contexts, sometimes dominating any discourse. e.g. “The riposte (? dog) runs into my way, always active – when my riposte (?friend) is around, it’s OK, full of riposte (?energy), as everyone likes him, when you throw him some riposte (?food) he stops all that work… comes running.” Thought block is a negative FTD – involves sudden arrest in the flow of thoughts; sometimes resembles an absence seizure though there is no amnesia for the idea that was discussed and no motor accompaniments typical of absences. Patients can elaborate on thought blocking with a delusional content of thought withdrawal. Stilted speech: This refers to pompous, formal speech often in an inappropriate context. Impaired lexical retrieval may underlie stilted speech in schizophrenia. A patient said ‘ Pliant rectitude is a trait more appropriate for successful living than hot-headedness, which is either stubborn or crusady. (McKenna, 1994). This patient would not have said’ pliant rectitude’ or ‘crusady’ unless more common words for the same concepts were not accessible. © SPMM Course Flight of ideas is characteristic of mania. Here thoughts follow each other so rapidly, that there is no general direction for thinking. Hence, chance associations take place to connect succeeding thoughts. These chance associations may arise from distractions in the environment or distractions in the elements of one’s own or someone else’s speech. An external environment driven association could be the following one - when talking about his breakfast, hears rustling newspaper and jumps to the topic of Iraq war or cost of petrol or elections, etc. Being cued by verbal associations (i.e. sound of words spoken) can be of three types: 1. Clang associations where thoughts are associated by the initial syllabic structure of words rather than their meaning. e.g., clover, cloud, clap, clan, etc. Others include 2. Punning: Here words get associated as one word has dual meaning e.g. fast – ‘to starve’ or ‘speed up’ and 3. Rhyming: Here words get associated as they have similar sounds e.g. cat, rat, bat, etc. In schizophrenic FTD, clang occurs in more often with first syllables as opposed to clangs in poetry, humour and manic speech where they occur more at the end syllables. Vorbeireden is talking past the point leading to approximate but not accurate answers to questions asked in an interview. It is described as a type of formal thought disorder, different from the flight of ideas. Though often described along with the Ganser syndrome, it is not exclusive to Ganser’s syndrome. It is also seen in acute schizophrenia and hebephrenic schizophrenia. Vorbeireden (‘talking past the point’) is often used interchangeably with vorbeigehen (‘going past the point’), although the latter was originally defined as part of the ‘Ganser syndrome’, whereby some criminals would give incorrect answers (‘approximate answers’) to simple questions that none the less suggested that the correct answer was known (e.g. saying dogs have five legs). Circumstantiality: In circumstantiality, thinking proceeds slowly, with many unnecessary details and digressions, before returning to the point. It is seen in some patients with temporal lobe epilepsy or alcohol-induced persisting dementia, learning difficulty and in obsessional personalities. It is a formal thought disorder where figure-ground differentiation apparently fails but not due to affective changes such as mania. Tangentiality: Circumstantiality must be differentiated from tangentiality - the patient never reaches the point in tangentiality, whereas they do reach the point in circumstantiality. Imagine a spiral that eventually touches its centre, while tangent scrapes through the edge and never reaches the centre. Circumstantiality may be related to loosened associations and usually develops within the setting of a delusional mood in schizophrenia; it may be due to an impairment of a central filtering process that normally inhibits external sensations and internal thoughts that are irrelevant to a given focus of attention. Concrete thinking: It is seen as literalness of expression and understanding, with failed abstraction. It is recognisable clinically but difficult to measure using psychometry. Goldstein studied this loss of abstract © SPMM Course thinking which can be tested using proverbs and similarities test. It seems concrete thinking is evident in speech-disordered (FTD) schizophrenia patients, but not the non-FTD group (Allen 1984). It is also seen in fronto temporal dementia. Testing the linguistics of schizophrenia: 1. Word association tests are abnormal in schizophrenia – despite the context of usage, patients preferred dominant meaning of a word e.g. court means ‘law-room’ not tennis court, in spite of the context of discussion being sports. 2. In cloze procedure parts of recorded speech are deleted to see if meaning could be still predicted; predictability was reduced in schizophrenia. In reverse cloze procedure patients are asked to predict the missing elements of someone else’s speech– again schizophrenia group performed worse in prediction. 3. Type –token ratio refers to the ratio between number of different words used during a discourse and total number of spoken words. Impoverished vocabulary was noted with low type-token ratio among schizophrenia patients. 4. Cohesion analysis (analysing links between sentences and words in a discourse) shows that schizophrenia patients use less referential ties (using pronouns without mentioning a subject in first place) and more lexical ties (connected words). Also, patients make more errors than controls when asked to construct complex sentences from simple phrases (Hunt test). Measuring FTD: Thought Language & Communication scale (TLC: Andreasen) and Thought and Language Index (TLI: Liddle) are commonly used scales. The latter uses projective stimuli from Thematic Apperception Test to elicit thought disturbances. Of various thought disorders classified by Andreasen, clanging and flight are more common in mania while derailment (loosening) and thought blocking and to some extent tangentiality, poverty of content of speech are seen often in schizophrenia - other items were largely non-specific. FTD is suggestive but not pathognomonic of schizophrenia; it is also seen in organic syndromes such as epilepsy. What causes Schizophrenic Speech Disturbance? There are various explanations from different scientific disciplines. 1. Von Domarus proposed that FTD is a result of loss of deductive reasoning – illogical thinking. (Von Domarus law – Kiwi cannot fly (premise 1), Kiwi is a bird (premise 2) - so birds cannot fly (conclusion); note that the inferences are based on insufficient premises.) 2. Schizophrenic thought disorder could be measured using Kelly’s personal construct theory - based repertory grids (Bannister). The patient is asked to score different elements (can be relatives or friends) under different constructs (qualities of them). Normally one would expect congruence between different constructs scored for an element, e.g. Mum is helpful, and she is also kind and supportive. But in schizophrenia the predictability of an element’s quality using prior constructs is affected. (Mum is helpful but scores low on kindness and support offered). This is called serial invalidation and is more pronounced for peoples than objects, showing that thought disorder affects interpersonal realm more than other spheres. The scores can be used to draw a semantic # 28 - Stream of Thought # Stream of Thought: © SPMM Course space, demonstrating graphical connections between people and qualities in the patient’s personal world. 3. Mortimer considered FTD to be a result of impaired semantic memory – so associations between words and qualities are lost. 4. Words carry a semantic halo – e.g. the word ‘London’ is linked, through symbolic meaning to words like ‘tube’ and also ‘Britain’, ‘England’, etc. Imagine that these words are cross-wired in the brain. So whenever the word London is stimulated, the closely cross-wired words also become available readily for the thought process to proceed uninterrupted. This activation is called direct semantic priming. In Indirect semantic priming, London activates tube; tube activates light (as in tube light) or pipes, etc. This indirect priming is usually minimal, preventing inappropriate deviation in determining the tendency of thought flow. In schizophrenia, it is proposed that direct priming is impaired but indirect one is activated more, to explain FTD. 5. Theory of mind refers to the ability to understand that other individuals have mental processes similar to self, leading to appropriate behaviour and conversation e.g. taking turns while conversing (as others also think and so want to speak). This is deficient in the development of autistic children and can become acutely deficient (but develops normally) in schizophrenia during psychotic episodes. This can explain some pragmatic errors in FTD. 6. Dysexecutive problems are increasingly proposed as the basis of FTD. Frontal lobe plays significantly in formation of the human language ad so the loss of executive functions can result in poor planning, error monitoring and correction of speech production. Stream of Thought: The term pressure of speech refers to the phenomenon of having excessive thoughts in mind accompanied by rapid voluminous speech, often disjointed and non-pragmatic. This is seen in mania. Crowding of thought occurs in schizophrenia. Here the patient describes his thoughts as being passively concentrated and compressed in his head. The associations are experienced as being excessive in amount, too fast, inexplicable and outside the person's control. Experientially, this is different from the manic flight of ideas. Retardation of thinking: Seen in depression. Train of thought is slowed down, though goal-directed, it is characterised by little initiative or planning, the long latency of response, increased pause times when speech is initiated and during speech. In both the above the mood state of the patient dictates the flow of thoughts. Perseveration: This could be considered under a stream of thought though traditionally, it is considered pathognomonic of organic brain disease; it is also discussed with disorders of motor action. The thought process tends to persist beyond a point at which they are relevant. It presents itself as repeatedly same answer or motor act even if the stimulus that elicits the response has changed and demands a different answer or motor act. Perseveration also occurs if there is clouded consciousness. # 29 - Possession Control of thought # Possession /Control of thought: © SPMM Course Possession /Control of thought: Obsessions are unwanted, intrusive, repetitive, senseless thoughts experienced by patients as troublesome and resisted; though the appearance of the thoughts themselves is appreciated to be beyond their control, they are not claimed to be due to external agency. Patients often regard them to be the products of one's own mind but against their values and needs; therefore they are termed as ego-alien. Intrusive thoughts occur before motor (compulsive) acts. But it is not necessary that every compulsion is preceded by an obsession or vice versa. Often during the course of OCD primary obsessions fade while compulsions dominate clinical picture; some compulsions can be mental compulsions like praying, counting, etc. Obsessional slowness can occur either when obsessional thoughts occur as part of a depressive illness or in cases of severe OCD where primary obsessional slowness ensues. Still another pattern is the obsession with symmetry or precision, which leads to a compulsion of slowness. Patients take hours to eat a meal or shave, in an attempt to do things ‘just right’. Unlike other patients with OCD, these patients do not resist their symptoms! The most common obsession is the fear of contamination, followed by pathological doubt, a need for symmetry, and aggressive obsessions. The most common compulsion is checking, which is followed by washing, symmetry, the need to ask or confess, and counting. Children with OCD present most commonly with washing compulsions, which are followed by repeating rituals. Thought alienation is a general term used to describe the experience that one’s thoughts are under the control of outside influences or that others participate in one’s thinking. This term is often confusing and better replaced with components of first rank symptoms – thought insertion, withdrawal and broadcast. # 30 - 7. Motor symptoms # 7. Motor symptoms # 31 - Catatonic symptoms # Catatonic symptoms: © SPMM Course 7. Motor symptoms Fish classified motor symptoms into a. Abnormal spontaneous movements: Tremors, Tics, chorea, athetosis and stereotypy noted in autistic spectrum disorders, hemi-ballismus, etc. b. Abnormal induced movement: Perseveration, automatic obedience, echo phenomenon and other catatonic signs Catatonic symptoms: Fink & Taylor have argued to include catatonia as a separate taxonomy in psychiatric nosology. Catatonia is decreasing in frequency in its classical form, largely due to early diagnosis, treatment and deinstitutionalisation. Catatonia is defined as rigidity during involuntary movements while volitional movement is carried out normally. Note that in neurological spasticity the tone is increased irrespective of passive or active movements. A patient with catatonia can use the affected limb or muscle group when needed with completely normal tone – for example, running out when there is a fire. Catatonia persists in sleep and can continue for weeks without improvement. Catatonia is mostly seen in advanced primary mood or psychotic illnesses. Among inpatients with catatonic presentation, 25 to 50 percent are related to mood disorders and approximately 10 percent are associated with schizophrenia. Catatonia results in both speech and motor disturbances. Ambitendence: Here a schizophrenic patient brings the spoon to his mouth dozens of times but never completes the act. In ambitendency, the patient makes a series of tentative, opposing alternate movements that do not reach the intended goal. This becomes evident when the patient is asked to carry out a motor act e.g. asking the patient to show his tongue will elicit repeated protrusion and retraction of tongue as if Prominent catatonic symptoms Non-catatonic motor symptoms seen in psychiatry Ambitendence Akathisia Automatic Obedience Perseveration Catalepsy Blepharospasm Echo-phenomenon Dystonia Gegenhalten Tardive dyskinesia Grimacing Tics Mannerism Astasia-abasia Mutism Chorea* Negativism Tremors* Posturing Athetosis* Stereotypy Hemiballismus* Stuporous immobility/excitement * Mostly neurological cause © SPMM Course the patient is undecided about showing his tongue. (Note ambivalence: Inability to make a decision – dilemma of the volitional faculty. It may also appear as affective ambivalence- e.g., To love and hate the same person at the same time or intellectual ambivalence-E.g. Assertion and denial of the same idea. This is not a catatonic symptom.) Automatic obedience: Exaggerated cooperation with examiner’s request or spontaneous continuation of movement requested. To demonstrate this, the examiner must ask the patient not to cooperate, but still the patient will carry out motor instructions. In days where ethics did not hamper research, Kraepelin demonstrated automatic obedience by pinching his patient’s tongue with a pin every time he protruded it; but the patient continued to obey Kraeplin’s commands in spite of this! Mitmachen and mitgehen are closely related to automatic obedience:  Mitmachen can be considered as a mildest form of automatic obedience where despite requests to resist manipulation, the patient yields himself to be placed in abnormal postures.  