21 - Medication Induced Movement Disorders and Oth

Medication-Induced Movement Disorders and Other Adverse Effects of Medication

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Medication-Induced Movement Disorders and Other Adverse Effects of Medication Medication-induced movement disorders are included in Section II because of their frequent importance in 1) the management by medication of mental disorders or other medical conditions and 2) the differential diagnosis of mental disorders (e.g., anxiety disorder vs. medication-induced akathisia; malignant catatonia [a particularly severe and potentially lifethreatening form of catatonia] vs. neuroleptic malignant syndrome; tardive dyskinesia vs. chorea). Although these movement disorders are labeled “medication induced,” it is often difficult to establish the causal relationship between medication exposure and the development of the movement disorder, especially because some of these movement disorders also occur in the absence of medication exposure. The conditions and problems listed in this chapter are not mental disorders. The term neuroleptic is becoming outdated because it highlights the propensity of antipsychotic medications to cause abnormal movements, and it is being replaced with the term antipsychotic medications and other dopamine receptor blocking agents in many contexts. Although newer antipsychotic medications may be less likely to cause some medication-induced movement disorders, those disorders still occur. Antipsychotic medications and other dopamine receptor blocking agents include so-called conventional, “typical,” or first-generation antipsychotic agents (e.g., chlorpromazine, haloperidol, fluphenazine); “atypical” or secondgeneration antipsychotic agents (e.g., clozapine, risperidone, olanzapine, quetiapine); certain dopamine receptor blocking drugs used in the treatment of symptoms such as nausea and gastroparesis (e.g., prochlorperazine, promethazine, trimethobenzamide, thiethylperazine, metoclopramide); and amoxapine, which is indicated for the treatment of depression. Medication-Induced Parkinsonism G21.11 Antipsychotic Medication– and Other Dopamine Receptor Blocking Agent–Induced Parkinsonism G21.19 Other Medication-Induced Parkinsonism Medication-induced parkinsonism (MIP), the second most common cause of parkinsonism after Parkinson’s disease, is associated with significant morbidity, disability, and treatment nonadherence, particularly in individuals with psychiatric disorders. Because early recognition is important, any new case of parkinsonism should prompt a thorough medication history, which is essential for diagnosis of MIP. A temporal relationship between medication initiation and onset of parkinsonism should be evident. A host of agents that may be prescribed in individuals with psychiatric disorders may also induce parkinsonism, but MIP is most often seen upon exposure

to antipsychotic medications that block dopamine D2 receptors. MIP occurs at higher rates with antipsychotics that have higher potency for the dopamine D2 receptor, such as haloperidol, fluphenazine, and risperidone, but there are no differences in the clinical features of parkinsonism between first- and second-generation antipsychotics. Other medications that can cause MIP include calcium channel antagonists (e.g., flunarizine, cinnarizine), dopamine depleters (e.g., reserpine, tetrabenazine), antiepileptics (e.g., phenytoin, valproate, levetiracetam), antidepressants (e.g., selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), lithium, chemotherapeutic drugs (e.g., cystosine arabinoside, cyclophosphamide, vincristine, doxorubicin, paclitaxel, etoposide), and immunosuppressants (e.g., cyclosporine, tacrolimus). Toxins (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], organophosphate pesticides, manganese, methanol, cyanide, carbon monoxide, and carbon disulfide) may also cause MIP. The time course for development of MIP varies. Usually, MIP develops a few weeks after starting or raising the dose of a medication known to cause parkinsonism or after reducing an antiparkinsonian medication (e.g., an anticholinergic agent) that is being used to treat or prevent medication-induced dystonia or parkinsonian symptoms. However, MIP may also develop rapidly after starting or raising the dose of a medication or have an insidious onset after many months of exposure. With antipsychotic medications or other dopamine receptor blocking agents, MIP typically develops 2–4 weeks after starting the medication and usually by 3 months. Mainly with calcium channel blockers, a second peak of symptom onset is reported after about 1 year. Reported rates of MIP are affected by absence of standard diagnostic criteria, incorrect diagnosis or misattribution of MIP signs to Lewy body disease (e.g., Parkinson’s disease), or a psychiatric condition, and overall lack of recognition, especially in milder cases. It is estimated that at least 50% of outpatients receiving long-term antipsychotic treatment with typical agents develop parkinsonian signs or symptoms at some point in their course of treatment. There are no clinical characteristics that distinguish MIP reliably from Parkinson’s disease. Because motor signs and symptoms in Parkinson’s disease begin unilaterally and progress asymmetrically, the subacute onset of bilateral parkinsonism within weeks of starting an antipsychotic or other MIP-causing agent is highly suggestive for MIP. Parkinsonian signs are often symmetric in MIP, but asymmetric patterns are not uncommon and should not exclude a diagnosis of MIP. In addition, the course and presentation of parkinsonism should not be better accounted for by psychiatric phenomena, such as catatonia, negative symptoms of schizophrenia, or psychomotor retardation in a major depressive episode; other nonparkinsonian medicationinduced movement disorders; another neurological or medical condition (e.g., Parkinson’s disease, Wilson’s disease); or antipsychotic-exacerbated Parkinson’s disease. In MIP, rigidity and bradykinesia are more often present, whereas tremor is somewhat less common and may be absent. Parkinsonian tremor, also referred to as a “pill-rolling tremor,” is a steady, rhythmic oscillatory movement (3–6 cycles per second) that is apparent at rest and is typically slower than other tremors. It may be intermittent, unilateral or bilateral, or dependent on limb position (i.e., positional tremor). The tremor may involve the limbs, head, jaw, mouth, lip (“rabbit syndrome”), or tongue. As it is present at rest, the tremor can be suppressed, especially

