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Table 70–3 lists the adverse effects of antipsychotics. Some of these effects develop primarily following overdose, but others can occur during the course of therapeutic use.
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Adverse Effects During Therapeutic Use
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The Extrapyramidal Syndromes.
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The EPS (Table 70–4) are a heterogeneous group of disorders that share the common feature of abnormal muscular activity. Among the typical antipsychotics, the incidence of EPS appears to be highest with the more potent antipsychotics such as haloperidol and flupentixol, and lower with less potent antipsychotics such as chlorpromazine and thioridazine. Atypical antipsychotics are associated with an even lower incidence of EPS. Although the physiologic mechanisms for this observation are not fully understood, several hypotheses have been put forth. In addition to the aforementioned antagonism of 5-HT2A receptors, some atypical antipsychotics dissociate more rapidly from the D2 receptor and incite a lower degree of nigrostriatal dopaminergic hypersensitivity during chronic use.57,58,71 However, it is important to note that EPS can occur during treatment with any antipsychotic drug, regardless of typicality or potency.
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Acute dystonia is a movement disorder characterized by sustained involuntary muscle contractions, often involving the muscles of the head and neck, including the extraocular muscles and the tongue, but occasionally involving the extremities. These contractions are sometimes referred to as limited reactions, reflecting their transient nature rather than their severity. All the currently available antipsychotics are associated with the development of acute dystonic reactions.119 Spasmodic torticollis, facial grimacing, protrusion of the tongue, and oculogyric crisis are among the more common manifestations. Laryngeal dystonia is a rare but potentially life-threatening variant that is easily misdiagnosed because it can present with throat pain, dyspnea, stridor, and dysphonia rather than the more characteristic features of dystonia.38
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Acute dystonia typically develops within a few hours of starting of treatment but may be delayed for up to a few days. Left untreated, dystonia resolves slowly over several days once the offending antipsychotic is withdrawn. Risk factors for acute dystonia include male gender, young age (children are particularly susceptible), a previous episode of acute dystonia, and recent cocaine use.120,132 Although the reaction may appear dramatic and sometimes is mistaken for seizure activity, it is rarely life threatening. Of note, drugs other than antipsychotics can sometimes cause acute dystonia, particularly metoclopramide, antidepressants, some antimalarials, histamine H2-receptor antagonists, anticonvulsants, and cocaine.120
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Treatment of acute dystonia.
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Acute dystonia is generally more distressing than serious, but rare cases compromise respiration, necessitating supplemental oxygen and, occasionally, assisted ventilation.38,120 The response to parenteral anticholinergics often is rapid and dramatic, and every effort should be made to administer benztropine as the first-line agent (2 mg intravenously {IV} or intramuscularly {IM} in adults, or 0.05 mg/kg in children). Often, diphenhydramine is more readily available and can be used instead (50 mg IV or IM in adults, or 1 mg/kg in children). Parenteral benzodiazepines such as lorazepam (0.05–0.10 mg/kg IV or IM) or diazepam (0.1 mg/kg IV) should be considered if patients do not respond to anticholinergics, but they may also be effective as initial therapy. It is important to recognize that because the elimination half-life of most anticholinergics is shorter than that of most antipsychotics, dystonia can recur, and administering additional doses of an anticholinergic may be necessary over the next 48 to 72 hours.27 Patients in whom acute dystonia jeopardizes respiration should be observed for at least 12 to 24 hours after initial resolution.
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Akathisia (from the Greek phrase “not to sit”) is characterized by a feeling of inner restlessness, anxiety, or sense of unease, often in conjunction with the objective finding of an inability to sit still. Patients with akathisia frequently appear uncomfortable or fidgety. They may rock back and forth while standing, or may repeatedly cross and uncross their legs while seated. Akathisia can be difficult to diagnose and is easily misinterpreted as a manifestation of the underlying psychiatric disorder rather than an adverse effect of therapy.
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Akathisia is common and may be an important determinant of adherence to therapy. Like acute dystonia, akathisia tends to occur relatively early in the course of treatment and coincides with peak antipsychotic concentrations in serum.132 The incidence appears highest with typical, high-potency antipsychotics and lowest with atypical antipsychotics. Although most cases develop within days to weeks after initiation of treatment or an increase in dose, a delayed-onset (tardive) variant is also recognized.