Mitgehen or “Anglepoise lamp” sign: The patient yields to slightest of pressures, without much resistance, similar to an angle poise lamp that bends easily. This happens even if the patient is instructed to resist any manipulation. This may be a milder form of automatic obedience. It is also called ‘magnet reaction’ as the patient may even follow the examiner around the room with light touch as if pulled by a magnet. Catalepsy or Waxy flexibility: Also called flexibilitas cerea. Here the patient shows wax-like plastic ‘mouldable’ quality. His limbs can be moved by the examiner to occupy certain postures, which are then maintained, even if these are uncomfortable and bizarre. Differentiating this from mitmachen / mitgehen (Automatic Obedience)  Unlike flexibilitas cerea, there is an explicit request to resist manipulation in mitmachen  The arm comes back to resting position when released by the examiner in mitmachen, but not in catalepsy  Unlike mitgehen, the manipulation is not gentle with finger tip but full and complete in catalepsy Echo-phenomenon: This is seen in catatonia, Latah (a culture-bound disorder) and also in Tourette’s syndrome. Echopraxia: mimicking examiner’s movements Echolalia: mimicking examiner’s speech. In Gegenhalten (aka paratonia or opposition) there is a resistance to passive movements with the proportional strength to the increase of muscle tone which seems to be voluntarily controlled by the patient. Patients with negativism resist or oppose all passive movements attempted by the examiner. This is an extreme form of opposition where apparently motiveless resistance to all interference is found. Negativism can be a frustrating symptom especially for carers involved in offering nursing assistance to the patient. The catatonic symptom of blocking or obstruction (or Sperrung) refers to a phenomenon # 32 - Non Catatonic symptoms # Non-Catatonic symptoms: © SPMM Course similar to thought blocking but occurs while carrying out motor acts. A patient with obstruction suddenly stops a motor act for no reason, without any warning. This may be demonstrated by asking the patient to move a part of his body; the movement is generally well begun, but then stops halfway without any indication. Grimacing refers to the maintenance of odd facial expressions. An odd variant of grimacing is called schnauzkrampf, where the patient cups his lips as if they are spastic (snout spasm). Stupor presents as immobility (usually the extreme opposite of excitement where no activity is noticeable though the patient is able to perceive stimuli). This is akin to akinetic mutism of neurological states. Paradoxically in extreme mania too, stuporous immobility can occur. But it is more common in depression. Catatonic excitement is characterised by extreme apparently non-purposeful hyperactivity, which presents as constant motor unrest. Unlike akathisia, this is often dramatic with no subjective component. Mannerisms: Odd, but purposeful movements (hopping, saluting passers-by or mundane movements). They are also known as idiosyncratic voluntary movements though the patient may claim unawareness. These often have a delusional meaning in schizophrenia. They are different from stereotypes as mannerisms appear as goal-directed movements. Mutism is discussed in detail along with speech disorders. Negativism is an extreme form of opposition – see above. Posturing refers to the maintenance of odd and bizarre postures. These might be spontaneously undertaken or derived from an arrested motor activity e.g. posture with swung arms as if one is frozen when walking. This is maintained despite efforts to be moved. It is also called catalepsy. Psychological Pillow: This is an extreme form of posturing. The patient holds their head several inches above the bed while lying and can maintain this uncomfortable posture for long periods of time. Stereotypes are non-goal directed motor activity (e.g., spinning one's hands, repeated touching, patting, rubbing self). These are seen in catatonia and also in pervasive developmental disorder and severe learning disabilities. Non-Catatonic symptoms: Agitation vs. akathisia: Psychotic agitation is very difficult to distinguish from akathisia secondary to antipsychotics. But such distinction is important, as the latter requires a decrease, not increase, in medications administered. Akathisia has a subjective component of restlessness together with objective evidence of unrest; at times one may have to resort to benzodiazepines when the distinction is unclear Some common mannerisms Tiptoe walking Finger to lip moves (‘shushing’) Clicking sounds during speech Odd robotic speech, without contractions (can not instead of can’t) Shrugging Grimacing Parakinesia (contracting entire facial muscles) Tapping, adjusting, saluting © SPMM Course though the dose required to treat one may be different from the dose required for the other. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1289895/ Astasia-abasia: Inability to walk, sit or stand upright without any obvious neurological deficits in motor strength and innervations. It is described that some patients with this syndrome cannot balance themselves upright but can run with a bizarre posture. Occurs as a motor conversion disorder. Blepharospasm is a type of focal cranial dystonia that must not be confused with catatonia. Blepharospasm may be seen in Tardive Dyskinesia. It usually begins gradually with excessive blinking. Initially, episodes are triggered by specific stressors, e.g., bright lights, fatigue, distress etc., and disappear with sleep. Concentrating on a specific task (such as watching TV) often decreases the frequency of the spasms. With time, the spasms may become progressively intense, functionally blinding the patient during each episode wherein the eyelids remain vehemently closed for longer periods. Perseveration: This refers to repeatedly same response – either verbal or motor, when different stimuli are delivered (questions or instructions). Irrespective of changes in stimuli that demand variation in responses, the response here remains the same. It is different from Verbigeration (see below) where verbal repetition occurs spontaneously, not just in response to questions or commands. Also note that perseverative responses are goal directed – they intend to answer a question or carry out an instruction, but stereotypes on other hand are not goal directed. It differs from echo phenomenon; the latter is a copying of other person’s responses, not repeating self-responses. Tics: These are sudden involuntary (but temporarily suppressible) jerking movements often seen in facial and vocal musculatures though it can affect any skeletal muscle group in the body. They typically have a waxing and waning course, worsening with low mood and fatigue and not seen in sleep. Some tics may appear as coordinated complex acts such as grunting, uttering syllables that may amount to coprolalia (obscenities) or echophenomenon. Tics seen in Tourette’s differ from other simple tics in that they are preceded by a palpable urge or prodromal sensation before the motor act. Tics have been conceived to share the pathophysiology of obsessions. Verbigeration: Repetition of phrases or sentences. This occurs spontaneously and without any goal. This should not be confused with echolalia. This is not catatonia. Stereotypy Mannerism Meaningless motor expression Behaviour has a special purpose or meaning Often repetitive Not particularly repetitive e.g. Repeated hand-wringing, or rocking movements e.g. wearing black goggles all the time, Patient cannot explain the behaviour At times, patient can come up with some explanation that may / may not be delusional # 33 - 8. Miscellaneous topics # 8. Miscellaneous topics # 34 - Pathology of familiarity # Pathology of familiarity: # 35 - Memory and dissociation # Memory and dissociation: © SPMM Course 8. Miscellaneous topics Pathology of familiarity: Déjà vu is the feeling of having seen or experienced an event, which is being experienced for the first time. The most consistent finding in the de´ja` vu literature is that the incidence with which it is experienced decreases with age. Brown (2003) estimates that 60% of people have experienced it. De´ja` vu occurs more frequently under stress and fatigue while it declines with age. Reports of de´ja` vu are greater in schizophrenics and temporal lobe (TL) epileptics. This suggests that neurophysiological stimulation or dysfunction of the TL may be involved in de´ja` vu. However, the nature and duration of de´ja` vu in these populations is different to that experienced by the general population, e.g. lasting for hours in schizophrenia and minutes in TL epilepsy, compared to the typical duration of seconds. De´ja` vecu refers to the perception that events happening now have been lived through before. Déjà pensee refers to the pathological familiarity for a thought or idea. Déjà entendu is a pathological familiarity for someone’s voice. Jamais vu is an experience that has been experienced before is not associated with feelings of familiarity. Both can occur in normal people, and also can occur in Temporal Lobe Epilepsy*. Note that some authors (Ellis, Young) include delusional misidentification syndromes with the pathology of familiarity. Memory and dissociation: Confabulation is a falsification of memory occurring in clear consciousness associated with organic states. Suggestibility is a prominent feature of confabulation. It is often described in Korsakov syndrome. There can either be confabulation of embarrassment or of fantastic nature. In pseudologia fantastica, there is fluent plausible lying (falsification of memory), with the statements made extreme and of grandiose nature. Is usually associated with dissocial or histrionic personality disorders. In a dissociative fugue, there is narrowing of consciousness, wandering away from surroundings and subsequent amnesia for the episode. There is marked memory loss and loss of identity, but the patient can carry out complicated patterns of behaviour and is able to look after himself. There is a gross discrepancy between memory loss and intact personality. For some reason, there always seems to be an MCQ on Ganser’s syndrome, considered as a hysterical dissociative disorder. Ganser’s syndrome includes:  Approximate answers  Clouding of consciousness with disorientation  Psychogenic, physical symptoms – analgesia & hyperaesthesia  Pseudohallucinations – not always present.  Patients with Ganser’s syndrome are amnesic for their abnormal behaviour. Couvade syndrome describes a sympathetic pregnancy that affects husbands (rarely other family members) during their wives pregnancies. Most frequent between 3-9 months of pregnancy - it is a # 36 - Depersonalisation # Depersonalisation: © SPMM Course conversion symptom not delusional as the husband does not think he is pregnant! Pseudocyesis is a condition where a woman experiences clinical signs of pregnancy without being pregnant, and the patient is convinced of pregnancy. Koro is a culture-bound anxiety state where the patient believes that his penis is shrinking into his abdomen, and he will die as a result. This is considered to be a desomatization (organ specific depersonalization) experience associated with folk beliefs (hence not a delusion as culturally relevant). It is seen in Malaysia and Singapore. In multiple personality disorders, one-way amnesia is common. (A knows B’s existence, B is not aware). Possession states can occur as a part of dissociation or in normal religious experiences, or under hypnosis. Possession states, where consciousness is preserved, can occur in schizophrenia. Consciousness is altered in dissociative states. Lycanthropy is a form of possession where the patient loses awareness and identity and believes he has been transformed into an animal, usually wolf. Out of body experiences, autoscopy, depersonalisation and transcendental experiences are clustered often in Near Death Experiences. The neurophysiological basis of near death experience (NDE) is unknown. Clinical observations suggest that REM state intrusion contributes to NDE. REM intrusion during wakefulness is a frequent normal occurrence and NDE elements can be explained by REM intrusion. A feeling of impending ego dissolution is noted in LSD intoxication. Depersonalisation: It is the third most common symptom in psychiatric clinics. It is defined as a change in self-awareness and the individual feels as if he is unreal. The ‘as if’ quality differentiates it from psychotic states. When a similar feeling occurs for objects and environment around an individual, it is termed as derealization (Mapother). It is always subjective, unpleasant with affective change invariably, and insight preserved. Emotional numbing, loss of feelings of agency and self-esteem, disturbed body image, altered perception of time, memory and sensory experiences of all modalities are reported. Temporal lobe epilepsy (lasts for minutes), hysterical dissociation, depression, any anxiety state (lasts for seconds) including anankastic personality, using tricyclic antidepressants, hallucinogens and cannabis can cause depersonalisation apart from fatigue or meditation/yoga in normal people. ECT can worsen depersonalisation by unknown mechanisms. In psychiatric population, the affect associated with the experience is extremely unpleasant as opposed to the normal population. The most common psychiatric diagnosis is depression followed by anxiety disorders. Dissociation is only infrequently associated. Depersonalisation is often difficult to distinguish from derealization, and they often occur together though the former being commoner. The patients often do not report the symptom as it is difficult to express. This may be related to the pathology of familiarity wherein familiarity of self being lost. Depersonalisation is associated with déjà vu / jamais vu where place familiarity is error prone. Depersonalisation is frequently situational and almost always episodic. In depersonalisation disorder (classified as a dissociative disorder in DSM 4) the experience lasts for hours. Roth described a PAD – Phobic anxiety depersonalisation syndrome. Typically a married female in thirties with agoraphobia and anxiety – worsens with ECT treatment. This is now relevant only historically. # 37 - Insight # Insight: # 38 - Phenomenology of epilepsy # Phenomenology of epilepsy: © SPMM Course Desomatisation refers to depersonalisation that is localised to a body