when the individual attempts to perform a task with the tremulous limb. Individuals may describe the tremor as “shaking” and report that it may worsen with anxiety, stress, or fatigue. Parkinsonian rigidity is experienced as an involuntary stiffness and inflexibility of the muscles of the limbs, shoulders, neck, or trunk. Rigidity is evaluated by assessing muscle tone, or the amount of resistance present when the examiner moves a limb (and stretches the muscles) passively around a joint. In lead-pipe rigidity, increased tone is constant throughout range of motion (in contrast to the clasp-knife rigidity spasticity). Cogwheel rigidity is thought to represent a tremor superimposed on rigidity. Most common in the wrists and elbows, it is experienced as a rhythmic, ratchet-like resistance (cogwheeling) when the muscles are passively moved around a joint. Individuals with parkinsonian rigidity may complain of generalized muscle tenderness or stiffness, tightness in their limbs, muscle or joint pain, body aching, or lack of coordination. Bradykinesia and akinesia are observable states of decreased or absent spontaneous motor activity, respectively. There is global slowing as well as slowness in initiating and executing movements. Everyday behaviors (e.g., grooming) can be difficult to perform normally and may be reduced. Individuals may complain of listlessness, lack of spontaneity and drive, or fatigue. Parkinsonian rigidity and bradykinesia manifest as gait abnormalities, including decreased stride length, arm swing, or overall spontaneity of walking. Other signs include a hunched posture with bent-over neck and stooped shoulders, a staring facial expression, and small shuffling steps. Drooling can arise as a result of reduced pharyngeal motor activity and swallowing, but because of anticholinergic properties of these medications, it may be less common in antipsychoticinduced parkinsonism as compared with other medications that cause MIP. MIP is associated with increased gait dysfunction, falls, and nursing home placement. As such, MIP is a serious iatrogenic movement disorder in older individuals that warrants recognition and early diagnosis. Associated behavioral symptoms may include depression and worsening of negative signs of schizophrenia. Other parkinsonian signs and symptoms include small handwriting (micrographia), reduced motor dexterity, hypophonia, decreased gag reflex, dysphagia, postural instability, reduced facial expression and blinking, and seborrhea. When parkinsonism is associated with severe decreased motor activity, medical complications of parkinsonism include contractures, bedsores, pulmonary emboli, urinary incontinence, aspiration pneumonia, weight loss, and hip fractures. Consistent risk factors are female gender, older age, cognitive impairment, other concurrent neurological conditions, HIV infection, family history of Parkinson’s disease, and severe psychiatric disease. MIP secondary to antipsychotic use is also reported in children. The risk of MIP is reduced if individuals are taking anticholinergic medications. Differential Diagnosis Parkinson’s disease and Parkinson’s-plus conditions such as multiple system atrophy, progressive supranuclear palsy, and Wilson’s disease are distinguished from MIP by their other signs and symptoms that accompany parkinsonism. For example, Parkinson’s disease is suggested by evidence of three or more cardinal features of Parkinson’s disease (e.g., resting

tremor, rigidity, bradykinesia, postural instability), hyposmia, sleep disturbances such as rapid eye movement (REM) sleep behavior disorder, and urinary and other autonomic symptoms common to Parkinson’s disease. These features are less likely to be present in MIP. Individuals with primary neurological causes of parkinsonism are also susceptible to worsening symptoms if treated with medications causing MIP. Nonparkinsonian tremors tend to be finer (e.g., smaller amplitude) and faster (10 cycles per second) and worsen on intention (e.g., when reaching out to grab an object). With substance withdrawal, there is usually associated hyperreflexia and increased autonomic signs. In cerebellar disease, tremor worsens on intention and may be associated with nystagmus, ataxia, or scanning speech. Choreiform movements associated with tardive dyskinesia lack the steady rhythmicity of a parkinsonian tremor. Strokes and other central nervous system lesions can cause focal neurological signs or immobility from flaccid or spastic paralysis, which is characterized by decreased muscle strength and increased tone on passive movement that gives way with further pressure (i.e., clasp-knife rigidity). This contrasts with the lead-pipe rigidity and normal muscle strength in MIP. Diagnostic alternatives to MIP are also suggested by a family history of an inherited neurological condition, rapidly progressive parkinsonism not accounted for by recent psychopharmacological changes, or presence of focal neurological signs (e.g., frontal release signs, cranial nerve abnormalities, a positive Babinski sign). Neuroleptic malignant syndrome involves severe akinesia and rigidity, but also characteristic physical and laboratory findings (e.g., fever, increased creatine phosphokinase). Psychomotor slowing, inactivity, and apathy seen in major depressive disorder can be indistinguishable from the motor slowness or akinesia of MIP, but major depressive disorder is more likely to include vegetative signs (e.g., early-morning awakening), hopelessness, and despair. Negative symptoms of schizophrenia, catatonia associated with schizophrenia, or mood disorders with catatonic features may also be difficult to distinguish from medication-induced akinesia. Rigidity may also manifest in psychotic disorders, delirium, major neurocognitive disorder, anxiety disorders, and functional neurological symptom disorder (conversion disorder). In parkinsonian rigidity, resistance to passive motion is constant through the full range of motion, whereas it is inconsistent in psychiatric disorders or other neurological conditions presenting with rigidity. In general, the constellation of associated physical signs on examination and symptoms associated with the tremor, rigidity, and bradykinesia of parkinsonism helps distinguish MIP-related rigidity and bradykinesia from other primary psychiatric causes of rigidity and decreased movement. Neuroleptic Malignant Syndrome G21.0 Neuroleptic Malignant Syndrome Individuals with neuroleptic malignant syndrome have generally been exposed to a dopamine antagonist within 72 hours prior to symptom development. Hyperthermia (>100.4°F or >38.0°C on at least two occasions, measured orally), associated with profuse diaphoresis, is a