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The pathophysiology of akathisia is incompletely understood but appears to involve antagonism of postsynaptic D2 receptors in the mesocortical pathways.71,119 Interestingly, a similar phenomenon is described in patients following the initiation of treatment with antidepressants, particularly the selective serotonin reuptake inhibitors (Chap. 75).8,67
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Treatment of akathisia.
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Akathisia can be difficult to treat. A reduction in the antipsychotic dose is sometimes helpful, as is substitution of another (generally atypical) antipsychotic. Treatment with lipophilic β-adrenergic antagonists such as propranolol may reduce the symptoms of akathisia, but little evidence supports their use.65,88 Benzodiazepines produce short-term relief, and anticholinergics such as benztropine or procyclidine may reduce manifestations of akathisia, but they are more likely to be effective for akathisia induced by antipsychotics with little or no intrinsic anticholinergic activity.20,66
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Antipsychotics can produce a parkinsonian syndrome characterized by rigidity, akinesia or bradykinesia, and postural instability. It is similar to the idiopathic Parkinson disease, although the classic “pill-rolling” tremor is often less pronounced.88 The syndrome typically develops during the first few months of therapy, particularly with high-potency antipsychotics. It is more common among older women, and in some patients it may represent iatrogenic unmasking of latent Parkinson disease. Parkinsonism is thought to result from antagonism of postsynaptic D2 receptors in the striatum.119
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Treatment of drug-induced parkinsonism.
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The risk of drug-induced parkinsonism can be minimized by using the lowest effective dose of antipsychotic. The addition of an anticholinergic often attenuates symptoms, at the expense of additional side effects. This strategy often is effective in younger patients, although the routine use of prophylactic anticholinergics is not recommended. Addition of a dopamine agonist such as amantadine is sometimes used, particularly in older patients who may be less tolerant of anticholinergics, but this may aggravate the underlying psychiatric disturbance.69
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The term tardive dyskinesia was coined in 1952 to describe the delayed onset of persistent orobuccal masticatory movements occurring in three women after several months of antipsychotic therapy.119 The adjective tardive, meaning delayed, was used to distinguish these movement disorders from the Parkinsonian movements described above. The incidence of tardive dyskinesia in younger patients is approximately 3% to 5% per year but rises considerably with age. A prospective study of older patients treated with high potency typical antipsychotics identified a 60% cumulative incidence of tardive dyskinesia after 3 years of treatment.53 Potential risk factors for tardive dyskinesia include alcohol use, affective disorder, prior electroconvulsive therapy, diabetes mellitus, and various genetic factors.119
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Several distinct tardive syndromes are recognized, including the classic orobuccal lingual masticatory stereotypy, chorea, dystonia, myoclonus, blepharospasm, and tics. It is generally accepted that the atypical antipsychotics are associated with a lower incidence of tardive dyskinesia and other drug-related movement disorders. However, whether this is true of all atypical antipsychotics is unclear. Among the atypical antipsychotics, clozapine is associated with the lowest incidence of tardive dyskinesia and risperidone with the highest incidence (when higher doses are used), but the reasons for this observation are uncertain.115,116,119
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Treatment of tardive dyskinesia.
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Tardive dyskinesia is highly resistant to the usual pharmacologic treatments for movement disorders. Anticholinergics do not alleviate tardive dyskinesia and indeed may worsen it. Calcium channel blockers, β-adrenergic antagonists, benzodiazepines, and vitamin E have all been used with limited success.36 Clozapine appears to suppress tardive dyskinesia temporarily. Although discontinuation of the causative antipsychotic may not produce total relief of symptoms, when possible, the antipsychotic should be discontinued as soon as signs or symptoms begin.
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Neuroleptic malignant syndrome.
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Neuroleptic malignant syndrome (NMS) is a potentially life-threatening drug-induced emergency. First described in 1960 in patients treated with haloperidol, this syndrome has been associated with virtually every antipsychotic.32 The reported incidence of NMS ranges from 0.2% to 1.4% of patients receiving antipsychotics,2,23,114 but less severe episodes may go undiagnosed or unreported. As a result, much of what is known about the epidemiology and treatment of NMS is speculative and based upon case reports and case series.
