70: Antipsychotics

The development of antipsychotic drugs changed the practice of psychiatry. Prior to the introduction of chlorpromazine in 1950, patients with schizophrenia were treated with nonspecific sedatives such as barbiturates and chloral hydrate. Highly agitated patients were housed in large mental institutions and often placed in physical restraints, and thousands underwent surgical disruption of the connections between the frontal cortices and other areas of the brain (leucotomy). By 1955, approximately 500,000 patients with psychotic disorders were hospitalized in the United States. The advent of antipsychotics in the 1950s revolutionized the care of these patients. These drugs, originally termed major tranquilizers and subsequently neuroleptics, dramatically reduced the characteristic hallucinations, delusions, thought disorders, and paranoia—the “positive” symptoms of schizophrenia.

Shortly after the introduction of these drugs, it became apparent that they caused significant toxicity following overdose, a common occurrence in patients with mental illness. Moreover, they were also associated with a host of adverse effects, principally involving the endocrine and nervous systems. The latter includes the extrapyramidal syndromes (EPS), a constellation of disorders that are relatively common, sometimes irreversible and occasionally life threatening.

The search for new drugs led to the development of multiple antipsychotics of several chemical classes. These drugs exhibited varying potencies and markedly different adverse effect profiles. The novel antipsychotic clozapine was first synthesized in 1959, but it did not enter widespread clinical use until the early 1970s. Clozapine was unusual because it conferred a relatively low risk of EPS, but also because it was often effective in patients who had not responded well to other xenobiotics. Moreover, unlike the other available xenobiotics, it often improved the “negative” symptoms of schizophrenia such as avolition, alogia, and social withdrawal—symptoms that, while often less outwardly apparent than the positive symptoms, result in significant disability. Reports of life-threatening agranulocytosis led to the withdrawal of clozapine from the market in 1974, although it was reintroduced in 1990.^9,49 However, the unique therapeutic and pharmacologic properties of clozapine led to its characterization as an atypical antipsychotic, the forerunner and prototype of many other second-generation antipsychotics that have now largely supplanted the earlier xenobiotics.

Most antipsychotic toxicity occurs by one of two mechanisms. Following overdose, antipsychotic toxicity is dose dependent and reflects an extension of the effects of the drug on neurotransmitter systems and other biologic processes. The features of antipsychotic drug overdose are therefore generally predictable based upon an understanding of the pharmacology of the drug. Unpredictable (idiosyncratic) adverse reactions also occur in the context of routine therapeutic use. These toxicities result from individual susceptibility, are sometimes pharmacogenetic in nature, and are less reliably correlated with the dose. In both types of toxicity, the severity of illness can range from minor to life threatening, depending on a number of other factors, including concomitant drug exposures, comorbidity, and access to medical care.

The true incidence of antipsychotic overdose and adverse reactions is not known with certainty. Some patients may not seek medical attention, whereas others may be misdiagnosed. Even among those who seek medical attention and are correctly diagnosed, notification of poison centers or other adverse event reporting systems is discretionary and incomplete (Chap. 136). With these limitations in mind, a few observations can be made.

In 2011, poison control centers in the United States were con­tacted about more than 3.6 million potential toxic exposures.¹⁶ Antipsychotic exposures are reported together with sedative-hypnotics, but these collectively represented 168,416 exposures (6.13% of all exposures). The vast majority of poison center calls involving antipsychotics pertain to intentional overdoses in patients 20 years or older, most of whom have a good outcome. However, antipsychotics were associated with more fatalities than any other group (n = 401 deaths), and most exposures involved atypical antipsychotics. Importantly, poison center data underestimate the annual incidence of poisoning and mortality associated with antipsychotics and likely identify only a small minority of adverse drug reactions involving these drugs.