distinguishing feature of neuroleptic malignant syndrome, setting it apart from other neurological side effects of antipsychotic medications and other dopamine receptor blocking agents. Extreme elevations in temperature, reflecting a breakdown in central thermoregulation, are more likely to support the diagnosis of neuroleptic malignant syndrome. Generalized rigidity, described as “lead pipe” in its most severe form and usually unresponsive to antiparkinsonian agents, is a cardinal feature of the disorder and may be associated with other neurological symptoms (e.g., tremor, sialorrhea, akinesia, dystonia, trismus, myoclonus, dysarthria, dysphagia, rhabdomyolysis). Creatine kinase elevation of at least four times the upper limit of normal is commonly seen. Changes in mental status, characterized by delirium or altered consciousness ranging from stupor to coma, are often an early sign of neuroleptic malignant syndrome. Affected individuals may appear alert but dazed and unresponsive, consistent with catatonic stupor. Autonomic activation and instability—manifested by tachycardia (rate > 25% above baseline), diaphoresis, blood pressure elevation (systolic or diastolic ≥ 25% above baseline) or fluctuation (≥ 20 mmHg diastolic change or ≥25 mmHg systolic change within 24 hours), urinary incontinence, and pallor—may be seen at any time but provide an early clue to the diagnosis. Tachypnea (rate > 50% above baseline) is common, and respiratory distress—resulting from metabolic acidosis, hypermetabolism, chest wall restriction, aspiration pneumonia, or pulmonary emboli—can occur and lead to sudden respiratory arrest. Although several laboratory abnormalities are associated with neuroleptic malignant syndrome, no single abnormality is specific to the diagnosis. Individuals with neuroleptic malignant syndrome may have leukocytosis, metabolic acidosis, hypoxia, decreased serum iron concentrations, and elevations in serum muscle enzymes and catecholamines. Findings from cerebrospinal fluid analysis and neuroimaging studies are generally normal, whereas electroencephalography shows generalized slowing. Autopsy findings in fatal cases have been nonspecific and variable, depending on complications. Evidence from database studies suggests incidence rates for neuroleptic malignant syndrome of 0.01%–0.02% among individuals treated with antipsychotics. A population-based study conducted in Hong Kong found an incidence risk of 0.11% in individuals treated with antipsychotic medication. The temporal progression of signs and symptoms provides important clues to the diagnosis and prognosis of neuroleptic malignant syndrome. Alteration in mental status and other neurological signs typically precede systemic signs. The onset of symptoms varies from hours to days after drug initiation. Some cases develop within 24 hours after drug initiation, most within the first week, and virtually all cases within 30 days. Once the syndrome is diagnosed and oral antipsychotic drugs and other dopamine receptor blocking agents are discontinued, neuroleptic malignant syndrome is self-limited in most cases. The mean recovery time after drug discontinuation is 7–10 days, with most individuals recovering within 1 week and nearly all within 30 days. The duration may be prolonged when long-acting antipsychotic medications are implicated. There have been reports of individuals in whom residual neurological signs persisted for weeks after the acute hypermetabolic symptoms resolved. Total resolution of symptoms can be obtained in most cases of neuroleptic malignant syndrome; however, fatality rates of 10%– 20% have been reported when the disorder is not recognized. Although many individuals do not

