26.5.8 Anxiety disorders 6501 Ted Liao and Steve E

26.5.8 Anxiety disorders 6501 Ted Liao and Steve Epstein

26.5.8  Anxiety disorders 6501 Adjunctive psychotherapy may enhance remission from acute de- pressive episodes but is not helpful during mania because patients often reject help and lack insight into their difficulties. Outcome The presenting type of mood disorder is familial and may have prog- nostic significance; a presentation with just mania has the best out- come. Once established, the characteristic pattern of episodes for that individual tends to recur. The occurrence of four or more mood episodes per year is referred to as rapid cycling, which occurs in be- tween 12% and 24% of people with bipolar disorder and is associ- ated with earlier age of onset, more comorbid substance misuse, and more severe depressive episodes. As most people with bipolar disorder present with a depressive episode, 40% initially receive a diagnosis of unipolar depression. The rate of switching from a diagnosis of unipolar disorder to one of bi- polar disorder is higher in younger people and plateaus at 1% per year by the age of 30. Bipolar disorder is a chronic illness, with a 40-​year follow-​up finding that only 16% had recovered (no episode in the last five years) and over 50% were experiencing recurrent episodes. The per- sistence of depressive symptoms is associated with poorer prognosis. There is also increasing evidence that significant impairment per- sists even in remitted states. On average people with bipolar disorder die nine years earlier than the rest of the population. Suicide risk is increased 10-​fold in women and 8-​fold in men. Suicide tends to occur early in the course of the illness, and between 25% and 50% attempt suicide at least once. Attempts are more likely in depressed and mixed affective states. Special circumstances Pregnancy Pregnancy and specifically the post-​partum period is a high-​risk period for women with bipolar disorder when as many as half relapse. Many of these relapses are depressive in nature and are most likely to occur in the first trimester, in women who have bipolar II disorder and in those who have discontinued medi- cation. The risk of relapse is especially high in the post-​partum period. There is a need to balance the risk of pharmacotherapy to the unborn fetus against the risk of recurrence of an affective episode in the mother. FURTHER READING BALANCE investigators, et al. (2010). Lithium plus valproate com- bination therapy versus monotherapy for relapse prevention in bipolar I  disorder (BALANCE):  a randomised open-​label trial. Lancet, 375, 385–​95. Craddock N, Sklar P (2013). Genetics of bipolar disorder. Lancet, 381, 1654–​62. Geddes JR, Miklowitz DJ (2013). Treatment of bipolar disorder. Lancet, 381, 1672–​82. Grande, I, et al. (2015) Bipolar disorder. Lancet, 387, 1561–​72. McKnight RF, et al. (2012). Lithium toxicity profile: a systematic re- view and meta-​analysis. Lancet, 379, 721–​8. Phillips ML, Kupfer DJ (2013). Bipolar disorder diagnosis: challenges and future directions. Lancet, 381, 1663–​71. 26.5.8  Anxiety disorders Ted Liao and Steve Epstein ESSENTIALS Anxiety is a common feeling, but also the central symptom of several psychiatric disorders:  generalized anxiety disorder, panic disorder, phobias, and obsessive-​compulsive disorder. Anxiety disorders are common and important in general medical practice as they often manifest with physical symptoms such as palpitations, chest pain, and dizziness that can be misdiagnosed as medical conditions and lead to unnecessary investigation and treatment. Anxiety disorder, especially phobic anxiety, can also lead to inability to adhere to med- ical treatments, for example, because of needle phobia interfering with blood tests and/​or injected drugs treatment. Both pharmaco- logical and psychological treatments are effective. For chronic anx- iety, selective serotonin reuptake inhibitors are the drugs of choice, with benzodiazepines being reserved for short-​term use. If available, cognitive behaviour therapy is similarly effective. Anxiety disorders usually respond to treatment but often recur. Introduction Feeling anxious is both a normal and common human experience. Words such as worry, nervousness, and apprehension all describe this everyday emotion. Normal worry can serve an adaptive func- tion, motivating individuals to take action to avoid negative con- sequences (e.g. studying for a test to avoid failing it) and can be an ordinary response to stressful situations (e.g. anxiety related to an- ticipated loss of independence following illness). Patients with anxiety disorders suffer from more than normal worry. They experience more pervasive and persistent anxiety, as well as other psychological and physiological symptoms. The se- verity of these is such that there is significant functional impairment. Whereas normal worry can spur people to action, anxiety disorders can cripple them. Box 26.5.7.3  Psychological treatment of bipolar disorder • Enhance ability to identify warning signs of recurrence and intervene early • Increase acceptance of illness • Enhance adherence to prescribed medication • Improve resilience to environmental stressors associated with symptoms • Stabilize sleep patterns and other daily routines • Enhance family relationships and communication • Reduce drug and alcohol misuse Adapted from Geddes & Miklowitz (2013).