part. Deaffectualisation is an extreme form of anhedonia wherein not only pleasure but also the capacity to feel any emotion is consistently lost. It is not specific to any organic syndrome. It is never reported in mania. Patients score high on neuroticism with introversion being predominant. Insight: Insight refers to a multidimensional concept which includes 4 A’s:  Awareness of one’s own symptoms (absence - anautognosia)  Attribution of symptoms to mental disorder appropriately (absence – dysautognosia)  Appraisal or analysis of consequences of such symptoms  Acceptance of treatment Insight is not an all or none phenomenon; it fluctuates within an illness for the same patient. More patients with psychoses have poor insight than those with neuroses. Loss of insight is not always related to the presence of delusions; as in manic states even without delusions nearly 50% patients show no insight during the acute episode. This may be different from schizophrenic insight loss that is seen even in the chronic stage. Insight has not been consistently associated with any psychopathology of schizophrenia; some studies show an association with disorganisation symptoms. In depression, insight may be higher than usual, called depressive realism. In acute psychosis presence of insight is associated with more selfharm and suicides. Loss of insight has been compared to anosognosia following stroke. Fronto parietal circuit may play an important role in insight. Levels of insight: 1. Complete denial 2. Slight awareness of being sick but denying it at the same time 3. Awareness of being sick but blaming it on others, on external factors 4. Awareness that illness is caused by something unknown in the patient 5. Intellectual insight: admission that the patient is ill and that symptoms or failures in social adjustment are caused by the patient's own particular irrational feelings or disturbances without applying this knowledge to future experiences 6. True emotional insight: emotional awareness of the motives and feelings of the patient and the important persons in his or her life, which can lead to basic changes in behaviour. Phenomenology of epilepsy: Temporal lobe epilepsy TLE:  Autonomic sensations are the most common of auras, causing epigastric aura, salivation, sometimes vertigo, etc.  Forced thinking The individual has a compulsion to think on a certain restricted topic.  The evocation of thought: Intrusion of stereotyped words or thoughts. © SPMM Course  Sudden obstruction to thought flow similar to schizophrenic thought block is also reported.  Panoramic memory: Here the individual recalls expansive memories in incredible detail as if running a video show of the past.  Psychic seizures: Isolated auras with hallucinations, depersonalization, micropsia or macropsia, déjà vu or jamais vu (especially if right sided origin) can occur.  Uncinate crises: Hallucinations of taste and smell of uncinate origin associated with dream-like reminiscence and altered consciousness.  Strong affective experiences are reported – fear and anxiety being very common. Dostoevsky’s epilepsy refers to ecstatic content in the epileptic aura. TLEs are the most common seizures with auras. The term complex partial seizure refers to TLE generally. Parietal lobe epilepsy: Somatosensory seizures: The most common type of seizure in parietal epilepsies - patients describe physical sensations of numbness and tingling, heat, pressure, electricity and/or pain. Some patients describe a typical “Jacksonian march”, in which the sensation “marches” in a predictable pattern from the face to the hand up the arm and down the leg. Pain is a rare symptom of seizures as such but is quite common in parietal seizures, occurring in up to 25% of patients. Somatic Illusions: During a somatic illusion patients may feel that their posture is distorted, that their arms or legs are in a weird position or are in motion when they are not (kinaesthetic hallucination), or that a part of their body is missing or feels like it does not belong (body image distortion). Vertigo is also reported. Visual illusions: Patients may experience objects as being too close, too far, too large, too small, slanted, moving or otherwise not right. Frontal lobe seizures: Complex partial seizures of frontal lobe origin are usually quite different from temporal lobe seizures. Frontal lobe seizures tend to be short (less than 1 minute), occur in clusters and during sleep, include strange automatisms such as bicycling movements, screaming, or even sexual activity. Sometimes a person may remain fully aware at the same time having wild movements of the arms and legs. A seizure from the frontal lobe may even involve laughing or crying as the only symptom, the former is called gelastic and the latter dacrystic seizures. These are also noted in temporal lobe seizures. Automatisms: Epileptic automatism is a state of clouding of consciousness which occurs during or immediately after a seizure. The impairment of awareness varies. The individual retains control of posture and muscle tone but performs simple or complex movements without being aware of what is happening. To the onlooker, the patient appears confused, and there is subsequent amnesia for the episode. Simple stereotyped behaviours (gesturing, grasping, lip-smacking and chewing movements) are often exhibited lasting few seconds to minutes. Very occasionally, automatisms are prolonged (fugue © SPMM Course states), or complex actions are carried out. If violent, these are never premeditated, seldom goal-directed, rarely involve the use of complex tools/weapons and are especially likely if restraining was attempted. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information. © SPMM Course Notes produced using excerpts from:  Andreasen N, Powers P. Overinclusion thinking in mania and schizophrenia. Br J Psychiatry 1974; 125:452456. 24.  Andreasen, N. C. (1979) Thought, language, and communication disorders: I. Clinical assessment, definition of terms, and evaluation of their reliability. Archives of General Psychiatry, 36, 1315-1321  Appelbaum, P.S. et al., Persistence and stability of delusions over time, Compr. Psychiatry 45 (2004), pp. 317–  Blackwood, N et al. Cognitive Neuropsychiatric Models of Persecutory Delusions. Am J Psychiatry 2001 158: 527-539  Bschor T, et al. Time experience and time judgment in major depression, mania and healthy subjects. A controlled study of 93 subjects. Acta Psychiatr Scand. 2004; 109:222–229.  Coltheart, M et al Schizophrenia and Monothematic Delusions. Schizophrenia Bulletin 2007 33(3):642-647  Ghaemi, N. Feeling and Time: The Phenomenology of Mood Disorders, Depressive Realism, and Existential Psychotherapy. Schizophrenia Bulletin, 2007; 33:122–130.  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007  Liddle PF, Crow TJ: Age disorientation in chronic schizophrenia is associated with global intellectual impairment. Br J Psychiatry 1984; 144:193–199  Lincoln, T. Relevant dimensions of delusions: Continuing the continuum versus category debate. Schizophrenia Research 2007, 93, 211-220.  Cermolacce, L. Sass, and J. Parnas, “What is Bizarre in Bizarre Delusions? A Critical Review,” Schizophr Bull 36, no. 4 (July 1, 2010): 667-679  Manschreck, T. C. (1995). Pathogenesis of delusions. Psychiatric clinics of North America, 18, 213  Nordgaard, J., et al. The diagnostic status of first rank symptoms. Schizophrenia Bulletin 2008 34(1):137-154  Palaniyappan, L. The Schizophrenic Disguise of Complex Partial Seizures. J Neuropsychiatry Clin Neurosci 2007 19: 479-480.  Schiltz, K et al. Neurophysiological Aspects of Synesthetic Experience. J Neuropsychiatry Clin Neurosci 11:58-65, February 1999  Sims, A (2003) Symptom in the Mind, 3rd ed. London: Elsevier Science  Swedo SE, et al. Obsessive-Compulsive Disorder in children and adolescents: Clinical phenomenology of 70 consecutive cases. Arch Gen Psychiatry 1989;46:335-41  Taylor M, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry 2003; 160:1–9  Scott, A. I. F. (1998). Mental State Examination. In Companion to psychiatric studies (eds E. C Johnstone, C.P.L Freeman, & A.K.Zealley) Chapter 9. Churchill Livingstone, Edinburgh.  http://www.med.nyu.edu/cec/epilepsy  Levenson, D. Psychiatric issues in surgery. Primary Psychiatry (2007). http://primarypsychiatry.com/psychiatric-issues-in-surgery-a-part-2-specific-topics/ # 18 - 523_Dynamic_Psychopathology # 01 - 1. Defence mechanisms # 1. Defence mechanisms # 02 - How is a defence mechanism formed # How is a defence mechanism formed? # 03 - Mature defences # Mature defences: © SPMM Course 1. Defence mechanisms Defence mechanisms are not descriptions; they are explanations for certain human behaviour and experiences. Hence they are a part of explanatory psychopathology. These defences operate both in normal individuals and under pathological conditions. Anna Freud organised Freudian defences; Klein and later contributors added some more defence mechanisms. Vaillant (1977) classified them and categorised them to mature, immature and neurotic defences. Kleinian defences are sometimes called as psychotic defences. Using a narrow repertoire of defences repeatedly and repeated use of immature or neurotic defences may be associated with disease states or traits. How is a defence mechanism formed? Mature defences: SASHA is a mnemonic for the mature defences. Altruism: Using constructive and gratifying service to others to receive a vicarious satisfaction. This does not involve giving up one’s pleasures. Altruism is distinguished from altruistic surrender, in which surrender of direct gratification of instinctual needs takes place to satisfy the needs of others to the detriment of the self. Wish or Impulse Wish or Impulse Prohibitions (moral, social or legal) Prohibitions (moral, social or legal) Signal Anxiety Signal Anxiety Defence operation Defence operation Symptoms formed Symptoms formed © SPMM Course ALTRUISM Conflict Result Process ‘Defeat’ in a situation Unconditional offer of help Replaces aggression and competition by support: Achieve vicarious satisfaction Humour: Here comedy is used to express feelings and thoughts overtly without personal discomfort and without producing an unpleasant effect on others. It allows the person to tolerate and yet focus on troublesome aspects. HUMOUR Conflict Result Process Failure, loss or destruction of belongings Highlighting amusing aspects of threat signals or outcome Anxiety converted to comedy or irony Anticipation: Here one plans realistically for future inner discomfort and expects worse to occur with mental preparation. Note that anticipation without specific target or goal is nothing but freefloating anxiety and this is not helpful; Anticipation mechanism is goal-directed and implies careful planning for potential difficulties. ANTICIPATION Conflict Result Process Sudden threat event Predicting probabilities and planning countermeasures Matching events and coping resources to achieve a sense of control Sublimation: Achieving impulse gratification but only after altering a socially objectionable impulse to a socially acceptable one. Sublimation allows instincts to be channelled, rather than blocked. SUBLIMATION Conflict Result Process Unacceptable impulses Socially acceptable behaviour Rechanneling impulses into acceptable expressions Suppression: Consciously or semiconsciously postponing attention to a conscious impulse or conflict. Issues may be deliberately cut off, but they are not avoided. Discomfort is acknowledged but minimized. ALTRUISM Conflict Result Process # 04 - Neurotic defences # Neurotic defences: © SPMM Course Painful event or sexual impulse Postponement of painful problems and feelings Intentional blocking of recall (this is NOT unconscious forgetting – contrast from repression) Neurotic defences: Neurotic defences act at the level of mental inhibition. As a result the patient is deprived of some degree of freedom in decision-making, but retains insight. Displacement: The process by which interest and/or emotion is shifted from one object onto another less-threatening, often less-retaliating one. For example one who is told off by her consultant during clinical supervision may displace the anger felt onto her spouse or dog (though the reaction may be extremely different from these two objects!) DISPLACEMENT Conflict Result Process Fear/threat by an object; love or hate for an object Expression of love/hate/anger or fear against an unprovoking stimulus (clinically: phobias) Transfer of feelings from one object to a substitute Dissociation: Temporarily but drastically modifying one's sense of personal identity to avoid emotional distress. Fugue states and hysterical conversion reactions are common manifestations of dissociation. Dissociation may also be found in counter-phobic behaviour; here a person with fear of heights takes up parachute diving and experiences dissociation during the act. DISSOCIATION Conflict Result Process Promiscuous, hostile or irresponsible behaviour (clinically: Multiple personalities, fugue, amnesia) Temporary alteration of identity including consciousness, memory and perception. Isolation: Splitting or separating an idea from the affect that accompanies it normally but is now repressed. Noted in OCD. ISOLATION Conflict Result Process Painful emotions or memories Talking about emotional events without feeling (clinically: obsessions) Separate content from affect, remove affect completely Rationalisation: Offering rational explanations in an attempt to justify attitudes, beliefs, or behaviour that may otherwise be unacceptable. Such underlying motives are usually instinctually © SPMM Course determined. It often involves finding excuses that will justify unacceptable behaviours when selfesteem is threatened, often seen in teenagers and those who abuse alcohol and drugs. RATIONALISATION Conflict Result Process Low self-esteem along with socially unacceptable behaviours Self-serving explanations and justification of behaviours False but socially acceptable explanations are offered for unacceptable behaviours Reaction formation: This involves transforming an unacceptable impulse into its exact opposite. Reaction formation is characteristic of obsessional neurosis, but it may occur in other forms of neuroses as well. If this mechanism is frequently used at any early stage of ego development, it can become a permanent character trait, as in an obsessional personality. REACTION FORMATION Conflict Result Process Feelings of hostility and disinterest Devotion, self-sacrificing behaviour, cleanliness, correctness Substituting wishes/feelings that are exactly opposite to true feelings Repression: This refers to expelling or withholding from consciousness an idea or feeling. Primary repression refers to the curbing of ideas and feelings before they have attained consciousness: secondary repression excludes from awareness what was once experienced at a conscious level. Note that this differs from suppression – suppression is mere postponement not the loss of thoughts from conscious perception. Repression is the primary defence. Other defences reinforce it. REPRESSION Conflict Result Process Threatening