experience a recurrence of neuroleptic malignant syndrome when rechallenged with antipsychotic medication, some do, especially when antipsychotic medications are reinstituted soon after an episode. Neuroleptic malignant syndrome is a potential risk in any individual after administration of an antipsychotic medication or other dopamine receptor blocking agent. It is not specific to any neuropsychiatric diagnosis and may occur in persons without a diagnosable mental disorder who receive dopamine antagonists. Clinical, systemic, and metabolic factors associated with a heightened risk of neuroleptic malignant syndrome include agitation, exhaustion, dehydration, and iron deficiency. A prior episode associated with antipsychotic medication and other dopamine receptor blocking agents has been described in 15%–20% of index cases, suggesting underlying vulnerability in some individuals; however, genetic findings based on neurotransmitter receptor polymorphisms have not been replicated consistently. Nearly all antipsychotic medication and other dopamine receptor blocking agents have been associated with neuroleptic malignant syndrome, although high-potency antipsychotics pose a greater risk compared with low-potency agents and atypical antipsychotics. Partial or milder forms may be associated with newer antipsychotics, but neuroleptic malignant syndrome varies in severity even with older drugs. Dopamine receptor blocking agents used in medical settings (e.g., metoclopramide, prochlorperazine) have also been implicated. Parenteral administration routes, rapid titration rates, and higher total drug dosages have been associated with increased risk; however, neuroleptic malignant syndrome usually occurs within the therapeutic dosage range of antipsychotic medications and other dopamine receptor blocking agents. Differential Diagnosis Neuroleptic malignant syndrome should be distinguished from other serious neurological or medical conditions, including central nervous system infections, inflammatory or autoimmune conditions, status epilepticus, subcortical structural lesions, and systemic conditions (e.g., pheochromocytoma, thyrotoxicosis, tetanus, heat stroke). Neuroleptic malignant syndrome also should be distinguished from similar syndromes resulting from the use of other substances or medications, such as serotonin syndrome; parkinsonian hyperthermia syndrome following abrupt discontinuation of dopamine agonists; alcohol or sedative withdrawal; malignant hyperthermia occurring during anesthesia; hyperthermia associated with misuse of stimulants and hallucinogens; and atropine poisoning from anticholinergics. In rare instances, individuals with schizophrenia or a mood disorder may present with malignant catatonia, which may be indistinguishable from neuroleptic malignant syndrome. Some investigators consider neuroleptic malignant syndrome to be a drug-induced form of malignant catatonia. Medication-Induced Acute Dystonia G24.02 Medication-Induced Acute Dystonia The essential feature of medication-induced acute dystonia is sustained abnormal muscle

contractions (increased muscle tone) and postures that develop in association with use of a medication known to cause acute dystonia. Any medication that blocks dopamine D2-like receptors can induce an acute dystonic reaction (ADR). Most commonly, ADRs occur after exposure to antipsychotics and antiemetic and promotility agents. A variety of other medication classes are also reported to have induced ADRs, including selective serotonin reuptake inhibitors, cholinesterase inhibitors, opioids, and methylphenidate. Dystonic reactions vary greatly in severity and location and can be focal, segmented, or generalized. They most often affect head and neck muscles, but can extend to upper and lower limbs or trunk. A common presentation is acute oro-mandibular (jaw) dystonia involving the tongue and mouth with tongue protrusion, or gaping or grimacing postures that can impair speech (dysarthria) and swallowing (dysphagia) and may evolve into frank trismus (lockjaw). Involvement of ocular muscles (oculogyric crisis) manifests as involuntary forced and sustained conjugate deviations of eyes upward, downward, or sideways that can last minutes to hours. Blepharospasm can also occur. Cervical (neck) dystonia presents as abnormal forward, backward, lateral, or twisting positions of the head and neck in relation to the body (e.g., antecollis, retrocollis, laterocollis, and torticollis). Focal limb dystonia, generally more distal than proximal, Pisa syndrome (lateral bending of the trunk with a tendency to lean to one side), and back arching that may evolve into opisthotonos (backward arching of head, neck, and spine) can also occur. Acute laryngeal dystonia is life-threatening, causing airway obstruction, and manifests as a “clutching of the throat,” stridor, dysphonia, dysphagia, dyspnea, and respiratory distress from the medication effects on vocal cords and laryngeal muscles. At least 50% of individuals develop ADR signs or symptoms within 24–48 hours of starting or rapidly raising the dose of antipsychotic medication or other dopamine receptor blocking agent or of reducing a medication being used to treat or prevent acute extrapyramidal symptoms (e.g., anticholinergic agents). Approximately 90% of affected individuals have onset of ADRs within 5 days. The symptoms must not be better accounted for by a mental disorder (e.g., catatonia) and must not be due to a primary neurological or other medical condition, or a tardive medication-induced movement disorder. Fear and anxiety often accompany ADRs given their intense nature, inability of the individual to control or stop the movements, and, when present, difficulty breathing, speaking, or swallowing. Some individuals experience pain or cramps in affected muscles. Individuals who are unaware of the possibility of developing a medication-induced dystonia can be especially distressed, increasing the likelihood of subsequent medication nonadherence. Thought disorder, delusions, or mannerisms in an individual with psychosis may cause the affected individual or others to mistakenly regard his or her dystonic symptoms as a feature of the psychiatric condition, which could lead to increased doses of the causative medication. The risk of developing ADRs is greatest in children and in adults younger than age 40 with psychosis, with a greater incidence in males than females in both children and adults. Other risk factors for developing ADRs include prior dystonic reactions to antipsychotic medications or other dopamine receptor blocking agents and use of high-potency typical antipsychotic medications. Differential Diagnosis It is important to distinguish between medication-induced ADRs and other causes of dystonia, especially in individuals being treated with antipsychotic or other dopamine receptor blocking