SECTION 26  Psychiatric and drug-related disorders 6502 Untreated, anxiety disorders can impair a patient’s ability to ad- here to medical treatments, and as a result can have negative reper- cussions on a patient’s overall health and quality of life. Appropriate diagnosis and treatment of anxiety disorders can reduce morbidity, minimize disability, and restore functionality. Aetiology Both genetic and psychosocial factors contribute to the aetiology of anxiety disorders. Estimates of heritability range from 15% to 50%. Early-​life influences (e.g. parents with anxiety) can exert a lasting influence on how patients respond to stressors. The brain regions most strongly implicated in the pathogenesis of anxiety disorders are the amygdala, the insular cortex, the cingulate cortex, and the prefrontal cortex. The neurotransmitters most strongly associated with anxiety disorders are γ-​aminobutyric acid, serotonin, and norepinephrine. Epidemiology Anxiety disorders are very common. Approximately one in five adults suffer from an anxiety disorder according to large popula- tion surveys performed in several international settings. Onset is commonly in childhood and adolescence. Anxiety disorders dis- proportionately affect women and are associated with high rates of disability. Patients with anxiety disorders frequently seek treatment in primary and specialty medical care settings, often initially pre- senting with physical symptoms. Clinical features The presenting complaints of patients with anxiety disorders can vary widely. The main psychological symptom of anxiety disorders is feeling anxious, tense, fearful, or agitated. Worry about future events is common. The associated behaviours include avoidance of feared situations and compulsive behaviours that serve to reduce the anx- iety (Table 26.5.8.1). Importantly, anxiety can also present with physical symptoms. These include fatigue, aches and pains, poor sleep, palpitations, breathlessness, dizziness, and chest pain. Episodic sudden onset of many physical symptoms suggests panic attacks. Common physical symptoms are listed in Table 26.5.8.2. Specific anxiety disorders Table 26.5.8.3 describes the key features of the specific anxiety disorders. Generalized anxiety disorder Generalized anxiety disorder (GAD) can be distinguished from other anxiety disorders by its lack of focus on a particular topic (in contrast with specific phobia or OCD), and by the long, consistent amount of worry (in contrast with circumscribed panic attacks). Panic disorder The most salient feature of panic attacks is their severity and short duration:  they peak and typically resolve within minutes. Many patients have some familiarity with the concept of a panic attack and mistakenly describe other anxiety symptoms as panic attacks. Accurately eliciting a history of panic attacks is the crucial step in distinguishing panic disorder from other anxiety disorders. Not every patient who has a panic attack should be diagnosed with panic disorder. The hallmark of panic disorder is not simply the pres- ence of panic attacks, but also a persistent worry about future attacks and/​or the actions taken to avoid future attacks. Agoraphobia (fear/​ avoidance of crowds, open spaces, or enclosed places) represents one such maladaptive response to the experience of panic attacks. Specific phobia Many individuals are afraid of some of the objects or situations (e.g. needles) that are the focus of specific phobias, but those individ- uals perceive an intensity of distress in excess of social norms. One category of phobias with particular relevance to clinicians is blood-​ injection-​injury phobia. This consists of specific aversions to blood, needles, or other invasive medical procedures. Specific phobias of this type may prevent patients from receiving other necessary med- ical care, and thus warrant prompt diagnosis and treatment. Table 26.5.8.1  Psychological symptoms of anxiety disorders Fear (distress about a concrete, imminent stressor) Anxiety (worry about abstract, future stressors) Other psychological symptoms Mood Sense of restlessness Irritability Derealization (feelings of unreality) Depersonalization (feelings of being detached from oneself) Cognitive Worry and obsessional thoughts Impaired concentration Behaviour Avoidance Compulsive behaviours Table 26.5.8.2  Common physical symptoms of anxiety disorders Constitutional Fatigue Insomnia Diaphoresis Chills Neurological/​musculoskeletal Headache Vertigo Dizziness and light-​headedness Unsteadiness Neck pain Muscle tension Tinnitus Paraesthesia Tremulousness or tremor Cardiopulmonary Chest pain Palpitations Tachycardia Dyspnoea Gastrointestinal Nausea Abdominal pain