Although all antipsychotics can exhibit significant toxicity in overdose, a substantial body of clinical experience and some observational data suggest that the low potency, first-generation antipsychotics such as thioridazine, chlorpromazine, and mesoridazine are associated with greater toxicity than other antipsychotics.^17,19 Inferences regarding the relative toxicity of the antipsychotics derived from administrative data should be extrapolated to individual patients with caution,^17,40 but at least one well done retrospective cohort study supports the notion that thioridazine is associated with greater cardiovascular toxicity than other antipsychotics.¹⁹

Classification

Antipsychotics can be classified in several ways, according to their chemical structure, their receptor binding profiles, or as “typical” or “atypical” antipsychotics. Table 70–1 outlines the taxonomy of some of the more commonly used antipsychotics. Classification by chemical structure was most useful prior to the 1970s, when phenothiazines and butyrophenones constituted most of the antipsychotics in clinical use. Currently, the number of different compounds and their structural heterogeneity renders this scheme of little utility to clinicians. It is worth noting, however, that the phenothiazine antipsychotics bear a high degree of structural similarity to the tricyclic antidepressants (TCAs) (Fig. 70–1) and share many of their manifestations in overdose. The phenothiazines can be further classified according to the nature of the substituent on the nitrogen atom at position 10 of the center ring as either aliphatic, piperazine, or piperidine compounds.

Of greater clinical utility is the classification of antipsychotics according to their binding affinities for various receptors (Table 70–2). However, by far the most widely used classification system categorizes antipsychotics as either typical or atypical. Typical (also called traditional, conventional or, increasingly, first-generation) antipsychotics dominated the first 40 years of antipsychotic therapy. They were subcategorized according to their affinity for the D₂ receptor as either low potency (exemplified by thioridazine and chlorpromazine) or high potency (exemplified by haloperidol). They ameliorated the positive symptoms of schizophrenia, such as hallucinations, delusions, paranoia, and disorganization of thought, but were of little benefit for the sometimes disabling negative symptoms including avolition, alogia, flattening of affect, and social withdrawal. Moreover, they were associated with acute, subacute, and long-term motor disturbances collectively referred to as EPS.

The concept of antipsychotic atypicality has evolved over time with the introduction of new compounds^94,113 and connotes different properties to pharmacologists and clinicians. From a clinical perspective, atypical ­antipsychotics (sometimes termed second-generation antipsychotics) treat both the positive and negative symptoms of schizophrenia, are less likely than traditional drugs to produce EPS at clinically effective doses, and cause little or no elevation of the serum prolactin concentration.⁵⁷ From a pharmacologic perspective, most atypical antipsychotics also inhibit the action of serotonin at the 5-HT_2A receptor. More than a dozen atypical antipsychotics are now in clinical use or under development. Despite their considerably higher cost, these drugs have largely supplanted traditional antipsychotics because of their effectiveness in treating the negative symptoms of schizophrenia and their somewhat more favorable adverse effect profile, in addition to the perception that they cause fewer long-term adverse effects than conventional antipsychotics—a belief that may result, in part, from the use of higher doses of older drugs in studies comparing the tolerability of typical and atypical antipsychotics.⁴⁸ Considerable controversy exists regarding the superiority of these drugs over those of the first-generation antipsychotics, and it is worth noting that the use of the newer antipsychotics for other indications is extremely common, including their use as adjunctive treatment for major depression, eating disorders, attention-deficit hyperactivity disorder, insomnia, posttraumatic stress disorder, personality disorders, and Tourette syndrome.⁶⁸ However, the most extensive off-label use of these drugs is for the management of agitation associated with cognitive impairment in the elderly.

Mechanisms of Antipsychotic Action

Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine hypothesis.¹⁰⁷ First advanced in 1967 and supported by in vivo data,¹ this theory holds that the “positive symptoms” of schizophrenia (hallucinations, delusions, paranoia, and disorganization of thought) result from excessive dopaminergic signaling in the mesolimbic and mesocortical pathways.⁷³ This hypothesis was borne in part from the observation that hallucinations and delusions could be produced in otherwise normal individuals by drugs that increase dopaminergic transmission, such as cocaine and amphetamine, and that these effects could be blunted by dopamine antagonists.