medications. A primary neurological or other medical condition is evident based on the time course and evolution of the dystonic phenomena (e.g., dystonia precedes exposure to the antipsychotic medication or progresses in the absence of change in medication) and, possibly, other evidence of focal neurological signs. Idiopathic focal or segmental dystonias usually persist for several days or weeks independent of medication. A family history of dystonia may also be present. Tardive dystonia secondary to medication exposure, including antipsychotic medication or other dopamine receptor blocking agents, does not have acute onset and may become evident when the dose of an antipsychotic medication is lowered. Other neurological conditions (e.g., epileptic seizures, viral and bacterial infections, trauma, space-occupying lesions in the peripheral or central nervous system) and endocrinopathies (e.g., hypoparathyroidism) can also produce symptoms (e.g., tetany) that resemble a medicationinduced acute dystonia. Other diagnoses that mimic an acute medication-induced dystonia include anaphylaxis, tardive laryngeal dystonia, and respiratory dyskinesia. Neuroleptic malignant syndrome can produce dystonia but differs in that it is also accompanied by fever and generalized rigidity. Catatonia associated with a mood disorder or schizophrenia can be distinguished by the temporal relationship between the symptoms and the exposure to antipsychotic treatment (e.g., dystonia preceding exposure to antipsychotic medication) and response to pharmacological intervention (e.g., no improvement after lowering of dose of the antipsychotic medication or in response to anticholinergic administration). Furthermore, individuals with medication-induced acute dystonia are generally distressed about the dystonic reaction and usually seek intervention. In contrast, individuals with the retarded type of catatonia are typically mute and withdrawn and do not express subjective distress about their condition. Medication-Induced Acute Akathisia G25.71 Medication-Induced Acute Akathisia The essential features of medication-induced acute akathisia are subjective complaints of restlessness and at least one of the following observed movements: fidgety movements or swinging of the legs while seated, rocking from foot to foot or “walking on the spot” while standing, pacing to relieve the restlessness, or an inability to sit or stand still for at least several minutes. Individuals experiencing the most severe form of medication-induced acute akathisia may be unable to maintain any position for more than a few seconds. The subjective complaints include a sense of inner restlessness, most often in the legs; a compulsion to move one’s legs; distress if one is asked not to move one’s legs; and dysphoria and anxiety. The symptoms typically occur within 4 weeks of initiating or increasing the dose of a medication that can cause akathisia, which includes antipsychotic medications and other dopamine receptor blocking agents, tricyclic antidepressants, selective serotonin reuptake inhibitors, dopamine agonists, and calcium channel blockers, and can occasionally follow the reduction of medication used to treat or prevent acute extrapyramidal symptoms (e.g., anticholinergic agents). The symptoms are not better explained by a mental disorder (e.g., schizophrenia, substance withdrawal, agitation from a

major depressive or manic episode, hyperactivity in attention-deficit/hyperactivity disorder) and are not due to a neurological or other medical condition (e.g., Parkinson’s disease, irondeficiency anemia). The subjective distress resulting from akathisia is significant and can lead to noncompliance with antipsychotic or antidepressant treatment. Akathisia may be associated with dysphoria, irritability, aggression, or suicide attempts. Worsening of psychotic symptoms or behavioral dyscontrol may lead to an increase in medication dose, which may exacerbate the problem. Akathisia can develop very rapidly after initiating or increasing the causative medication. The development of akathisia appears to be dose dependent and to be more frequently associated with particular high-potency antipsychotic medications or drugs with higher affinity for central dopamine receptors. Acute akathisia tends to persist for as long as the causative medication is continued, although the intensity may fluctuate over time. The reported prevalence of akathisia among individuals receiving antipsychotic medication or other dopamine receptor blocking agents has varied widely (20%–75%). Variations in reported prevalence may be attributable to a lack of consistency in the definition, antipsychotic prescribing practices, study design, and the demographics of the population being studied. Differential Diagnosis Medication-induced acute akathisia may be clinically indistinguishable from syndromes of restlessness due to certain neurological or other medical conditions, and to agitation presenting as part of a mental disorder (e.g., a manic episode). The akathisia of Parkinson’s disease and iron-deficiency anemia is phenomenologically similar to medication-induced acute akathisia. The frequently abrupt appearance of restlessness soon after initiation or increase in medication usually distinguishes medication-induced acute akathisia. Serotonin-specific reuptake inhibitor antidepressant medications may produce akathisia that appears to be identical in phenomenology and treatment response to akathisia induced by antipsychotic medication or other dopamine receptor blocking agents. Tardive dyskinesia also often has a component of generalized restlessness that may coexist with akathisia in an individual receiving antipsychotic medications or other dopamine blocking agents. Antipsychotic medication and other dopamine blocking agent–induced acute akathisia is differentiated from antipsychotic medication and other dopamine blocking agent–induced tardive dyskinesia by the nature of the movements and their relationship to the initiation of medication. The time course of symptomatic presentation relative to medication dose changes may aid in this distinction. An increase in antipsychotic medication will often exacerbate akathisia, whereas it often temporarily relieves the symptoms of tardive dyskinesia. Medication-induced acute akathisia should be distinguished from symptoms that are better accounted for by a mental disorder. Individuals with depressive episodes, manic episodes, generalized anxiety disorder, schizophrenia spectrum and other psychotic disorders, attentiondeficit/hyperactivity disorder, major neurocognitive disorder, delirium, substance intoxication (e.g., with cocaine), or substance withdrawal (e.g., from an opioid) may also display agitation that is difficult to distinguish from akathisia. Some of these individuals are able to differentiate