26.5.8  Anxiety disorders 6503 Social anxiety disorder (social phobia) Social anxiety disorder is a phobia of social situations. The distinc- tion between simple shyness and social phobia depends on severity and the effect on the person’s life. For instance, a person with normal shyness may keep to herself or himself at a large social gathering, but interact more openly with close friends, whereas a person with social anxiety disorder may avoid social functions altogether and consequently become socially isolated. Patients with social anxiety often self-​medicate with alcohol, leading to an association with al- cohol misuse disorders. Obsessive-​compulsive disorder Most patients with obsessive-​compulsive disorder experience both obsessions and compulsions. It is important to note that the clin- ical definition of the term ‘obsession’ in the context of obsessive-​ compulsive disorder (OCD) differs from the lay meaning of the term. The obsessions in OCD are not voluntarily experienced and are not a source of pleasure; rather they are persistent, unwanted, and aversive. For example, a woman had obsessions that the food in her home was rotten. Compulsions similarly do not bring patients pleasure, merely temporary relief from the distress associated with the obsessions. They are also not realistically related to the obsessions that drive them, or are clearly excessive. For instance, in the aforementioned case, the woman could only relieve her anxiety by ritualistically checking and rechecking the expiration date on every food item in her kitchen. Assessment of the patient with OCD must include a determin- ation of the time spent on obsessions and/​or compulsions in order to determine symptom severity and degree of functional impairment. The woman mentioned here spent 90 minutes every evening com- pulsively checking her food instead of going to her evening class, making the behaviour clearly abnormal. Differential diagnosis Anxiety is most commonly understandable and situational. For ex- ample, seeing a physician to hear whether a serious disease such as cancer has progressed will cause many patients anxiety. Sometimes, however, the severity and persistence of anxiety means it is con- sidered a psychiatric disorder as described here. Other psychiatric differentials to consider are alcohol or drug withdrawal, developing delirium or dementia, and occasionally anxiety secondary to the delusions and hallucinations of a psychotic disorder. Some medical conditions can present with symptoms of anxiety (Table 26.5.8.4). There should be increased suspicion of these and other medical causes of anxiety if a patient is over 35 with no per- sonal or family history of anxiety, has no history of using the sub- stances and medications listed here, lacks significant stressors, and if standard pharmacological treatment of anxiety fails. Anxiety may also be a result of prescribed medication. Table 26.5.8.5 lists several substances and medications for which ingestion or withdrawal may produce significant anxiety. Particular emphasis should be paid to screening for stimulant ingestion and withdrawal from ethanol or benzodiazepine use. Assessment Detection Anxiety disorders cause a wide variety of physiological symptoms. Table 26.5.8.2 lists these symptoms, grouped by bodily system. Awareness of this form of presentation reduces the risk of mis- diagnosing anxiety as a medical disorder. It can also help prevent Table 26.5.8.3  Features of specific anxiety disorders Generalized anxiety disorder (GAD) –​ Excessive anxiety and worry about multiple issues that is difficult to control. –​ Occurs more days than not for at least six months. –​ Associated with some of the following: impaired concentration, irritability, muscle tension, insomnia, and fatigue. Panic disorder –​ Recurrent panic attacks: surges of intense fear or anxiety that peak within minutes, associated with palpitations, diaphoresis, tremulousness, dyspnoea, chest pain, nausea, abdominal pain, dizziness, or paraesthesias. –​ Associated fear of collapse or death. –​ Persistent concern about future attacks. Specific phobia –​ Marked fear or anxiety about a specific object or situation (e.g. flying, heights, animals, seeing blood), which is actively avoided if possible. – The fear or anxiety is out of proportion to the actual danger. –​ These symptoms persist for six months or more. Obsessive-​ compulsive disorder (OCD) –​ Obsessions are persistent, distressing thoughts that are unwanted. –​ Compulsions are repetitive behaviours or mental acts, rigidly performed to prevent or reduce distress. They are not however connected in a realistic way with what they are designed to prevent, or are clearly excessive. –​ Symptoms consume more than one hour per day or cause impairment. Social phobia –​ Significant recurrent anxiety about one or more social situations related to scrutiny by others, out of proportion with the actual threat posed, which causes avoidance and lasts for six months or more. –​ Associated fears about outwardly showing symptoms of anxiety. Table 26.5.8.4  Other medical conditions that may cause anxiety Common Thyroid dysfunction Asthma or other pulmonary disease Electrolyte abnormality (e.g. hypercalcaemia) Anaemia Diabetes Cardiac disease (e.g. tachyarrhythmias) Delirium (in hospital settings) Less common Pheochromocytoma Other endocrine conditions (e.g. hypogonadism) Brain neoplasm or metastases