feelings / memories/ fears Gaps in memory; often unnoticed Banning thoughts and feelings from recall; subject unaware (not conscious) Intellectualisation: This refers to excessively using intellectual processes to avoid affective expression or experience. Here the needless emphasis is focused on the inanimate to avoid intimacy with people; attention is paid to external reality to avoid the expression of inner feelings, and irrelevant details are emphasised to avoid perceiving the whole. Intellectualization is closely allied to rationalization but unlike rationalisation, intellectualisation is not an attempt to substantiate one’s instinctual impulses. © SPMM Course INTELLECTUALISATION Conflict Result Process Disturbing feelings and thoughts (‘dissonance’) Abstract thinking, doubting, indecisiveness, generalizations Removing personal and emotional components of an event and focusing only on factual aspects Intellectualisation Rationalisation No instinctual impulses/drives involved Instinctual impulses/urges involved Avoid experience of unpleasant affect Might experience the affect, but attempts to reduce the impact Deals with inanimate objects i.e. emphasize details and facts instead of feelings Provides ‘excuses’: e.g. alcohol, teenage conduct Identification with the aggressor: Observed where the victim of aggression begins to assume the qualities of the proponent of aggression. IDENTIFICATION WITH THE AGGRESOR Conflict Result Process Sexual threat or life / limb threatening violence Perpetrates violent acts Identify with aggressor, may reduce direct resistance and aid in survival during acute trauma Undoing: This is seen in OCD and is associated with magical thinking and rituals. A student might think that if he taps his table three times before the start of his exam, he will surely succeed! UNDOING Conflict Result Process Sadistic wishes, unacceptable impulses Superstitions (compulsive behaviour clinically) Symbolic negating of an impulse # 05 - Narcissistic defences # Narcissistic defences: © SPMM Course Repression Dissociation Information is stored in the unconscious in archaeological way – at various depths. Information is stored in a horizontal fashion; all units are equally accessible to retrieval. Motivated forgetting underlies repression Amnestic barriers maintain dissociation Information is scattered across time e.g. Dynamic conflicts. Information is discrete and delimited in time Information is transformed and disguised Untransformed storage Uncovering requires repeated trials with later interpretation Direct retrieval e.g., hypnosis Interpretation and working through transference is needed in therapy Integration of memories and working through traumatic events is required in therapy Narcissistic defences: Projection and denial are often called narcissistic defences though some authors may dispute this and regard them as immature defences. Projection: This refers to perceiving and reacting to unacceptable inner impulses as though they originated outside the self. For example, the person who attributes hostility to others may be unconsciously projecting their own hostility. Thus, internal threats become externalised and then are easier to handle. PROJECTION Conflict Result Process Hostility, unacceptable wishes Ideas of reference, prejudice, suspiciousness, injustice Attributing one’s own feelings to be coming from others Denial: It is the explicit refusal to acknowledge a threatening reality. It may persist despite constant explanation of the facts. It is not same as conscious avoidance of painful topics or thoughts. DENIAL Conflict Result Process Painful reality Stubborn and angry negation of reality that is visible to onlookers Refusal to acknowledge the awareness of reality; disavow problems at unconscious level # 06 - Kleinian defences # Kleinian defences: © SPMM Course Kleinian defences: (SIPDOG – splitting, introjection, projective identification, denial, omnipotence, grandiosity) Splitting: It is seen most often in those with borderline personality. Here qualities of an object or person are split into black and white i.e. either good or bad with no grey area in between. SPLITTING Conflict Result Process Overwhelming experience of negative qualities of oneself or positive qualities of others Idealization alternating with devaluation (denigration) Stripping off either all positive or all negative qualities of others Idealisation and denigration: These two are often accompanied by splitting in those with borderline traits. Here an object is either glorified, and supremacy is ascribed (idealised, omnipotence ascribed) or considered very negatively and cursed! (Denigration). Psychiatrists are treating such patients often experience phases of both idealisation and denigration. Projective identification: It is a Kleinian defence. Here an aspect of self is projected onto someone else. The projector influences the recipient to identify with what has been projected and projector herself now believes that the aspect originated from the reactor. This may result in the recipient behaving in a manner similar to the projector. Now the projector identifies his feelings as reactions to the recipient’s aggression (identification of the origin, but wrongly attributed to the other person). (Please read psychoanalytic psychology for further explanation). It may be seen in psychotic paranoid states. PROJECTIVE IDENTIFICATION Conflict Result Process Hostility, hate and anger Ideas of reference, prejudice, suspiciousness, injustice Converting own hostile impulses to justifiable reactions to the hostility expressed by others Ogden’s model divides projective identification into three steps.  Step 1 is the projection of a part of oneself onto an external object. Step 1a is the blurring of self and object representations (may or may not be seen).  Step 2 is an interpersonal interaction in which the projector actively pressures the recipient to think, feel, and act in accordance with the projection.  Step 3 is the reinternalization of the projection after the recipient has psychologically processed it Note that step 3 is absent while step 2 is not necessary to define ‘projection’. Projective identification has manifold aims: – It may be directed toward the ideal object to avoid separation, or it may be directed toward the bad object to gain control of the source of danger. # 07 - Immature defences # Immature defences: © SPMM Course – Various parts of the self may be projected, with various aims: bad parts of the self may be projected in order to get rid of them as well as to attack and destroy the object, good parts may be projected to avoid separation or to keep them safe from bad things inside or to improve the external object through a kind of primitive projective reparation. Introjection: This involves internalizing the qualities of an object. It is seen in normal development too. INTROJECTION Conflict Result Process Need for gratification Accusing others of causing distress Internalising the qualities observed in an external ‘object’ e.g. mother, friend, etc Omnipotence: Original Freudian description pertains to the belief that one can transform or influence the external world through one's thoughts alone. Seen in OCD (e.g. a woman with depressive obsessions says ‘I keep getting thoughts that something might happen to my baby: I am distressed because I think something will actually happen due to these thoughts’). OMNIPOTENCE Conflict Result Process Helplessness Obsessions, narcissistic features Attaching great value (‘power’) to thoughts and believing they can influence external objects Grandiosity: Klein’s description pertains to manic defence, closely associated with narcissism. See the box below for Kleinian definition GRANDIOSITY Conflict Result Process Inferiority feelings, guilt Self-glorification, presumption and entitlement Converting inferiority to superiority feelings Immature defences: These are mostly normal in early phases of development and do not essentially convey abnormality. Acting out: This refers to the expression of an unconscious wish or impulse through action to avoid being conscious of an accompanying affect. The unconscious fantasy is lived out impulsively in behaviour, thereby gratifying the impulse instead of prohibiting it. ACTING OUT Conflict Result Process © SPMM Course Sexual and aggressive impulses Violence, stealing, rape, lies Non-reflective and uncontrolled wish-fulfillment Passive aggression: Expressing aggression towards authorities indirectly through passive obstructive activities. For example to ‘defeat’ one’s boss, one may involve in procrastination, and take sick leave that affects the boss more than oneself. PASSIVE AGGRESSION Conflict Result Process Resentment, hostility, low selfesteem Procrastination, loss of followthrough Expression through inactivity Somatisation: Converting psychological states and tension to bodily symptoms. SOMATISATION Conflict Result Process Threat or unidentified fear Bodily Complaints Converting mental tension to physical symptoms Regression: Moving back into childish or earlier developmental phase to avoid confronting a conflict. Regression is also considered an essential concomitant of the creative process. REGRESSION Conflict Result Process Threat or humility Childish, immature behaviour Moving back to earlier developmental stages (seen during normal development too) Somatosensory Amplification: The tendency to experience bodily sensations as unusually intense or distressing, and this is thought to underpin somatisation and the somatoform disorders. SOMATOSENSORY AMPLIFCATION Conflict Result Process Threat or fear unidentified Bodily complaints, fear of catastrophic illness Oversensitivity to innocuous bodily features # 08 - Defences and disorders # Defences and disorders © SPMM Course Defences and disorders Disorder Defenses commonly used Alcoholism Denial, rationalization Anorexia Denial, rationalization Borderline Splitting, idealization, denigration, projection, dissociation, acting out Depression Regression Dissocial personality Acting out Fugue or amnesia Dissociation Hysteria Repression, conversion OCD Isolation of affect, undoing, reaction formation, magical thinking Paranoid delusions Projection Phobia Displacement, avoidance Schizoid personality Fantasy, avoidance Somatoform disorders Somatisation Narcissistic personality Projection, splitting # 09 - 2. Dynamic models of the mind # 2. Dynamic models of the mind: # 10 - Topographical theory # Topographical theory # 11 - Problems with topographic theory # Problems with topographic theory: © SPMM Course 2. Dynamic models of the mind: Topographical theory This was elaborated in The Interpretation of Dreams in 1900. Here, the mind is divided into three regions: the conscious system, the preconscious system, and the unconscious system. The functions of these regions are based on one of the two principles. The Pleasure Principle is the innate tendency to avoid pain and seek pleasure. The reality principle is a learned function, which requires delay or postponement of wish fulfillment according to environmental reality. The conscious system  Receives and process information from the outside world.  Its contents are communicated via speech and behaviour.  Attention cathexis refers to the investment of psychic energy on a particular idea or feeling to process it consciously.  Operates secondary process thinking mainly. The unconscious system:  Contains the contents of censored or repressed wishes, etc.  Characterized by primary-process thinking,  Governed by the pleasure principle.  Shift of cathexis happens very often and quickly  Evident via parapraxes (Freudian slips) and dreams. The preconscious system:  As and when needed service  Interfaces with both unconscious and conscious - contents of unconscious become conscious by ‘squeezing’ through the preconscious  Maintains the ‘repressive barrier’ to censor unacceptable wishes and desires (not the repressed contents). Problems with topographic theory: When someone employs defense mechanisms such as displacement, repression etc., he or she are not aware of the process of this defense. Hence, these cannot be represented by preconscious as Freud thought – as preconscious is available to conscious as and when needed. An unconscious need for punishment was frequently noted among Freud’s patients – topographical theory fails to explain this. # 12 - Instinctdrive theory # Instinct/drive theory # 13 - Hierarchy of anxiety # Hierarchy of anxiety # 14 - Analytical Psychology (Jungian Model) # Analytical Psychology (Jungian Model) © SPMM Course Instinct/drive theory This theory has derived most of its terms from biology. Drive and instinct are often used interchangeably. An instinct has four principal characteristics: source, impetus, aim, and object.  Source – part of body where instinct originates from  Impetus - intensity/force of the instinct.  Aim - action directed towards the discharge of energy/tension  Object - the target for action. Dual instinct theory holds that sexual energy and aggressive energy are the dual instincts. Libido is the force by which the sexual instinct is represented in the mind. It can also be considered as a part of Eros. Aggression is an instinct with destruction as aim and originates in skeletal muscles. It can also be considered as part of Thanatos (see below) Eros and Thanatos are life and death instincts respectively. According to Freud, the dominant force in biology is Thanatos. Hierarchy of anxiety  Signal anxiety – unconscious perception of external or internal threat leads to resource mobilization and aversion of threat. This forms the basis of defence mechanisms discussed earlier.  Disintegration / annihilation anxiety - concerns about fusion with an external object.  Stranger anxiety – around 7-9 months age  Separation anxiety – when mother is recognized as independent object  Fear of object loss / loss of love – especially in girls at phallic stage  Castration anxiety  Superego anxiety – mature form of anxiety – id vs. ego conflicts. Analytical Psychology (Jungian Model)  Jung founded analytic psychology. His construct of psychic apparatus is shown in the figure.  Collective unconscious (CU) – all mankind’s collective symbolic past. (Something like a DNA in psychoanalytical terms!). This must be differentiated from the personal unconscious (PU), which is same as Freudian unconscious, a collection of repressed © SPMM Course individual memories.  Archetypes – part of CU. Includes representational images with universal symbolic meaning (e.g. Hero, Old Wise Man, Tree, etc.)  Complexes – part of PU and are stimulated by interpersonal interactions. Feeling toned ideas are developing as a result of the interactions of complexes with archetypes.  Persona – mask covering one’s personality – presented to outside world  Anima – unconscious feminine aspect of a man  Animus - unconscious masculine aspect of a woman  Shadow – an archetype - a personification of unacceptable aspects of oneself symbolized as a dark internal alien.  