akathisia from the anxiety, restlessness, and agitation characteristic of a mental disorder by their experience of akathisia as being different from previously experienced feelings. Other evidence that restlessness or agitation may be better accounted for by a mental disorder includes the onset of agitation prior to exposure to the causative medication, absence of increasing restlessness with increasing doses of the causative medication, and absence of relief with pharmacological interventions (e.g., no improvement after decreasing the dose of the causative medication or treatment with another medication intended to treat the akathisia). Tardive Dyskinesia G24.01 Tardive Dyskinesia The essential features of tardive dyskinesia are abnormal, involuntary movements of the tongue, jaw, trunk, or extremities that develop in association with the use of medications that block postsynaptic dopamine receptors, such as first- and second-generation antipsychotic medications and other medications such as metoclopramide for gastrointestinal disorders. The movements are present over a period of at least 4 weeks and may be choreiform (rapid, jerky, nonrepetitive), athetoid (slow, sinuous, continual), or semirhythmic (e.g., stereotypies) in nature; however, the movements are distinctly different from the rhythmic (3-6 Hz) tremors commonly seen in medication-induced parkinsonism. Signs or symptoms of tardive dyskinesia develop during exposure to the antipsychotic medication or other dopamine blocking agent, or within 4 weeks of withdrawal from an oral agent (or within 8 weeks of withdrawal from a long-acting injectable agent). There must be a history of the use of the offending agent for at least 3 months (or 1 month in individuals age 60 years or older). Although a large number of epidemiological studies have established the etiological relationship between dopamine blocking drug use and tardive dyskinesia, any dyskinesia in an individual who is receiving antipsychotic medication is not necessarily tardive dyskinesia. Abnormal orofacial movements are the most obvious manifestations of tardive dyskinesia and have been observed in most individuals afflicted with tardive dyskinesia; however, approximately one-half can have limb involvement, and up to one-quarter can have axial dyskinesia of the neck, shoulders, or trunk. Involvement of other muscle groups (e.g., pharyngeal, diaphragm, abdominal) may occur but is uncommon, especially in the absence of dyskinesia of the orofacial region, limbs, or trunk. Limb or truncal dyskinesia without orofacial involvement may be more common in younger individuals, whereas orofacial dyskinesias are typical in older individuals. The symptoms of tardive dyskinesia tend to be worsened by stimulants, antipsychotic medication withdrawal, and anticholinergic medications (such as benztropine, commonly used to manage medication-induced parkinsonism) and may be transiently worsened by emotional arousal, stress, and distraction during voluntary movements in unaffected parts of the body. The abnormal movements of dyskinesia are transiently reduced by relaxation and by voluntary movements in affected parts of the body. They are generally absent during sleep. Dyskinesia may be suppressed, at least temporarily, by increased doses of antipsychotic medication.

The overall prevalence of tardive dyskinesia in individuals who have received long-term antipsychotic medication treatment ranges from 20% to 30%. The overall incidence among younger individuals ranges from 3% to 5% per year. Middle-age and elderly individuals appear to develop tardive dyskinesia more often, with prevalence figures reported up to 50% and an incidence of 25%–30% after an average of 1 year’s cumulative exposure to antipsychotic medication. Prevalence also varies depending on setting, with tardive dyskinesia tending to be more common among chronically institutionalized individuals. Variations in reported prevalence may be attributable to a lack of consistency in the definition of tardive dyskinesia, antipsychotic prescribing practices, study design, and the demographics of the population being studied. There is no obvious gender difference in the susceptibility to tardive dyskinesia, although the risk may be somewhat greater in postmenopausal women. Greater cumulative amounts of antipsychotic medications and early development of acute extrapyramidal side effects (such as medication-induced parkinsonism) are two of the most consistent risk factors for tardive dyskinesia. Mood disorders (especially major depressive disorder), neurological conditions, and alcohol use disorder have also been found to be risk factors in some groups of individuals. Second-generation antipsychotics are associated with a somewhat lower incidence of tardive dyskinesia compared with first-generation antipsychotics, but the difference is not as large as once thought, especially when the dose of the first-generation antipsychotic is taken into account; the most important risk factors are age and cumulative exposure. Onset of tardive dyskinesia may occur at any age and is almost always insidious. The signs are typically minimal to mild at onset and escape notice except by a keen observer. In many cases, tardive dyskinesia is objectively mild but, although it has been thought of as a cosmetic problem, can be associated with significant distress and social avoidance. In severe cases, it may be associated with medical complications (e.g., ulcers in cheeks and tongue; loss of teeth; macroglossia; difficulty in walking, swallowing, or breathing; muffled speech; weight loss; depression; suicidal ideation). In older individuals there is a greater likelihood that tardive dyskinesia may become more severe or more generalized with continued antipsychotic medication use. When antipsychotic medications are discontinued, some individuals experience symptom improvement over time; however, for others tardive dyskinesia can be enduring. Differential Diagnosis It is imperative to distinguish medication-induced parkinsonism from tardive dyskinesia because the treatments commonly used to manage medication-induced parkinsonism (i.e., anticholinergic medications) may worsen the abnormal motor movements associated with tardive dyskinesia. Moreover, treatments used to manage tardive dyskinesia (i.e., VMAT2 inhibitors) may worsen the symptoms of medication-induced parkinsonism. Dyskinesia that emerges during withdrawal from an antipsychotic medication or other dopamine receptor blocking agent may remit with continued withdrawal from the medication. If the dyskinesia persists for at least 4 weeks, a diagnosis of tardive dyskinesia may be warranted. Tardive dyskinesia must be distinguished from other causes of orofacial and body dyskinesia.