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The pathophysiology of NMS is incompletely understood but appears to involve abrupt reductions in central dopaminergic neurotransmission in the striatum and hypothalamus, altering the core temperature setpoint,43 and leading to impaired thermoregulation and other manifestations of autonomic dysfunction. Blockade of striatal D2 receptors contributes to muscle rigidity and tremor.13,25,121 In some cases, a direct effect on skeletal muscle may play a role in the pathogenesis of hyperthermia.43 Altered mental status is multifactorial and may reflect hypothalamic and spinal dopamine receptor antagonism, a genetic predisposition, or the direct effects of hyperthermia and other drugs.44 Serotonin also appears to play a role in the pathogenesis of NMS, because antipsychotics that antagonize 5-HT2A receptors seem to be associated with a lower incidence of NMS.4
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Although NMS most often occurs during treatment with a D2 receptor antagonist, withdrawal of dopamine agonists can produce an indistinguishable syndrome. The latter typically occurs in patients with long-standing Parkinson disease who abruptly change or discontinue treatment with dopamine agonists such as levodopa/carbidopa, amantadine, or bromocriptine.13 The resulting disorder is sometimes referred to as the parkinsonian-hyperpyrexia syndrome, and mortality rates of up to 4% are reported.79 Hospitalization for aspiration pneumonia, a common occurrence in older patients with Parkinson disease, is a particularly high-risk setting for this complication, and is particularly dangerous because the cardinal manifestations of NMS are easily misattributed to the combined effects of pneumonia and the underlying movement disorder.
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The vast majority of NMS cases occur in the context of therapeutic use of antipsychotics rather than following overdose. Postulated risk factors for the development of NMS include young age, male gender, extracellular fluid volume contraction, use of high-potency antipsychotics, depot preparations, cotreatment with lithium, multiple drugs in combination, and rapid dose escalation.2,24,63,81 One large observational study81 suggests that treatment with high-potency first-generation antipsychotics is associated with a more than 20-fold increase in the risk of NMS, although this may partly reflect heightened suspicion of the disorder in patients receiving those antipsychotics. The mortality rate of NMS associated with first-generation antipsychotics is estimated at approximately 16%, whereas the rate associated with second-generation antipsychotics is estimated at 3%.118
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The manifestations of NMS include the tetrad of altered mental status, muscular rigidity (classically described as “lead pipe”), hyperthermia, and autonomic dysfunction. These symptoms can appear in any sequence, although a review of 340 NMS cases found that mental status changes and rigidity usually preceded the development of hyperthermia and autonomic instability.122 Occasionally, rigidity is not present when creatine kinase concentrations are elevated but emerges thereafter.82 Signs typically evolve over a period of several days, with the majority occurring within 2 weeks of initiation. However, it is important to recognize that NMS can occur even after prolonged use of an antipsychotic, particularly following a dose increase, the addition of another agent, or the development of intercurrent illness. It is also worth noting that the clinical course of NMS can fluctuate rapidly, sometimes waxing and waning dramatically over a few hours.
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There is no universally accepted set of criteria for the diagnosis of NMS, and more than a dozen sets of criteria have been proposed.3,23,34,63 The operating characteristics of these criteria have not been formally evaluated, in part because of the absence of a gold standard. An international group has published the results of a Delphi consensus panel regarding the diagnosis of NMS.42 While these too have not yet been validated, the criteria and their relative importance are shown in Table 70–5.
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It may be difficult to distinguish NMS from other toxin-induced hyperthermia syndromes, such as the anticholinergic (antimuscarinic) syndrome (Chap. 49) and serotonin toxicity (Chap. 75), all of which share the common features of elevated temperature, altered mental status, and neuromuscular abnormalities. The most important differentiating feature is the medication history, with dopamine antagonists, antimuscarinics, and direct or indirect serotonin agonists (often in combination) as the most likely causal agents, respectively. The time course of the illness may also help differentiate among the disorders. Serotonin toxicity and the antimuscarinic syndrome tend to develop rapidly after exposure to causative substances, while NMS typically develops more gradually, often waxing and waning over several days or more. Occasionally, clinicians must attempt to differentiate NMS from these disorders in the absence of a reliable medication history. The physical examination can be of some utility in this regard.87 While NMS is classically characterized by rigidity, the presence of ocular or generalized clonus is more suggestive of serotonin toxicity, particularly when accompanied by shivering and hyperreflexia, features that are not typical of NMS. Because skeletal muscle contraction is effected by nicotinic rather than muscarinic transmission, patients with antimuscarinic syndrome have few muscular abnormalities. However, such patients can sometimes be resistant to physical restraint, giving the appearance of increased muscle tone.
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Treatment of neuroleptic malignant syndrome: General measures.