Individuation – ultimate goal of life where an individual develops a sense of self- identity  Introduced terms extraversion and introversion # 15 - 3. Dynamic interpretation of dreams # 3. Dynamic interpretation of dreams © SPMM Course 3. Dynamic interpretation of dreams Freud was initially trained as a neurologist. Joseph Breuer & Freud together treated Bertha Pappenheim, (Anna O.), after which hypnosis became a psychoanalytic technique. Freud later used the cathartic method of abreaction - the process of recovering and verbalizing suppressed feelings that cause the symptoms. However, Freud encountered patients who could not recall significant memories – he called this resistance. He later proposed resistance to being caused actively by largely unconscious forces involved in repression - which leads to symptom production. This made him abandon abreaction/catharsis and pursue free association – where patients are allowed to ‘speak their mind’ without censor. Patients often reported their dreams during free association - Freud noted that dream content was related closely to repressed memories and unconscious. Freud declared dreams were the ‘royal road to the unconscious’. According to his wish fulfillment theory, dreams are attempts to fulfill unconscious wishes in a surrogate manner. The content of dreams may include nocturnal sensory stimuli (e.g. thirst, hunger, etc.), the daytime residue (thoughts and ideas from waking life), and repressed impulses. Freud distinguished two types/layers of dream content - manifest content refers to what is recalled by the dreamer; latent content refers to unconscious thoughts and wishes that threaten to awaken the dreamer. The unconscious mental operation by which latent content is transformed into manifest content is called the dream work.  Condensation - several unconscious impulses are combined into a single image in the manifest dream content. e.g., One’s father and the horrible teacher may be unified and occur as a single dreadful monster in a child’s dream.  Irradiation or diffusion – this is the converse of condensation where multiple images in dreams represent one unconscious impulse  Displacement refers to the transfer of energy from an original object to a symbolic representation of the object. It is not the mere formation of alternate substitute but includes transfer of affective energy on that substitute – cathexis.  Symbolic representation - highly charged objects or abstract concepts could be represented by using innocent images that were in some way connected with the original object. e.g., a dream of intense dancing may represent one’s desire to attract a colleague sexually.  The mechanisms of condensation, displacement, and symbolic representation characterize the primary process thinking that defies logic, lacks a sense of time and space, can accept © SPMM Course Notes produced using excerpts from  Casey, P. & Kelly, B. (Ed) Fish’s Clinical Psychopathology. 3rd ed. RCPsych publications.  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007  Vaillant GE. Adaptation to Life. Boston: Little, Brown; 1977  http://www.eric.vcu.edu/home/resources/pipc/Other/Personality/Table_Defenses.pdf  Semrad E: The operation of ego defenses in object loss. In The Loss of Loved Ones, DM Moriarity, editor. Charles C Thomas, Springfield, IL, 1967; the presence of contradictory items simultaneously, and often incoherent. (This primary process thinking is the modus operandi for Id – refer below).  A more mature aspect of the ego helps to organize primitive aspects of dreams more coherently; this is called secondary revision. The process by which secondary revision occurs is called secondary process – this is logical, with intact time and space boundaries and is mature.  According to Freud, anxiety dreams reflect a failure in the protective function of the dream-work mechanisms.  Punishment dreams defy wish fulfillment theory – Freud explained that these dreams existed as a compromise between conscience and repressed wish. The wish for punishment is supposed to exist as an unconscious wish. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information. # 19 - 527_Rating_Scales # 01 - 1. General principles # 1. General principles © SPMM Course 1. General principles Rating scales give clinicians an objective benchmark to support critical treatment decisions. Regular use of rating scales can provide information that aids in diagnosis, prognosis and therapeutic monitoring. Further, when self-report scales are used, an item-by-item analysis can help to identify the exact symptoms that a patient considers most troublesome and challenging so they can be targeted during the consultation process. Rating scales can be used for (1) screening for the presence of a psychiatric condition (2) diagnosis of a psychiatric illness (such scales are often termed diagnostic schedules) (3) estimating severity of various conditions and their response to treatment (4) assess functional capacity and well-being. Rating scales can be either self-rated or observer rated. Some observer-rated scales require clinical experience (clinician-rated) while trained non-clinical personnel can use others. Self-rated Observer rated Beck’s Depression Inventory Zung Depression Inventory Symptoms checklist SCL GHQ Lunser’s (extrapyramidal) Edinburgh postnatal depression scale Dementia scales PANSS BPRS HAMD MADRS YBOCS SCID Scales are based on psychometric properties; aim to measure dimensions of psychopathology (symptoms) often at the present state (the duration of which is defined variously). Schedules are based on clinical expectations; deal with categories of disorders (syndromes) based on known classification systems. A schedule may be devised to focus on either past or present status or both. Two types of procedures are used when selecting items (symptoms) for scales. The first method is based on the previous clinical literature to determine the appropriate items. The second method is based on calibration. In this method, a large number of questions are tested to find the most discriminating items between a ‘known ill’ and a ‘presumed well’ group. The items that are most significant in a statistical sense are chosen to represent the scale that is devised. Considerations for selecting a screening measure for use in a study include  Characteristics of the population to be screened,  Psychometric properties of the instrument,  Time required to complete the measure,  Ease of use, and  Cost of obtaining the measure © SPMM Course General Health Questionnaire is an all-purpose screening tool that is often used as a first-level assessment instrument in epidemiological studies before detailed diagnostic schedules are employed.  Goldberg introduced the General Health Questionnaire (GHQ)  GHQ was developed as a screening tool to detect those likely to have or be at risk of developing psychiatric disorders  It is available in a variety of versions using 12, 28, 30 or 60 items, the 28-item version is used most widely.  Each item is scored as a 4 point Likert (0-3) allowing a total possible score on the GHQ 28 of 0 to 84.  Using alternative binary scoring method (with least symptomatic items scoring 0 and the most symptomatic items scoring 1), the 28- and 30-item versions classify any score exceeding the threshold value of 4 as achieving ‘psychiatric caseness’. The caseness threshold is 3 for the 12-item version. Psychiatric caseness is a probabilistic term—whereby, if such respondents presented in general practice, they would be likely to receive further attention.  It should be noted that the GHQ is not usually used for predictive purposes.  Reliability coefficients have ranged from 0.78 to 0.95 in various studies. # 02 - 2. Diagnostic schedules # 2. Diagnostic schedules © SPMM Course 2. Diagnostic schedules Scale Mode of administration Features Clinical Interview Schedule (CIS) Clinician administered – fully structured. A revised version for lay interviewers also available (CIS-R). Used in National Psychiatric Morbidity Surveys of Great Britain. Developed by Goldberg et al. Aims to identify common disorders found in primary care & community settings (focus on neurotic conditions). Composite International Diagnostic Interview (CIDI) Clinician administered CIDI was an improvised schedule that incorporated principles of both PSE and DIS. It was produced by WHO to be used with both ICD and DSM diagnoses. Diagnostic Interview Schedule (DIS) Non-clinicianadministered; fully structured interview. Used in ECA study. Lifetime DSM diagnoses made initially; later a time period can be specified for ‘current diagnoses’. Hopkins Symptom Check List (HSCL) Trained primary care workers (HSCL-25) or self-reported (original) HSCL has a 58 items self-report version that measures ‘neurotic’ symptom distress in outpatients (somatisation, OCD symptoms, interpersonal sensitivity, anxiety and depression) and a 25 item objective version that measures symptoms of anxiety (10 items) and depression (15 items). SCL-90R and Brief Symptom Inventory (BSI) are derivatives of HSCL. Patient Health Questionnaire (PHQ) Self-report scale It is the self-report version of Primary Care Evaluation of Mental Disorders (PRIME-MD) developed by Spitzer et al. on the basis of DSM-III. Aims to diagnose common neurotic conditions in primary care settings. PHQ-9 is a derivative that focuses on the 9 depression criteria in DSM-IV. GAD-7 on anxiety and PHQ-15 on depression with somatic features. Present State Examination (PSE) Clinician-administered semi-structured clinical interview Provides clinical diagnoses in the lines of ICD system. CATEGO is the computerize version of PSE schedule. Schedule for Affective Disorders and Schizophrenia (SADS) Clinician-administered semi-structured Covers all major mental illnesses (depression, bipolar disorder, schizophrenia and anxiety disorders). A regular, a lifetime and a change version are available. A children version called Kiddie-SADS is also available. Schedule for Assessment in Neuropsychiatry (SCAN) Semi-structured interview for use by trained clinicians Developed by Wing et al. on the basis of PSE and has replaced PSE at present. Focused on adult psychopathology. Extensive (28 sections and 1872 items in total, but many can be skipped) Structured ClinicalInterview for DSMIV (SCID) Clinicianadministered semistructured To be used for patients in whom a psychiatric diagnosis is suspected. Non-patient version available for epidemiological studies. SCID-II is available for axis 2 disorders. © SPMM Course Some general observations on diagnostic schedules currently available in psychiatry 1. Most schedules are either DSM or ICD based; only a few cater both simultaneously. 2. A number of primary-care oriented schedules focus largely on nonpsychotic disorders 3. Many schedules have computerized forms; nevertheless a number of them are timeconsuming to complete routinely or during initial clinical contact. 4. Almost all of them are clinician-administered though self-report forms have evolved in recent times. # 03 - 3. Depression rating scales # 3. Depression rating scales: © SPMM Course 3. Depression rating scales: 2 Questions scale (also called PHQ-2): An affirmative response to the following two questions may be as effective as using longer screening measures or may indicate the need for the use of more in-depth diagnostic tools: (1) "Over the past two weeks, have you ever felt down, depressed, or hopeless?" and (2) "Have you felt little interest or pleasure in doing things?" HAMD/HDRS – Hamilton depression rating scale:  Observer rated.  17 – 21 items- 2 versions  Refers to last 1-2 weeks  More items for biological features  Remains a reference standard MADRS – Montgomery-Asberg Depression rating scale:  10 items version  Most sensitive to change  Requires clinical interview like HDRS BDI – Beck depression inventory:  Self-rating 21 items  Max score 63  Last 2 weeks profile  0-13 minimal; 14-19 mild; 20-28 moderate; >28 severe  Lacks discriminatory power among very severely ill  More psychological than somatic factors included  Can be repeated at short intervals Zung Depression Inventory:  20 items  Self-rated  Avoids imbalance towards psychological factors seen in Beck’s  Poor correlation with observer rating  Insensitive to change Visual Analogue Scale (VAS)  Easiest way to quantify depression severity  10cm line where patient indicates the state of mood © SPMM Course Depression screening in special cases: Children with depression  Depression screening for children and adolescents are generally appropriate in children who are at least seven years of age. Reynolds Child Depression Scale and the Children's Depression Inventory (full version with 27 items; screening version with 10 items) were developed specifically for children and are written at lower reading levels. Measure Age appropriateness (years) Children's Depression Inventory (CDI) 7 to 17 Center for Epidemiological Studies-Depression Scale for Children (CES-DC) 12 to 18 Center for Epidemiological Studies-Depression Scale (CES-D) 14 and older Reynolds Child Depression Scale 8 to 12 Reynolds Adolescent Depression Scale 13 to 18 Beck Depression Inventory (BDI) 14 and older Mood and Feelings Questionnaire (MFQ) 8 to 18 Adapted from an online version at www.aafp.org/afp/20020915/contents.html.  Advantages of the BDI and CES-D include ease of scoring, low-cost, and comparable psychometric properties.  MFQ is endorsed by the NICE and has a self and a parent-rated versions. Perinatal depression:  The BDI, CES-D, and Edinburgh Postnatal Depression Scale (EPDS) have been used to screen for depression in women during the antepartum and postpartum periods.  The BDI and CES-D tend to produce higher scores and more false-positive results in symptomatic pregnant women.  Edinburgh Postnatal Depression Scale was specifically developed for assessing postpartum depression and relies much less on somatic questions.  Questions on the Edinburgh scale (10 items, can be self or clinician-rated) are framed within the "past seven days", and the response format is frequency-based.  Routine use of EPDS during the postpartum period has been shown to increase the detection of postpartum depression compared with usual care. Geriatric depression:  The GDS – Geriatric depression scale was specifically developed for use in geriatric patients, and it contains fewer somatic items. Questions pertain to symptoms within the past week, and responses require only a "yes" or ‘no’.  In patients who have cognitive deficits, interviewer-administered instruments such as the Cornell Scale for Depression in Dementia or the Hamilton Rating Scale for Depression are preferred. © SPMM Course  The Cornell measure should be administered to the patient's primary caregiver.  The Brief Assessment Schedule Depression Cards (BASDEC) system is designed for general hospital use and eliminates the likelihood of questions being overheard on geriatric wards. Patients choose answers from a deck of 19 cards presented one at a time. Depression in schizophrenia:  Most depression scales are tuned to assess depression in nonpsychotic patients.  These scales contain items, which do not distinguish depressed from nondepressed psychotic patients (e.g. delusions of nihilism that can be present in psychosis in the absence of depression).  