These conditions include Huntington’s disease, Wilson’s disease, Sydenham’s (rheumatic) chorea, systemic lupus erythematosus, thyrotoxicosis, heavy metal poisoning, ill-fitting dentures, dyskinesia due to other medications such as L-dopa or bromocriptine, and spontaneous dyskinesias. Factors that may be helpful in making the distinction are evidence that the symptoms preceded the exposure to the antipsychotic medication or other dopamine receptor blocking agent or that other focal neurological signs are present. It should be noted that other movement disorders may coexist with tardive dyskinesia. Because spontaneous dyskinesia can occur in more than 5% of individuals and is also more common in elderly persons, it may be difficult to prove that antipsychotic medications produced tardive dyskinesia in a given individual. Tardive dyskinesia must be distinguished from symptoms that are due to a medication-induced acute movement disorder (e.g., medication-induced parkinsonism, acute dystonia, acute akathisia). Acute dystonia and acute akathisia can develop quickly within hours to days, and medication-induced parkinsonism develops within weeks of initiating or increasing the dose of an antipsychotic medication or other dopamine receptor blocking agent (or reducing the dose of a medication used to treat the acute extrapyramidal symptoms). Tardive dyskinesia, on the other hand, generally develops after more prolonged exposure to antipsychotic medication (months to years) and can appear after the withdrawal of antipsychotic medication; the minimum exposure history required for the diagnosis of tardive dyskinesia is antipsychotic medication use for at least 3 months (or 1 month in middle-age and elderly individuals). Tardive Dystonia Tardive Akathisia G24.09 Tardive Dystonia G25.71 Tardive Akathisia This category is for tardive syndromes involving other types of movement problems, such as dystonia or akathisia, which are distinguished by their late emergence in the course of treatment and their potential persistence for months to years, even in the face of discontinuation of an antipsychotic medication or other dopamine receptor blocking agent or dosage reduction. Medication-Induced Postural Tremor G25.1 Medication-Induced Postural Tremor The essential feature of this condition is a fine tremor occurring during attempts to maintain a posture, which develops in association with the use of medication. Medications with which such a tremor may be associated include lithium, β-adrenergic medications (e.g., isoproterenol), stimulants (e.g., amphetamine), dopaminergic medications, anticonvulsant medications (e.g., valproic acid), antidepressant medications, and methylxanthines (e.g., caffeine, theophylline). The tremor is a regular, rhythmic oscillation of the limbs (most commonly hands and fingers), head, mouth, or tongue, most commonly with a frequency of between 8 and 12 cycles per second. It is most easily observed when the affected body part is held in a sustained posture (e.g., hands outstretched, mouth held open). The tremor may worsen in severity when the affected

body part is moved intentionally (kinetic or action tremor). When an individual describes a tremor that is consistent with postural tremor but the clinician does not directly observe the tremor, it may be helpful to try to re-create the situation in which the tremor occurred (e.g., drinking from a cup and saucer). Most available information concerns lithium-induced tremor. Lithium tremor is a common, usually benign, and well-tolerated side effect of therapeutic doses. However, it may cause social embarrassment, occupational difficulties, and noncompliance in some individuals. As serum lithium levels approach toxic levels, the tremor may become coarser and be accompanied by muscle twitching, fasciculations, or ataxia. Nontoxic lithium tremor may improve spontaneously over time. A variety of factors may increase the risk of lithium tremor (e.g., increasing age, high serum lithium levels, concurrent antidepressant or antipsychotic medication or another dopamine receptor blocking agent, excessive caffeine intake, personal or family history of tremor, presence of alcohol use disorder, and associated anxiety). The frequency of complaints about tremor appears to decrease with duration of lithium treatment. Factors that may exacerbate the tremor include anxiety, stress, fatigue, hypoglycemia, thyrotoxicosis, pheochromocytoma, hypothermia, and alcohol withdrawal. Tremor can also be an early feature of serotonin syndrome. Differential Diagnosis Medication-induced postural tremor should be distinguished from a preexisting tremor that is not caused by the effects of a medication. Factors that help to establish that the tremor was preexisting include its temporal relationship to the initiation of medication, lack of correlation with serum levels of the medication, and persistence after the medication is discontinued. If a preexisting, nonpharmacologically induced tremor is present (e.g., essential tremor) that worsens with medication, such a tremor would not be considered to be medication-induced postural tremor. The factors described above that may contribute to the severity of a medication-induced postural tremor (e.g., anxiety, stress, fatigue, hypoglycemia, thyrotoxicosis, pheochromocytoma, hypothermia, alcohol withdrawal) may also be a cause of tremor independent of the medication. Medication-induced postural tremor is not diagnosed if the tremor is better accounted for by medication-induced parkinsonism. A medication-induced postural tremor is usually absent at rest and intensifies when the affected part is brought into action or held in a sustained position. In contrast, the tremor related to medication-induced parkinsonism is usually lower in frequency (3–6 Hz), worse at rest, and suppressed during intentional movement and usually occurs in association with other symptoms of medication-induced parkinsonism (e.g., akinesia, rigidity). Other Medication-Induced Movement Disorder G25.79 Other Medication-Induced Movement Disorder This category is for medication-induced movement disorders not captured by any of the specific disorders listed earlier. Examples include 1) presentations resembling neuroleptic malignant syndrome that are associated with medications other than antipsychotic medications and other dopamine receptor blocking agents and 2) other medication-induced tardive conditions.