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Treatment recommendations are largely based on general physiologic principles, case reports, and case series. Therapy should be individualized according to the severity and duration of illness and the modifying influences of comorbidity.13,95,123 The provision of good supportive care is the cornerstone for treatment of NMS. It is essential to recognize the condition as an emergency and to withdraw the offending antipsychotic immediately. When NMS ensues after abrupt discontinuation of a dopamine agonist such as levodopa, the drug should be reinstituted promptly. Most patients with NMS should be admitted to an intensive care unit. Supplemental oxygen should be administered, and assisted ventilation may be necessary in cases of respiratory failure, which can result from central hypoventilation, loss of protective airway reflexes, or rigidity of the chest wall muscles.
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The hyperthermia associated with NMS is multifactorial in origin and, when present, warrants aggressive treatment. Submersion in an ice-water bath is rapidly effective, although this may be impractical in some settings (Chap. 30). Other strategies include the use of active cooling blankets, the placement of ice packs in the groin and axillae, or evaporative cooling, which can be accomplished by removing the patient’s clothing and exposing the patient to cooled water or towels immersed in ice water, while maintaining constant air circulation with the use of fans.127
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Hypotension should be treated initially with generous volumes of isotonic crystalloid, followed by vasopressors if necessary. Alkalinization of the urine with sodium bicarbonate may reduce the incidence of myoglobinuric acute kidney injury (AKI) in patients with high creatine kinase concentrations, but maintenance of intravascular volume and adequate renal perfusion are of far greater importance. Tachycardia does not require specific treatment, but bradycardia may necessitate the use of transcutaneous or transvenous electrical pacing. Venous thromboembolism is a major cause of morbidity and mortality in patients with NMS, and prophylactic doses of low-molecular-weight heparin should be considered in patients who likely will be immobilized for more than 12 to 24 hours.
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Treatment of neuroleptic malignant syndrome: Pharmacologic measures.
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Benzodiazepines are the most widely used pharmacologic adjuncts for treatment of NMS and are considered first-line therapy. Dantrolene and bromocriptine are not well studied, and their incremental benefit over good supportive care is debated.95,100 However, these drugs are associated with relatively little toxicity, and their use is therefore easily justified, particularly in patients with moderate or severe NMS.
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Benzodiazepines are frequently used in the management of NMS because of their rapid onset of action, which is particularly important when patients are agitated or restless. They attenuate the sympathetic hyperactivity that characterizes NMS by facilitating GABA-mediated chloride transport and producing neuronal hyperpolarization, in a fashion analogous to their beneficial effects in cocaine toxicity.44 The primary disadvantage of benzodiazepines is that they may cloud the assessment of mental status.
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Dantrolene reduces skeletal muscle activity by inhibiting ryanodine receptor calcium release channels, interfering with calcium release from the sarcoplasmic reticulum. In theory, this process should reduce body temperature and total oxygen consumption. It also should lessen the risk of myoglobinuric AKI. Dantrolene has been suggested to be particularly useful when muscular rigidity is a prominent feature of NMS.13 It can be given by mouth (50–100 mg/d) or by IV infusion (2–3 mg/kg/d, or up to 10 mg/kg/d in severe cases), although the latter requires laborious reconstitution. A review of 271 published cases of NMS that included information regarding drug treatment found that combination therapy including dantrolene was associated with a prolonged clinical recovery, but also that dantrolene monotherapy was associated with higher mortality than other treatment modalities including supportive care.95 The authors concluded that dantrolene was not an evidence-based therapy. However, it is also a relatively nontoxic drug that remains a reasonable therapeutic option in patients with NMS, particularly those with prominent and refractory rigidity.
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Bromocriptine is a centrally acting dopamine agonist that is given orally or by nasogastric tube at doses of 2.5 to 10 mg, 3 to 4 times daily. The rationale for its use rests in the belief that reversal of antipsychotic-related striatal D2 antagonism will ameliorate the manifestations of NMS. Other dopamine agonists anecdotally associated with success include ropinirole, levodopa,84,110 and amantadine.41,52,114 When these drugs are used, they should be tapered slowly after the patient improves to minimize the likelihood of recrudescent NMS. In severe cases, dantrolene and a dopamine agonist can be used in combination. Of note, dopaminergic agents may be associated with exacerbation of underlying psychiatric illness.
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Electroconvulsive therapy.