Calgary Depression Scale for Schizophrenia (CDSS) focuses on symptoms of depression in the presence of schizophrenia. # 04 - 4. Alcohol rating scales # 4. Alcohol rating scales: © SPMM Course 4. Alcohol rating scales: CAGE Questions: 1. Have you ever felt like cutting down on your drinking? 2. Have people annoyed or criticized you for drinking? 3. Have you ever felt bad or guilty about your drinking? 4. Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (eye-opener)? A positive answer should raise suspicion of an alcohol problem, and a score of 2 is highly suggestive. The instrument takes less than a minute to administer. AUDIT: Alcohol Use Disorders Identification Test; Saunders et al., 1993: This is a 10-item questionnaire, covering quantity, frequency, inability to control drinking, withdrawal relief, loss of memory, injury and concern by others. A score of 8 or more indicates that the person is drinking to a degree that is harmful or hazardous, whereas a score of 13 or more in women and 15 or more in men is indicative of dependent drinking. It is widely used and recommended by WHO for primary care use. MAST: Michigan Alcohol Screening Test (Selzer, 1971): This is a simple, self-report, 25-item test, which has yes/no answers. A score of 3–5 is an early indicator of a problem drinker, whereas someone who scores 6 or more is highly likely to be a problem drinker. There are variants on this test, e.g. the Brief MAST, which can discriminate problem drinkers from nonproblem drinkers on the basis of 10 items only. There are also a G-MAST and a Brief G-MAST for older people with slightly different phraseology. CIWA: Clinical Institute Withdrawal Assessment for Alcohol: (Sullivan et al., 1989) Health professionals use this scale to rate the severity of alcohol withdrawal. It consists of 10 items, 9 of which can be scored in a range of 0–7 and one on a range of 0–4 (total of 67). It can be used regularly throughout the day and night to assess the extent of withdrawal and the impact of treatment. It covers nausea; tremor; paroxysmal sweating; anxiety; agitation; auditory, visual and tactile disturbances; headache and orientation. # 05 - 5. Scales used in child psychiatry # 5. Scales used in child psychiatry © SPMM Course 5. Scales used in child psychiatry The Child & Adolescent Functional Assessment Scale:  A rating scale to assess the degree of impairment in functioning due to emotional, behavioural, or psychiatric problems.  It is completed by a clinical staff and takes about 10 minutes.  It is useful for assessing outcome over time and for directing case management activities.  It measures aggression and conduct problems especially in age between 7 to 17 years. The Child Behavior Checklist (CBCL):  It records the behavioural problems and competencies of children aged 4 through 16, as reported by their parents or others (e.g., teachers) who know the child well.  The checklist is composed of 113 items in a Likert scale.  The instrument provides three scores: a total score and scores on internalizing behaviours (fearful, shy, anxious, and inhibited) and externalizing behaviours  (Aggressive, antisocial, and under controlled).  This instrument can either be self-administered or administered through an interview. The CBCL can also be used to measure a child's change in behavior over time or following a treatment.  Teacher Report Forms, Youth Self-Reports and Direct Observation Forms are also available for the Child Behavior Checklist.  Two versions of this instrument exist: one for children ages 1 1/2 - 5 and another for ages 6 - 18. Diagnostic Interview Schedule for Children (DISC):  Originally developed in the early 1990s  Fully structured diagnostic interview for making DSM-based diagnoses in children. Conners Rating Scales  A family of instruments that measure a range of childhood psychopathology  Most commonly used in the assessment of ADHD.  Teacher, parent, and self-report (for adolescents) versions are available  Both short and long (up to 80 items) forms are available with # 06 - 6. Scales used in old age psychiatry # 6. Scales used in old age psychiatry © SPMM Course 6. Scales used in old age psychiatry  The Geriatric Mental State Schedule (GMSS) is a widely used instrument for measuring a variety of psychopathology in community surveys of the elderly. AGECAT is a computerised algorithm based on GMSS.  The Mini-Mental State Examination (MMSE) is a popular cognitive screening instrument for the elderly. It takes 10 minutes to administer by a trained interviewer. A cut-off score of 23 for the presence of cognitive impairment has been suggested. Educational status affects MMSE scores. MMSE does not pick frontal lobe deficits, a major drawback of using it as a screening instrument for dementias. It is also claimed to have only moderate to minimal sensitivity to change in mild cognitive impairment states.  Abbreviated Mental Test Score is a brief 10-point questionnaire to assess memory and orientation in 3 minutes (Hodkinson, 1972). Its origins can be traced back to the Blessed Dementia Scale. A cut-off score of 7/8 out of 10 is suggested to suspect cognitive impairment in the elderly.  The Alzheimer's Disease Assessment Scale (ADAS) is a standardised assessment of cognitive function, and non-cognitive features that take 45 minutes to be administered by a trained professional. The cognitive section is termed ADAS-Cog. It is the gold standard for measuring the change in cognitive function in anti-dementia drug trials. A fall of about 10% per year is expected (deemed average) in Alzheimer's disease.  The BEHAVE—AD is a clinician-administered scale to document behavioural symptoms in patients with Alzheimer's disease. It covers paranoid and delusional ideation; hallucinations; activity disturbances; aggression; diurnal variation; mood; and anxieties and phobias.  The Neuropsychiatric Inventory (NPI) can be used to record severity of associated behavioural symptoms of dementia over ten domains: (delusions; hallucinations; dysphoria; anxiety; agitation/aggression; euphoria; disinhibition; irritability/lability; apathy; and aberrant motor behaviour). It is scored from 1 to 144. The severity and frequency of behavioural symptoms are independently assessed.  MOUSEPAD stands for Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia. It is administered to carers by an experienced clinician for the measurement of behavioural and psychiatric symptoms of dementia (BPSD).  Clifton assessment procedure for the elderly - CAPE (Pattie & Gilleard, 1979) is intended to assess the level of disability and estimate need for care in the elderly. It consists of a short cognitive scale and a behavioural rating scale. The latter has four sub-scales: physical disability, apathy, communication difficulties and social disturbance. It is quick and easy to administer. © SPMM Course  Bristol Activities of Daily Living Scale assesses 20 daily living abilities in patients with dementia. It is a caregiver-rated scale designed for community use by trained health professionals. # 07 - 7. Other clinical rating scales # 7. Other clinical rating scales © SPMM Course 7. Other clinical rating scales SCALE Mode of administration Features Positive and Negative Symptom Scale (PANSS) Clinician-administered rating scale For assessment of severity and monitoring of change of symptoms in patients with a diagnosis of schizophrenia. 30 items are covering positive symptoms, negative symptoms, and general psychopathology. Yale-Brown ObsessiveCompulsive Scale (YBOCS) Clinician-administered semi-structured interview Allowing rating of severity in patients with a pre-existing diagnosis of OCD. SCOFF SCOFF is a mnemonic for eating disorder screening (similar to CAGE for alcohol). It has a high sensitivity (2 or more questions positive). Do you 1. Make yourself SICK when you feel uncomfortably full? 2. Worry you have lost CONTROL over how much you eat? 3. Recently lost more than 14 pounds within three months? 1. ONE stone's worth of weight 4. Believe you are FAT when others say you are too thin? 5. Would you say that FOOD dominates your life? Minnesota Multiphasic Personality Inventory (MMPI) Results generate information useful for a broad range of clinical applications. A self-report questionnaire consisting of 567 questions covering 8 areas of psychopathology, 2 additional areas of personality type, and 3 scales assessing truthfulness. Results are compared with normative data from non-clinical populations. NOT A PROJECTIVE TEST. International Personality Disorder Examination (IPDE) Semi-structured clinical interview for use by clinicians producing ICD-10personality disorder diagnosis. 67 standardized probe questions. 57-item true/false questionnaire also included for screening purposes. Clinical Global Improvement (CGI) Clinician rated based on clinical judgment A two-item instrument - CGI-S (severity) – the current condition on a scale of 1–7 & CGI-I (improvement) – the extent of improvement since the start of treatment on a scale of 1–7. Can be used for any psychiatric disorder encountered in a clinic or ward. Brief Psychiatric Rating Scale (BPRS) Rated by the physician on the basis of a semi-structured interview (18 items, 7 points for each, maximum of 108) Developed by Overall, 1960. One of the most widely used clinical rating scales. It was originally intended for use in controlled clinical trials of new psychotropic drugs. However, it has also been widely employed in studies of the clinical (that is, symptom) correlates of cognitive and neurobiological phenomena. The ratings include observations as well as patient reports. Factor analysis yields five factors (hostility-suspiciousness, withdrawalretardation, thinking disturbance, depression-anxiety, and activation). © SPMM Course Scale for Assessment of Positive Symptoms (SAPS) and the Scale for Assessment of Negative Symptoms (SANS) Clinician rated based on clinical interview Not intended as diagnostic devices. They have been used primarily in studies of the neurobiological correlates of symptom groupings. SAPS - 34 items divided into hallucinations, delusions, bizarre behavior, and formal thought disorder. SANS comprises 25 items divided into affective flattening or blunting, alogia, apathy, asociality, and inattention. Personality Diagnostic Questionnaire-4+ (PDQ4+) Self-report instrument assessing 12 personality disorders described in the DSMIV using 99 true-false items. A brief structured interview (Clinical Significance Scale) is used as a follow-up after the self-report to estimate whether (a) the trait is enduring (criterion D for DSM-IV); (b) it is present in the absence of other disorders (criteria E and F); and (c) it leads to distress or impairment (criterion C). # 08 - 8. Outcome scales in psychiatry # 8. Outcome scales in psychiatry # 09 - Some examples of outcome scales # Some examples of outcome scales © SPMM Course 8. Outcome scales in psychiatry The purpose of clinical intervention in psychiatry is to achieve a desirable outcome for the patient, his/her family and the society. Treatment outcomes are not single constructs but are multidimensional. Outcome measures can be broadly classified as follows:  Psychopathological rating scale: measuring individual symptom severity in a disorder e.g. PANSS, BPRS. These scales can also provide modified measures such as relapse, remission, etc. that are sued as outcome variables in various studies.  
Global outcome measure: an overall appraisal of disease severity and its impact on overall functioning e.g. Global Assessment of functioning (GAF) or Global Assessment Scale (GAS).  Generic patient-based outcome measure: measuring several domains of health-related quality of life applicable to populations irrespective of illness. e.g. Short Form 36 (SF36)  Disease-specific patient based outcome measure: measuring several domains of healthrelated quality of life applicable to specific patient groups.  Domain specific patient based outcome measure: measuring a specific domain associated with health-related quality of life e.g. focusing on social function or interpersonal relationships or cognitive capacity or service-level satisfaction. Any useful outcome measure must satisfy the following criteria to be incorporated into trials and clinical practice: Some examples of outcome scales Global Assessment of Functioning Scale (GAF) is available as an appendix to DSM-IV. It measures overall psychosocial functioning in patients on a 10-item (100 points) scale, rated on the •Is the instrument appropriate to the question addressed by the trial or the benefit desired by the clincial service? Appropriate Appropriate •Is the measure reproducible, internally cosnsitent, precise and accurately reflecting the construct of interest? Reliable & valid Reliable & valid •Is it sensitive to change over time? Responsive Responsive •Are the scores intuitively meaningful and comparable to real life states? Readily Interpretable Readily Interpretable •Is the tool readily applicable in clincial settings and not too onerous on clinicans and patients? Acceptable & feasible Acceptable & feasible © SPMM Course basis of self-report and information from the clinical interview. GAF was used in axis V of the multiaxial diagnostic system in DSM-IV. It combines symptomatic severity and functional impairment and is based on the clinician’s appraisal of the functional limitation. Social and Occupational Functioning Assessment Scales (SOFAS) was proposed as a new axis in Appendix B of DSM-IV. It is related to GAF but focuses only on functioning and not on symptoms. SOFAS does not try to discriminate between functional changes related to psychiatric and nonpsychiatric causes. It is rated by clinicians on a 100-point scale based on all available information, with descriptors for each 10-point interval. Guided tools for administering SOFAS (e.g. Personal and Social Performance scale –PSP) are available for use in clinical trials. Short Form health survey-36 or SF-36 was designed for wide use in a variety of settings: clinical practice, research, policy evaluations, and community surveys. SF-36 can be self-administered by persons 14 years of age and older, or by a trained interviewer. It assesses eight health concepts: 1) limitations in physical activities because of ill health; 2) limitations in social activities because of physical or emotional problems; 3) limitations in role performance due to physical health problems; 4) bodily pain; 5) general mental distress and well-being; 6) limitations in role performance because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The health of the Nation Outcome Scales (HoNoS): HONOS is the most widely used psychiatric outcome scale within the NHS. It was developed by the RCPsych and commissioned by the Department of Health in 1993. It has 12 items measuring behaviour, impairment, symptoms and social functioning, measured on the basis of routine clinical assessments in various clinical settings and has influenced various policymaking processes in the English NHS over the last 2 decades. # 10 - 9. Psychometry of rating scales # 9. Psychometry of rating scales: © SPMM Course 9. Psychometry of rating scales: When developing measurement scales, we are concerned about two important properties. Can we use this scale to measure the actual phenomenon we want to measure? Can this scale provide consistent results when it is used? A highly valid scale will measure what it is supposed to measure – the truth. A highly reliable scale will provide consistent results. Reliability refers to the replicable nature of research studies / tools. Note that high reliability does not guarantee scientific validity but guarantees consistency.  