Antidepressant Discontinuation Syndrome T43.205A Initial encounter T43.205D Subsequent encounter T43.205S Sequelae Discontinuation symptoms may occur following treatment with all types of antidepressants. The incidence of this syndrome depends on the dosage and half-life of the medication being taken, as well as the rate at which the medication is tapered. Short half-life medications that are abruptly discontinued (or when the dose is significantly reduced) rather than tapered gradually may pose the greatest risk. The short-acting antidepressants paroxetine and venlafaxine are the agents most commonly associated with discontinuation symptoms. Antidepressant discontinuation syndrome may occur in the context of intermittent non-adherence to treatment and therefore may be irregularly present in some individuals who have not actually stopped taking the medication. This is especially true for very short half-life medications (e.g., venlafaxine). By contrast, long half-life medications like fluoxetine seldom produce significant discontinuation effects. Unlike withdrawal syndromes associated with opioids, alcohol, and other substances, antidepressant discontinuation syndrome has no pathognomonic symptoms. Instead, the symptoms tend to be vague and variable. Symptoms typically begin 2–4 days after the last dose of the antidepressant. For selective serotonin reuptake inhibitors, symptoms such as dizziness, tinnitus, “electric shock”–like sensations, insomnia, and acute anxiety are described. The antidepressant use before discontinuation must not have incurred hypomania or mixed state (i.e., there should be confidence that the discontinuation syndrome is not the result of fluctuations in mood stability associated with the previous treatment). For the tricyclic antidepressants, sudden discontinuation has been associated with gastrointestinal symptoms (cramping—reflecting cholinergic overactivity after stopping an anticholinergic tricyclic antidepressant) as well as rebound hypomania. The antidepressant discontinuation syndrome is based solely on pharmacological factors and is not related to the reinforcing effects of an antidepressant. Unlike the discontinuation of substances with reinforcing effects like opioids, drug craving does not occur. Also, when a stimulant is used to augment an antidepressant, abrupt cessation may result in stimulant withdrawal symptoms (see “Stimulant Withdrawal” in the chapter “Substance-Related and Addictive Disorders”) rather than the antidepressant discontinuation syndrome described here. The prevalence of antidepressant discontinuation syndrome is unknown but is thought to vary according to any of the following factors: the dosage before discontinuation, the half-life (i.e., occurring more commonly with short half-life medications) and receptor-binding affinity of the medication (e.g., more likely to occur with serotonin reuptake inhibitors), and possibly the individual’s genetically influenced rate of metabolism for this medication. Therefore, discontinuation reactions occur more frequently with short half-life medications, but may also be influenced by rapid or ultrarapid metabolizer status of cytochrome enzymes that metabolize the antidepressant.

Because longitudinal studies are lacking, little is known about the clinical course of antidepressant discontinuation syndrome. Symptoms appear to abate over time with very gradual dosage reductions. Symptoms are usually short-lived, lasting no more than 2 weeks, and are seldom present more than 3 weeks after discontinuation. Differential Diagnosis The differential diagnosis of antidepressant discontinuation syndrome includes a relapse of the disorder for which the medication was prescribed (e.g., depression or panic disorder), somatic symptom disorder, bipolar I or bipolar II disorder with mixed features, substance use disorders, migraine, or cerebrovascular accident. Discontinuation symptoms often resemble symptoms of a persistent anxiety disorder or a return of somatic symptoms of depression for which the medication was initially given. It is important not to confuse discontinuation syndrome with a relapse of the original depressive or anxiety disorder for which the medication was being prescribed. Antidepressant discontinuation syndrome differs from substance withdrawal in that antidepressants themselves have no reinforcing or euphoric effects. Individuals typically do not escalate the dose of medications on their own, and they generally do not engage in drug-seeking behavior to obtain additional medication. Criteria for a substance use disorder are not met. Other Adverse Effect of Medication T50.905A Initial encounter T50.905D Subsequent encounter T50.905S Sequelae This category is available for optional use by clinicians to code side effects of medication (other than movement symptoms) when these adverse effects become a main focus of clinical attention. Examples include severe hypotension, cardiac arrhythmias, and priapism.