SECTION 26  Psychiatric and drug-related disorders 6504 missed medical diagnoses in patients with concurrent anxiety by highlighting those symptoms (e.g. diplopia) that are unlikely to be due to anxiety. The two-​item Generalized Anxiety Scale (GAD-​2) can be administered as a rapid screening measure for anxiety dis- orders (Table 26.5.8.6). It is important to note that anxiety com- monly coexists with depression and that all anxiety patients should be assessed for depression. Diagnosis When a patient is anxious, it is important to first ask how persistent and severe the anxiety is. To determine the associated functional im- pairment, the clinician must assess the patient’s level of function in multiple areas of their life (work, romantic, and family relationships, friendships, hobbies, and so on). For patients whose level of func- tioning is poor, also asking about functional level prior to the onset of symptoms can help establish the extent to which anxiety is con- tributing to functional impairment. Treatment When a medical patient is anxious, the first step is to ask them why and see if information and addressing their fears, for example, about prognosis, is effective. Anxiety disorders, while highly common and frequently debilitating, are usually treatable. Both drug and psychological treat- ment are effective and may be used in combination, especially for severe anxiety disorders. Pharmacotherapy Drugs used to treat anxiety disorders are listed in Table 26.5.8.7. The most commonly used drugs are now the serotonin reuptake in- hibitors, which while also used as antidepressants have proven to be even more effective for the treatment of anxiety. Benzodiazepines such as diazepam and lorazepam are highly effective in relieving anxiety, but these agents are now generally restricted to short-​term use because of the risk of dependence. While many physicians are more comfortable prescribing medi- cation than providing psychotherapy, it is important to ask the pa- tient what their preference is. For mild to moderate anxiety, either modality may be effective as a first-​line treatment. For patients with moderate to severe anxiety, pharmacotherapy on a short-​ or long-​ term basis is usually needed. Serotonin reuptake inhibitors The serotonin reuptake inhibitors are now first-​line treatment for anxiety disorder. There is no clear difference in efficacy among these agents, but side effect profiles differ. Many anxious patients are highly sensitive to medications, so it is important to start slowly and provide education about the frequency of side effects and time course of response, in order to avoid premature discontinuation. Patients need to understand that these medications must be taken daily, and are not effective on an ‘as-​needed’ basis. Every physician should become comfortable using a few selective serotonin reuptake inhibitors (SSRIs) as some patients may prefer one or have had a prior good or poor response to a particular agent. Most are now available as generics. They can all be given once daily making adherence relatively easy. The most common side effects of SSRIs are gastrointestinal and sexual. Many patients will experience initial gastrointestinal dis- comfort including nausea, but it is important to reassure the patient that this side effect disappears for almost everyone within the first week of treatment. They should be told to take the medication with food, at least until the gastrointestinal side effects have remitted. For some patients, it may be beneficial to start at a lower than usual starting dosage and titrate up once the gastrointestinal side effects abate (e.g. starting at sertraline 25 mg daily). Sexual side effects include decreased interest and anorgasmia for women and erectile or ejaculatory dysfunction for men. These side effects do not dissipate but are fully reversible upon discontinuation. If a patient has benefited from an SSRI and wants to continue it des- pite these effects, it may be helpful to use PDE5 inhibitors such as sildenafil or tadalafil. Some may benefit from the addition of bu- propion 100–​200 mg daily. For those who do not want to continue an SSRI because of sexual side effects, mirtazapine is an alternative. It is important to monitor response and not settle for only partial improvement. If after four to six weeks of treatment there has not been substantial improvement, the dosage can be increased. If there is still no improvement, alternative agents or psychotherapy may be needed. Abrupt discontinuation of SSRIs may cause an uncomfortable withdrawal state, characterized by insomnia, anxiety, agitation, and sometimes electric-​like sensations. Patients need to be educated not Table 26.5.8.6  The two-​item Generalized Anxiety Scale (GAD-​2) Over the past two weeks, how often have you been bothered by the following problems?