Reliability can be assessed by test-retest correlation by administering an instrument twice to the same population. The time difference between test and retest must be long enough to avoid practice effect, but short enough so the underlying state (e.g. depression) does not change very much: 2 to 14 days range is often used in psychiatry.  Cronbach’s alpha measures the internal consistency of a test by correlating each item with the total score and averaging the correlation coefficients. It can take values between negative infinity and 1 as a maximum; but only positive values make sense. Arbitrary cut-off of 0.70 is used commonly to call the evaluated test to be internally consistent.  The split-half reliability refers to splitting a scale into two parts and examining the correlation.  Interrater reliability is measured using two or more raters rating the same population using the same scale.  The intraclass correlation coefficient is used for continuous variables; it is nothing but the proportion of total variance of the measurement that reflects true between subject variability. It ranges between 0 (unreliable) and 1 (perfect reliability). ICC can be measured by either relative agreement or absolute agreement; the relative ICC is always higher than the absolute ICC. ICC of 0.6 is considered fair while 0.8 is very good and 0.9 as excellent, arbitrarily. ANOVA intraclass coefficient is used for quantitative data with more than 2 raters/groups.  For nominal data that has more than two categories, a kappa or weighted kappa can be used. (More details are given below) Validity of an instrument is the extent to which an instrument measures what it proposes to measure.  Face validity refers to a subjective measure of deciding whether the test measures the construct of interest on its face value.e.g., Hamilton depression scale clearly has a face value in measuring depression; but not for measuring obsessions. © SPMM Course  Construct validity measures whether a test really measures the (theoretical) construct of interest or something else. One way of classifying the construct validity is considering unified construct validity. Here construct validity is taken to consist of both content validity and criterion validity (referred as unified construct validity).  Content validity refers to whether the contents i.e. each individual subscales, items or elements of the test are in line with the general objectives or specifications the test was originally designed to measure. It looks for a good coverage of all domains thought to be related to the measured condition. This often cannot be statistically tested, but experts are called for comments on this aspect of validity.  Criterion validity refers to the performance against an external criterion such as another instrument (concurrent) or future diagnostic possibility (predictive).  Concurrent validity refers to the ability of a test to distinguish between subjects who differ concurrently in other measures (using other instruments). e.g., those who score high on a scale of insomnia may score high on a scale of fatigue ratings too.  Predictive validity refers to the ability of a test to predict future group differences according to current group differences in score. e.g., high aggression score in childhood and high criminal incidents in adult life. (On a similar note, Incremental validity refers to the ability of a measure to predict or explain variance over and above other measures) Another way of considering the construct validity is by classifying it to convergent, discriminant and experimental/interventional validity:  Convergent validity refers to agreement between instruments that measure same construct e.g. between BDI and HAMD for depression. This agreement can be tested in contrasted groups i.e. depressed and non-depressed, both groups showing a high correlation between the two scales.  Discriminant validity refers to the degree of disagreement between two scales measuring different constructs. e.g., to say that HAMD measures some construct (depression) different from that measured by Hamilton Anxiety scale (anxiety) poor correlation must be demonstrated between HAMD and HAS  Experimental validity: This refers to the sensitivity to change. An instrument must show the difference in results when an intervention is carried out to modify the measured domain. © SPMM Course Note: Factorial validity is a form of construct validity established via factor analysis of items in a scale. Precision and accuracy Precision is the degree to which a calculated central value (e.g. mean) varies with repeated sampling. The narrow the variation, the precise the value is. Random errors lead to imprecision. Factors reducing precision includes 1. Having wider the limits of the interval 2. Expecting higher confidence interval (e.g. 99.7% versus 95%). Accuracy refers to the correctness of the mean value – i.e. how close is it to the true population value. Precision is comparable to reliability while accuracy is comparable to validity. Bias in a study compromises validity / accuracy. VALIDITY QUESTION IT ANSWERS Face Does this scale appear to be fit for the purpose of measuring the variable of interest? Content Does this scale appear to include all the important domains of the measured attribute? Criterion Is the scale consistent with what we already know (concurrent) and what we expect (predictive)? Convergent Does this new scale associate with a different scale that measures a similar construct? Discriminant Does the new scale disagree with scales that measure unrelated constructs? # 11 - 10. Risk assessment # 10. Risk assessment © SPMM Course 10. Risk assessment Risk is the likelihood that harm will occur. Risk assessment is a process of scientific (statistical/clinical) calculation of likelihood of an adverse event; this includes specifying 1. What will happen? 2. When will this happen? 3. By whom will this happen? 4. How will this happen? Risk management is integral to assessment; Assessment is not carried out to label people and categorise into groups – it is a dynamic process and specific to the event of importance. Risk cannot be eliminated but only reduced. Problems with ‘predicting’ risk:  Low base rate: The events of interest are usually very rare. Hence the predictive value is generally low. Serious violence is rare amongst the severely mentally ill disordered, killing or maiming of others is measured in probabilities of less than 1% (Wallace 1998). This low base rate seriously compromises the predictive utility of risk assessment because of the false positive rate of even an exceptionally good risk assessment instrument.  Multifactorial: Risk is dependent on several factors, which tend to change over time.  Unknown interactions: Comprehensive risk evaluations are time-consuming; often the degree and nature of interaction among various factors is unknown. Risk factors for any untoward incident (suicide, crime or violence) can be categorized as static, stable and dynamic factors (Bouch & Marshall, 2003).  Static risk factors: These are fixed and historical: e.g. family history of suicide. They cannot be modified.  Stable risk factors: These are long term, enduring issues but are modifiable to some extent and not fixed: e.g. diagnosis of personality disorder.  Dynamic risk factors fluctuate markedly in both duration and intensity: the e.g. presence of acute anxiety symptoms or akathisia. A dynamic risk factor can act synergistically and multiply the effect of underlying static and stable risk factors if not addressed promptly. Certain dynamic factors may occur only in future (e.g. upon discharge, a patient may feel helpless). A comprehensive risk assessment should consider static, stable, dynamic and future risk factors and include them in devising risk management strategies. # 12 - Approaches to risk assessment # Approaches to risk assessment # 13 - Clinical approach # Clinical approach # 14 - Actuarial approach # Actuarial approach # 15 - Structured professional judgment # Structured professional judgment © SPMM Course Approaches to risk assessment Clinical approach In this approach, a clinicians’ subjective, intuitive judgment informed by experience and knowledge is used to estimate risk and guide decisions about treatment. But professional opinions are often highly variable for a given case and have poor predictive value, not supported by many policymakers. Most risk assessment currently performed by clinical methods. They are based on clinical experience, individuals knowledge and person-specific assessment to reach a conclusion. Only 1/3rd of pure clinical judgments are estimated to be correct in retrospective studies. Actuarial approach This approach is very popular in forensic services. This uses formal, algorithmic and objective procedures for quantifying risk as a numerical probability of a future outcome: e.g. patient A has a 60% chance of killing herself in the next 2 years, etc. It is found to be superior to other methods of predicting the risk of violence and sexual offending, but does not inform the clinician much about the risk factors that require targeting to mitigate risk. There are hardly any actuarial tools available for self-harm and suicide risk, but there are many available for violence risk assessment. Problems of actuarial tools include: 1. Historical aspects are given more importance – so a pessimistic view of risk with insensitivity to change results. 2. High false positive rates using these tools. 3. As mentioned above generalisation of actuarial tools developed in one setting to the other is difficult. 4. Further, actuarial approaches are often too focused on static and stable risk factors rather than dynamic and modifiable factors. Thus, though actuarial instruments more accurately identify at-risk groups, structured risk instruments may be more clinically useful for enhancing clinical decision-making. Structured professional judgment Structured professional judgment is an approach that aims to combine the evidence base for risk factors with an individual clinical assessment to complement psychiatric opinion. A structured, scales-based assessment is used when formulating risk management plan. Several risk assessment instruments are available to support structured professional judgment (e.g. HCR–20 to assess risk for violence in forensic settings) It is important to note that neither actuarial nor structured judgments should replace conventional clinical assessment; they must be employed as an additional aide for systematically identifying and addressing relevant risk factors. # 16 - Stages in risk assessment # Stages in risk assessment # 17 - Commonly used tools # Commonly used tools # 18 - Structured Risk Tools # Structured Risk Tools © SPMM Course Stages in risk assessment According to Bouch & Marshall, the following stages are identified for risk assessment and management. A. Identifying the need for a full structured risk assessment (not everyone will need this) B. Assessing static, stable, dynamic and future risk factors and considering protective factors C. Individual formulation of risk applied to the context of current presentation D. Considering possible interventions and the level of support required E. Anticipating the impact of possible interventions F. Developing a management plan with specified short and long term implementations G. Reviewing and revising the management plan with variations in risk factors. Commonly used tools Structured Risk Tools HCR-20 (Webster): It is a popular structured clinical assessment tool for violence risk. HCR-20 (Historical, Clinical and Risk) shows good inter-rater reliability. It has  10 historical items (history of previous violence, PCLR score, etc.)  5 Clinical items (lack of insight, diagnosis of PD) and  5 risk management items (feasibility of plans, lack of support, etc.) It has been useful in predicting inpatient violence and community violence in discharged patients. Historical items Clinical items Risk items Previous violence history Negative attitudes to health services Management plan lacks feasibility Young age at first incident Active symptoms Exposure to destabilisers (e.g. alcohol) Unstable relationships Impulsivity Non-compliance Major mental illness Treatment unresponsiveness Stress Substance use Lack of insight Lack of personal support Psychopathy Employment issues Personality disorder Early maladjustment Previous supervision failure # 19 - Actuarial instruments # Actuarial instruments © SPMM Course SARA: Spousal assault risk assessment guide SARA is a 20 item set of risk factors for use in the assessment of spousal assault. It can be used to help gauge the risk of future violence in men arrested for spousal assault. SVR-20 is a sexual violence risk 20 scale - this is a 20 item guide for assessing violence risk in sex offenders. SAD PERSONS Score: 10 major demographic risk factors used in a mnemonic to assess immediate suicidal risk often in acute general hospital setting. The scores can guide in making a decision to admit or discharge a patient. S – Sex: 1 if male; 0 if female; (more females attempt, more males succeed) A – Age: 1 if < 20 or > 44 D – Depression: 1 if depression is present P – Previous attempt: 1 if present E –Ethanol abuse: 1 if present R – Rational thinking loss: 1 if present S – Social Supports Lacking: 1 if present O – Organized Plan: 1 if plan is made and lethal N – No Spouse: 1 if divorced, widowed, separated, or single S – Sickness: 1 if chronic, debilitating, and severe Beck Hopelessness Scale consists of 20 true-false statements focused on pessimism and negativity about the future. The degree of hopelessness measured using this tool is a good indicator of suicidal risk with scores: 0 –3 indicating minimal, 4 – 8 mild, 9 –14 moderate, and 15– 20 severe risk. Beck Scale for Suicidal Ideation is a self-report 24-item scale (5 screening items) that assesses a patient’s thoughts, plans and intent to commit suicide. The total scores could range from 0 to 48 (each item scored from 0 to 2). Higher scores reflect greater suicide risk though no defined cutoffs are identified for categorizing the risk profiles. Actuarial instruments Group data is obtained from high-risk individuals and then to applied to the patient in question. It gives a group risk, and it should be applied with caution. Different types include: VRAG (violence risk appraisal guide – Quinsley 1995) entirely reliant on historical factors. Validated at Canadian prisons. It is made of 12 items and includes PCL_R as a subscale. © SPMM Course Violence risk appraisal guide PCL-R Absence of schizophrenia (Presence is counted to decrease risk!) Elementary school difficulties Victim injury (minimal or none) Personality disorder Alcohol abuse Younger age Female victim Separated from parents before age 16 Failed conditional release/supervision order Never married History of non violent offence Violence Risk Scale has 23 dynamic and 6 static variables. PCL-R (Hare) is a scale to diagnose Psychopathy, informs risk assessment and treatment decisions. 