There are at least five subtypes of dopamine receptors (D₁ through D₅), but schizophrenia principally involves excess signaling at the D₂ subtype,¹⁰⁷ and antagonism of D₂ neurotransmission is the sine qua non of antipsychotic activity. Antipsychotics have different potencies at this receptor, reflected by the dissociation constant (K_d), which in turn reflects release of the drug from the D₂ receptor. For example, the receptor releases clozapine and quetiapine more rapidly than it does any other drugs.^105,107

Dopamine receptors are present in many other areas of the central nervous system (CNS), including the nigrostriatal pathway (substantia nigra, caudate, and putamen, which collectively govern the coordination of movement), tuberoinfundibular pathway, hypothalamus and pituitary, and area postrema of the brainstem, which contains the chemoreceptor trigger zone (CTZ). Antipsychotic-related blockade of D₂ neurotransmission in these areas is associated with many of the beneficial and adverse effects of these drugs. For example, D₂ antagonism in the CTZ alleviates nausea and vomiting, whereas blockade of hypothalamic D₂ receptors increases pituitary prolactin release, resulting in gynecomastia and galactorrhea. Blockade of nigrostriatal D₂ receptors underlies many of the movement disorders associated with antipsychotic therapy.^119,132

Antipsychotics interfere with signaling at other receptors to varying degrees, including muscarinic receptors, H₁ histamine receptors, and α-adrenergic receptors. The extent to which these receptors are blocked at therapeutic doses can be used to predict the adverse effect profile of each antipsychotic.²¹ For example, drugs that antagonize muscarinic receptors at clinically effective doses (most notably the aliphatic and piperidine phenothiazines as well as clozapine, loxapine, olanzapine, and quetiapine) often produce anticholinergic adverse effects during routine use and can produce pronounced anticholinergic manifestations following overdose (Table 70–2). Similarly, blockade of peripheral α₁-adrenergic receptors by the aliphatic and piperidine phenothiazines, clozapine, risperidone, and others renders them more likely to cause postural hypotension during therapy and clinically important hypotension following overdose. In contrast, haloperidol overdose is not characterized by marked antimuscarinic effects or hypotension.

Several antipsychotics also block voltage-gated fast sodium channels (I_Na). Although this effect is of little consequence during therapy, in the setting of overdose this can slow cardiac conduction (phase 0 depolarization) and impair myocardial contractility. This effect, most notable with the phenothiazines, is both rate- and voltage-dependent, and is therefore more pronounced at faster heart rates and less negative transmembrane potentials.¹⁸ Blockade of the delayed rectifier potassium current (I_Kr) can produce prolongation of the QT interval, creating a substrate for development of torsade de pointes.⁷⁸ QT interval prolongation is sometimes evident during maintenance therapy, particularly in patients with previously unrecognized repolarization abnormalities or additional risk factors for QT prolongation. This effect may partially explain the dose-dependent increase in risk of sudden cardiac death among patients treated with typical and atypical antipsychotics.^92,93

Several antipsychotics exhibit a relatively high degree of antagonism at the 5-HT_2A receptor, which conveys two important therapeutic properties: (1) greater effectiveness for the treatment of the negative symptoms of schizophrenia and (2) a significantly lower incidence of extrapyramidal side effects. Others antipsychotics are distinguished by unique effects at different receptors. For example, loxapine and clozapine inhibit the presynaptic reuptake of catecholamines and antagonize γ-aminobutyric acid (GABA)_A receptors,¹¹² which may explain the apparent increase in seizure activity with these antipsychotics.⁸⁹ A more detailed description of the pharmacology of the most commonly used second-generation antipsychotics is warranted in light of their increasing role in therapy.

Clozapine, a dibenzodiazepine compound, binds to dopamine receptors (D₁–D₅) and serotonin receptors (5-HT_1A/1C, 5-HT_2A/2C, 5-HT₃, and 5-HT₆) with moderate to high affinity.^9,90,98 It also antagonizes α₁-adrenergic, α₂-adrenergic, and H₁ histamine receptors. It has the highest binding affinity of any atypical antipsychotic at M₁ muscarinic receptors.⁹⁷ Despite this feature, clozapine paradoxically activates the M₄ subtype of the muscarinic receptor and frequently produces sialorrhea during therapy.⁹⁶

Olanzapine, a thienobenzodiazepine, binds avidly to serotonin (5-HT_2A/2C, 5-HT₃, and 5-HT₆) and dopamine receptors (D₁, D₂, and D₄), although its potency at D₂ receptors is lower than that of most traditional antipsychotics.^60,98 It is an exceptionally potent H₁ antagonist, binding more avidly than pyrilamine, which is a widely used antihistamine. It is also has a high affinity for M₁ receptors and is a relatively weak α₁ antagonist.