1. Feeling nervous, anxious, or on edge Not at all = 0 Several days = 1 More than one-​half of the days = 2 Nearly every day = 3
2. Being unable to stop or control worrying Not at all = 0 Several days = 1 More than one-​half of the days = 2 Nearly every day = 3 Two-​item total score of greater or equal to 3 represents a positive screen. Table 26.5.8.5  Substances and medications relevant to the assessment of anxiety Use may cause anxiety Prescription stimulants (e.g. methylphenidate) Cocaine Caffeine Cannabinoids Antidepressants Corticosteroids (including asthma inhalers) β2-​adrenergic agonists (including asthma inhalers) Androgens or oestrogens Sympathomimetics (e.g. ephedrine) Opioid antagonists (due to precipitated withdrawal) Withdrawal may cause anxiety Ethanol Benzodiazepines Barbiturates Opiates

26.5.8  Anxiety disorders 6505 to stop an SSRI abruptly and that they should be tapered over weeks under the supervision of a physician. Pharmacologic treatment for panic disorder should continue for at least six months after the symptoms have resolved. For patients with chronic or recurrent panic disorder, or years of generalized anxiety disorder, treatment may continue indefinitely. Some patients may be reluctant to taper off if there are ongoing severe psychosocial stressors. Long-​term treatment with SSRIs is generally quite safe and late side effects do not occur. The physician should always care- fully monitor medical conditions and concurrent medications when SSRIs are given for a long duration (e.g. if a healthy patient develops peptic ulcer disease this should lead to reconsideration of SSRI use, given their potential for causing gastrointestinal bleeding). Other agents Benzodiazepines, while still widely used, should not usually be first line for an anxiety disorder as they can cause sedation and cognitive dysfunction, are addictive, and commonly abused. However, they are useful for short-​term anxiety, such as that associated with a med- ical procedure. They may also be used in the occasional patient who is refractory to treatment with SSRIs, and without a history of al- cohol or drug abuse. For a patient with significant anxiety, it may be useful to start an SSRI and daily benzodiazepine. After a few weeks when the SSRI has had time to become effective, the benzodiazepine can be gradually tapered off. The serotonin and norepinephrine reuptake inhibitors venlafaxine and duloxetine are usually effective alternatives for anxiety. They may be preferentially indicated for patients with comorbid pain such as neuropathic pain or fibromyalgia. Blood pressure should be checked as they may cause mild increases. Duloxetine rarely causes hepatic dysfunction. Other drugs sometimes used to treat anxiety are gabapentin and pregabalin. Atypical antipsychotic drugs such as quetiapine are also effective. β-blockers are often prescribed but are only useful in redu- cing the physical symptoms of performance anxiety. Psychological treatments Where available, psychotherapy is the treatment of choice for many patients with anxiety disorders. The physician can offer brief psy- chological interventions themselves that are often effective, particu- larly for those with mild to moderate anxiety. Cognitive behavioural therapy (CBT) is effective for most anxiety disorders. For patients with generalized anxiety and panic disorder, the primary care physician can use elements of CBT. For example, they may encourage patients to question fearful thoughts, replacing undue fears with more realistic appraisals, and listing the worst possible scenarios in order to help the patient see that they can handle feared future events. CBT-​type treat- ment is increasingly available as internet-​based self-​treatment and may be useful when access to a therapist is difficult. Referral for specialized treatments Patients should be referred for consultation or treatment with a psychologist or psychiatrist for severe or refractory symptoms, pa- tient preference, or selected disorders that are generally beyond the expertise of the primary care physician (Table 26.5.8.8). Obsessive-​compulsive disorder can be challenging, and psychiat- rists and other mental health professionals who are expert in CBT should generally treat it. All of the SSRIs are beneficial, but may need to be given at higher doses than for generalized anxiety disorder Table 26.5.8.7  Medications to treat anxiety Class Examples When to use Selected side effects Additional notes Serotonin reuptake inhibitor Sertraline, escitalopram First line for anxiety disorders Sexual, gastrointestinal, sedation Serotonin and norepinephrine reuptake inhibitor Venlafaxine, duloxetine First line for anxiety disorders Sexual, gastrointestinal May also help with pain Tricyclic antidepressant Nortriptyline, imipramine Second line Cardiac, anticholinergic, sedation Benzodiazepines Lorazepam, clonazepam, diazepam First line for severe anxiety Sedation, confusion, addiction potential, avoid alcohol Ideally on short-​term basis only; caution in elderly Calcium current inhibitor Pregabalin Second line Sedation, dizziness Recently approved for anxiety in Europe Table 26.5.8.8  Some examples of when to refer for consultation or treatment Practitioner Modalities used Patient preference for psychotherapy Psychologist, psychiatrist, other trained mental health professional Cogntive behavioural therapy, trauma-​focused psychotherapy, insight-​oriented psychotherapy, and others Severe or refractory symptoms Psychiatrist Consultation, pharmacotherapy, psychotherapy Diagnostic uncertainty Psychiatrist Thorough review of history, medical issues Social anxiety Psychologist or psychiatrist Behavioural therapy, medication Obsessive-​compulsive disorder Psychologist or psychiatrist CBT (exposure and response prevention), selective serotonin reuptake inhibitors (SSRIs), or clomipramine Simple phobias Psychologist or psychiatrist Behavioural therapy (systematic desensitization)