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Electroconvulsive therapy (ECT) has been reported to dramatically improve the manifestations of NMS, presumably by enhancing central dopaminergic transmission. In one report, five patients received an average of 10 ECT treatments, and resolution generally occurred after the third or fourth session.83 Whether this result represents a true effect of ECT or simply the natural course of NMS with good supportive care alone is not clear. As with drug therapies for NMS, the efficacy of ECT remains unclear and its indications speculative, but its use seems reasonable in patients with severe, persistent, or treatment-resistant NMS and for those with residual catatonia or psychosis following resolution of other manifestations.13,84
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Adverse Effects on Other Organ Systems.
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Sedation, dry mouth, and urinary retention occur commonly with antipsychotics, particularly during the initial period of therapy. These symptoms occur most commonly with drugs having potent antihistaminic and antimuscarinic activity. All antipsychotics can lower the seizure threshold, but seizures are uncommon during therapeutic use. Because hypothalamic dopamine inhibits pituitary prolactin release, hyperprolactinemia and galactorrhea can occur. All antipsychotics are associated with metabolic derangements, including weight gain, dyslipidemia, and steatohepatitis. The metabolic syndrome appears most commonly in association with clozapine, olanzapine, and chlorpromazine.31 Rare but dramatic instances of glucose intolerance, including fatal cases of diabetic ketoacidosis, are also described.6,47,91,117 The mechanism of this is incompletely understood, but it is not adequately explained by the weight gain associated with antipsychotic therapy, because glucose disturbances often develop shortly after therapy is instituted. Other idiosyncratic reactions reported with use of antipsychotics include photosensitivity, skin pigmentation, and cholestatic hepatitis (particularly with the phenothiazines), myocarditis, and agranulocytosis, which occurs with many antipsychotic drugs, most notably clozapine (in up to 2% of patients).75 Most of these conditions result from an immunologically based hypersensitivity reaction and develop during the first month of therapy. Finally, an increasing number of reports associate antipsychotics with venous thromboembolism.46,55 This may partially explain the high incidence of thromboembolic disease found in patients with NMS (see above).
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Antipsychotic overdose can produce a spectrum of toxic manifestations affecting multiple organ systems, but most serious toxicity involves the CNS and cardiovascular systems. Some of these manifestations are present to a minor degree during therapeutic use, although they tend to be most pronounced during the early period of therapy and dissipate with continued use.
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Impaired consciousness is a common and dose-dependent feature of antipsychotic overdose, ranging from somnolence to coma. It may be associated with impaired airway reflexes, but significant respiratory depression is uncommon. Many antipsychotics, including several of the atypical drugs, are potent muscarinic antagonists and can produce anticholinergic features in overdose.11,21,26 Peripheral manifestations include tachycardia, decreased production of sweat and saliva, flushed skin, urinary retention, diminished bowel sounds and mydriasis, although miosis also occurs. These findings may be present in isolation or coexist with central manifestations, including agitation, delirium, psychosis, hallucinations, and coma, some of which may be mistakenly attributed to the underlying psychiatric illness.
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Mild elevations in body temperature are common and reflect impaired heat dissipation as a result of impaired sweating, and increased heat production in agitated patients. Hyperthermia should always prompt a search for other features of NMS. Tachycardia is a common finding in patients with antipsychotic overdose and reflects reduced vagal tone and, when present, a compensatory response to hypotension. Bradycardia is distinctly uncommon, and while it may be a preterminal finding, its presence should prompt a search for alternate causes including an ingestion of negative chronotropic drugs such as β-adrenergic antagonists, calcium channel blockers, cardiac glycosides, and opioids. Hypotension is a common feature of antipsychotic overdose and is generally due to peripheral α1-adrenergic blockade and decreased myocardial contractility.
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The electrocardiographic (ECG) manifestations of antipsychotic overdose exhibit similarities to those of cyclic antidepressant toxicity (Chaps. 16 and 71) and include widening of the QRS complex and a rightward deflection of the terminal 40 msec of the QRS complex, typically manifesting as a tall, broad terminal component of the QRS complex in lead aVR. These changes reflect blockade of the inward sodium current (INa). Prolongation of the QT interval results from blockade of the delayed rectifier potassium current (IKr), creating a substrate for development of torsade de pointes.78 This situation is sometimes evident during maintenance therapy and may underlie the apparent increase in sudden cardiac death among users of antipsychotics.92,93 A published meta-analysis of the operating characteristics of the ECG in patients with cyclic antidepressant toxicity found the ECG was a relatively poor predictor of seizures, dysrhythmia, and death.7 However, the ECG is a dynamic instrument, particularly in the initial hours following overdose, and few studies have evaluated longitudinal changes in the ECG.64