0 – 40 score range; 0-2 for each item; 20 items in total. Cut off of 25 used to diagnose psychopathy. In the strictest sense, PCL was not designed to be an actuarial tool for risk assessment on its own. The Static-99 is a ten item actuarial assessment instrument created by Hanson and Thornton, for use with adult male sexual offenders who are at least 18 year of age at the time of release to the community. SORA (Sexual risk offender appraisal guide) is a 14 item actuarial instrument that incorporates PCL_R. The Manchester Self Harm Rule (MSHR) is an actuarial instrument for self-harm risk assessment produced by Cooper et al. 2006. It has high sensitivity but low specificity. © SPMM Course Notes produced using excerpts from:  Achenbach, T. M. (1991). Manual for the Child Behavior Checklist/4-18 and 1991 Profile. Burlington, VT: University of Vermont, Department of Psychiatry.  Bouch, J., & Marshall, J. J. (2005). Suicide risk: structured professional judgement. Advances in Psychiatric Treatment, 11(2), 84-91.  Burns, A., Lawlor, B., & Craig, S. (2002). Rating scales in old age psychiatry. The British Journal of Psychiatry, 180(2), 161-167.  Casey, P. & Kelly, B. (Ed) Fish’s Clinical Psychopathology. 3rd ed. RCPsych publications.  Cooper J, Kapur N, Dunning J, et al. A clinical tool for assessing risk after self-harm. Ann Emerg Med. 2006;48:459–466.  Cox JL, et al. Validation of the Edinburgh Postnatal Depression Scale (EPDS) in postnatal women. J Affect Disord 1996;39:185-9.  http://www.static99.org/  http://www2.massgeneral.org/schoolpsychiatry/screeningtools_table.asp  https://www.cnsforum.com/educationalresources/ratingscales/psychiatry  Jackson. C. The General Health Questionnaire. Occupational Medicine 2007 57(1):79;  Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007  Morgan et al.(1999), SCOFF Questionnaire. BMJ 319:1467  Sharp LK, Lipsky MS. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Physician 2002;66: 1001-8. http://www.aafp.org/afp/2002/0915/p1001.html  Ware Jr, J. E., & Sherbourne, C. D. (1992). The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Medical care, 473-483. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information. # 20 - 530_Eponyms # 01 - 530_Eponyms # 530_Eponyms.pdf Eponyms Eponyms & uncommon syndromes Angelman syndrome: Congenital syndrome of mental retardation and epilepsy that is distinctive for puppetlike movements, compulsive laughter, and heritability. Anton syndrome: Condition of blindness in which patient denies he cannot see and confabulates; a particular type of anosognosia. This condition is classically but not exclusively associated with bilateral occipital cortex lesions. Balint syndrome: Constellation of symptoms that include fixation of gaze, neglect of objects in visual surround, and misreaching, usually due to bilateral superior parietooccipital lesions. Bell mania: Disorganized hyperactivity (as opposed to waxy flexibility and rigidity in lethal catatonia) that can be fatal if untreated; the syndrome is rare, probably because of the widespread use of antipsychotics, and the eponym is antiquated. Binswanger disease: A particular type of multi-infarct dementia (a subtype of DSM-IV Vascular Dementia) in which infarcts selectively affect the white matter. Briquet syndrome: Somatization Disorder; the disorder of multiple somatic complaints across different organ systems as a manifestation of anxiety. Brueghel syndrome: Trigeminal dystonia that affects the mouth, sometimes provoked by antipsychotics. Capgras syndrome: The belief that strangers in disguise have replaced persons known to the patient. Charcot-Wilbrand syndrome: "Global cessation of dreaming"; the loss of all or part of dreaming after brain injury. Charles Bonnet syndrome: Visual hallucinations in the context of reduced eyesight. Clerambault-Kandinsky syndrome: The syndrome that includes any paranoid psychosis in which thought insertions predominate, regardless of etiology. [Cornelia] de Lange syndrome: Congenital mental retardation distinctive for patients' self-injury, hyperactivity, sleeplessness, and aggression. Cotard syndrome: Patient's belief that he does not exist, that part of him is not there (e.g., his organs), or that he is dead. Eponyms Creutzfeldt-Jakob disease: Rapidly progressive dementia caused by transmissible prions (proteinaceous infectious particles) and distinctive for ataxia, myoclonus, EEG triphasic waves, and the diffuse spongiform appearance of the patient's brain after death. Da Costa syndrome: Panic Disorder; the condition of debilitating anxiety attacks accompanied by attempts to avoid such attacks. De Clerambault syndrome: Erotomania, or more specifically a female patient's belief that a wealthier older man, whom she does not know, loves her. Ekbom syndrome: 1) delusional parasitosis, the belief that the skin is infested with parasites, sometimes associated with cocaine use; 2) restless legs syndrome, the condition of annoying sensations in the extremities that disturbs sleep onset. European physicians prefer the first definition, Americans the second. Fahr disease: Idiopathic calcification of basal ganglia that causes dementia and abnormal extra movements, often comorbid with obsessive-compulsive and mood symptoms. Fregoli delusion: Belief that strangers are actually persons well known to the patient, in disguise. Ganser syndrome: The symptom of answering all questions approximately; e.g., "2+2=5."27 Gardner-Diamond syndrome: Purpura associated with psychological stress; subcutaneous injection of patients' own blood reproduces the rash in the (mostly female) sufferers. Gélineau syndrome: Narcolepsy; a disorder with daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and association with various human lymphocyte antigens. Gerstmann syndrome: Finger agnosia, agraphia, right-left disorientation, and dyscalculia, associated with dominant parietal lobe lesions. Gerstmann-Sträussler-Scheinker disease: Transmissible prion disease that causes dementia and affects only individuals with particular autosomaldominant defects of chromosome Geschwind syndrome: Constellation of interictal behavior including hyposexuality, hyperreligiosity, hypergraphia, and "viscosity" (not observing appropriate social boundaries in conversation), all seen in some patients with chronic temporal lobe epilepsy. Gjessing syndrome: "Periodic catatonia"; a disorganized state of withdrawal or agitation that fluctuates on and off. Hakim-Adams syndrome: Normal pressure hydrocephalus; the accumulation of cerebrospinal fluid in the ventricles without a significant rise in intracranial pressure, which often causes dementia, gait apraxia, and incontinence; shunting reverses the dementia if it is identified in time. Heller syndrome: Childhood Disintegrative Disorder; the loss of milestones in multiple domains after age Hoigne syndrome: Acute psychosis due to the intravenous injection of penicillin. Eponyms Hoover sign: Unconsciously exerted downward pressure with a healthy leg when the paretic leg is challenged; its absence demonstrates a feigned deficit. Kahlbaum syndrome: Catatonia; a syndrome of waxy posturing or purposeless agitation or speech, treated with benzodiazepines and ECT. Kanner syndrome: Autism; a developmental disorder with abnormal communication, impaired social interaction, repetitive behavior, and symptoms before the age of 3 years. Kleine-Levin syndrome: Syndrome of hyperphagia, hypersexuality, and hypersomnia classically described in male adolescents. Klüver-Bucy syndrome: Syndrome of temporal lobe damage involving hypersexuality and hyperorality. Korsakoff syndrome: Chronic amnesia characterized by difficulty in learning new information (anterograde amnesia), manifesting as confabulation; caused by thiamin deficiency and wholly or partially reversible in some cases. Kozhevnikov syndrome: Continuous partial epilepsy leading to progressive cognitive deterioration. Landau-Kleffner syndrome: Continuous partial simple epilepsy selectively causing loss of language development in children. Langfeldt psychosis: Psychosis without the declining course of schizophrenia. Lesch-Nyhan syndrome: Congenital mental retardation caused by a chromosome 26 deletion, with defective purine metabolism and ferocious self-injury. Lhermitte syndrome: Peduncular hallucinosis; bizarre hallucinations (classically, visions of Lilliputians) without other psychosis, due to a lesion in the midbrain.51 Marchiafava-Bignami disease: Dementia due to callosal degeneration, associated with chronic alcohol (particularly wine) abuse. Marinescu reflex: Palmomental reflex; the movement of the chin after stroking the palm, which, when unilateral, suggests frontal or diffuse brain damage. Martin-Bell syndrome: Fragile X– linked mental retardation, a condition due to trinucleotide repeats on the X chromosome that is the most common genetic cause of mental retardation; particularly important in psychiatry because many patients suffer from autism and virtually all have attentiondeficit hyperactivity disorder. Meige syndrome: Dystonic blepharospasm; recurrent involuntary blinking caused by a hypodopaminergic state such as that induced by antipsychotics. Morvan disease: Involuntary muscle fiber activity, hyperhidrosis, and sleeplessness that leads to death in weeks if not treated; possibly autoimmune. Myerson sign: Glabellar tap reflex; a failure to extinguish blinking after 4 taps on the forehead that suggests frontal, diffuse, or extrapyramidal disease. Parkinson disease/syndrome: The "disease" is the idiopathic degeneration Eponyms of the substantia nigra that causes resting tremor, bradykinesia, and rigidity; the "syndrome" is these symptoms due to some other cause, such as medication. Pick disease: Dementia with frontal and temporal atrophy, early personality change, and Pick bodies found postmortem. Prader-Willi syndrome: a congenital form of mental retardation distinctive for patients' compulsive eating and self-mutilation; caused by a chromosome 15 deletion. Rasmussen syndrome: Unilateral brain atrophy and continuous epilepsy that results in cognitive decline until the affected portion of the brain is removed. Rett syndrome: Developmental disorder caused by an X-linked dominant mutation that is found mostly in girls and involves acquired microcephaly, reversal of cognitive and social development, ataxia, and "hand-wringing (stereotypic hand movements and manual dyspraxia)." Sanfilippo syndrome: Congenital mental retardation caused by a chromosome 12 deletion, distinctive for aggression and insomnia. Smith-Magenis syndrome: Congenital mental retardation distinctive for severe self-injury and "self-hugging" behavior. Steele-Richardson-Olszewski disease: Dementia with ataxia, loss of ability to look up or down, and parkinsonism. Strauss syndrome: AttentionDeficit/Hyperactivity Disorder; the condition of inattention and/or hyperactivity once known as "minimal brain damage syndrome."67 Sydenham chorea: Movement disorder that follows rheumatic fever; often preceded by obsessivecompulsive symptoms (first described by Osler) that have been characterized recently as "PANDAS" when they occur alone. Tourette syndrome: Disorder with both motor and vocal tics (sometimes coprolalia), often comorbid with obsessive-compulsive symptoms. Von Economo disease: Encephalitis lethargica, a syndrome that afflicted many victims of a viral epidemic in the early 20th century and distinctive for Parkinsonism, lethargy, and obsessivecompulsive symptoms. Wernicke encephalopathy: Triad of delirium, ataxia, and abnormal eye movements associated with thiamin deficiency, particularly in alcohol abusers. Williams syndrome: Congenital syndrome of mental retardation with a deletion on chromosome 7, distinctive for patients' fluent verbal ability and "elfin" face. Wilson disease: Congenital recessive condition of defective copper metabolism due to a defect in chromosome 13, characterized by hepatic symptoms and later psychiatric symptoms and choreoathetosis as various organ systems are overwhelmed by copper. It can be diagnosed (once the central nervous system is affected) by finding KaiserFleischer rings in the cornea with a slit-lamp though these are not universally present. A more reliable diagnosis depends on low Eponyms ceruloplasmin and elevated copper in urine and liver biopsies. Wolfram syndrome: Rare autosomal recessive syndrome caused by a defect in chromosome 4, with diabetes, bilateral optic atrophy, and diverse psychiatric disorders. Heterozygotes for the Wolfram mutation are extremely common (occurring in 1% of the population), and those having them may be at high risk for psychiatric illness. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgments have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug-related information using external sources; no part of these notes should be used as prescribing information. This excerpt is from: Bresch, D. (2002) Beyond Wernicke’s: A Lexicon of Eponyms in Psychiatry J Neuropsychiatry Clin Neurosci 14: 155-160 # 21 - AdvEffectsChart_v3 # 01 - AdvEffectsChart_v3 # AdvEffectsChart_v3.pdf Worsening of glaucoma: paroxetine, quetiapine, TCAs Retinal pigmn: Thioridazine Corneal deposits: CPZ Visual field defects: vigabatrin Osteoporosis: hyperprolatinaemic antipsychotics WBC suppression: ^zapines(olanz, mirtaz, cloz, carbama), mianserin Haemolytic anaemia: nomifensine Myocarditis / Pul Embolism: clozapine QT prolong: all antipsychotics esp .Thioridazine, Pimozide, droperidol Arrythmias: high dose TCAs High BP: VFX, TCAs Hypersalivation: clozapine Bruxism: stimulants Hypothyroidism: Li Fine tremors: therapeutic dose of lithium, TCAs Coarse tremors: antipsychotic Parkinsonism, Wt gain: all antipsychotics (less for APZ, ZPD), TCAs, Li, VPA, CBZ Wt loss: Topiramate, Bupropion Guillian Barre: Zimeldine Pedal oedema: MAOIs Cramps: AchEs Orthostatic hypotension: all TCAs, all antipsychotics Priapism: Trazodone, risperidone PCOD: Valproate Erectile dysfunction: all TCAs, antipsychotics Delayed ejacln or anorgasmia: SSRIs Hepatic damage: nefazodone, VPA, tacrine Enz induction: CBZ, phenytoin, barbiturates Ac. Pancreatitis: VPA P.ileus: clozapine GI bleed: SSRIs, AChEs Renal damage: Lithum Nephrolithiasis: topiramate EPSEs: all neuroleptics (less for Anticholinergic neuroleptics e.g. CPZ), higher dose atypicals Delirium: Anticholinergic TCAs, Anticholinergic antipsychotics Seizures: bupropion, clozapine Tics: stimulants Amnesia: BDZ Rashes, SJS: CBZ, Lamotrigine Thrombocytopenia: Valproate Sweating: all SSRIs, TCAs, esp. VFX Acne, psoriasis: Li Psychotropics Adverse Effects Chart © SPMM Course AchEs: Anticholinesterases, BDZ: Benzodiazepines, CBZ: carbamazepine, CPZ: Chlorpromazine VFX: Venlafaxine VPA: Valproate, SJS: Steven Johnson Syndrome,