Risperidone, a benzisoxazole derivative, has high affinity for several receptors, including serotonin receptors (5-HT_2A/2C), D₂ dopamine receptors, and α₁ and H₁ receptors.^60,96,98 It has no appreciable activity at M₁ receptors. Its primary metabolite (9-hydroxyrisperidone) is nearly equipotent as the parent compound at D₂ and 5-HT_2A receptors.⁶⁰ Available orally and as a long-acting parenteral preparation, paliperidone is the major active metabolite of risperidone and exhibits a similar receptor-binding profile.

Quetiapine, a dibenzothiazepine, is a weak antagonist at D₂, M₁, and 5-HT_1A receptors, but it is a potent antagonist of α₁-adrenergic and H₁ receptors.⁶⁰ Of its 11 metabolites, at least 2 are pharmacologically active, but they circulate at low concentrations and likely contribute little to its clinical effect. A considerable proportion of fatalities involving antipsychotic drugs reported to North American Poison Control Centers involve quetiapine, usually in combination with other drugs.¹⁶

Ziprasidone, a benzothiazole derivative, is an antagonist at dopaminergic D₂ and several serotonin (5-HT_2A/2C, 5-HT_1D, and 5-HT₇) receptors, but it also displays agonist activity at 5-HT_1A receptors.^60,61,98 Its α₁-antagonist activity is particularly strong, with a binding affinity approximately one tenth that of prazosin. In addition, it is a strong inhibitor of the delayed rectifier channel (I_Kr) and can significantly prolong repolarization.^61,70

Aripiprazole, a quinolinone derivative, is a novel compound that binds avidly to dopamine D₂ and D₃ receptors and serotonin 5-HT_1A, 5-HT_2A, and 5-HT_2B receptors.^77,98 Some evidence suggests that its efficacy in the treatment of schizophrenia and its lower propensity for EPS may relate to partial agonist activity at dopamine D₂ receptors.⁷⁶ Aripiprazole acts as a partial agonist at serotonin 5-HT_1A receptors but is an antagonist at serotonin 5-HT_2A receptors. Its principal active metabolite, dehydroaripiprazole, has affinity for dopamine D₂ receptors and thus has pharmacologic activity similar to that of the parent compound.⁷⁷

Like aripiprazole, bifeprunox is a partial agonist at D₂ and 5-HT_1A receptors. It has been characterized as a third-generation antipsychotic and has no appreciable affinity for serotonin 5-HT_2A and 5-HT_2C histaminergic or muscarinic receptors.^28,80,106

Amisulpride is a substituted benzamide derivative that preferentially blocks dopamine receptors in limbic rather than striatal structures. At low doses, it blocks presynaptic D₂ and D₃ receptors, thereby accentuating dopamine release, while at high doses it blocks postsynaptic D₂ and D₃ receptors. It has relatively low affinity for serotonergic, histaminergic, adrenergic, and cholinergic receptors.

Sertindole is a second-generation antipsychotic drug that was recently reintroduced into the market after being voluntarily withdrawn in 1998 over concerns about its effects on the QT interval. It binds to striatal D₂ receptors, although less avidly than olanzapine, and also exhibits antagonism at 5-HT2A and α₁-adrenergic receptors.^59,86,111 It is estimated that 3.1% to 7.8% of patients receiving sertindole develop QT intervals greater than 500 milliseconds.¹³⁰

With a few exceptions, the antipsychotics have similar pharmacokinetic characteristics regardless of their chemical classification. Most are ­lipophilic, have a large volume of distribution, and are generally well absorbed, although anticholinergic effects may delay absorption of some antipsychotics. Serum concentrations generally peak within 2 to 3 hours after a therapeutic dose, but this can be prolonged following overdose.

Most antipsychotics are substrates for the various isozymes of the hepatic cytochrome P450 (CYP) enzyme system. For example, haloperidol, perphenazine, thioridazine, sertindole, and risperidone are extensively metabolized by the CYP2D6 system, which is functionally absent in approximately 7% of white patients and overexpressed in 1% to 25% of patients, depending on ethnicity.⁵³ These polymorphisms appear to influence the tolerability and efficacy of treatment with these antipsychotics during therapeutic use^{15,29,30,56,124} but are unlikely to significantly alter the severity of acute antipsychotic overdose.

Drugs that inhibit CYP2D6 (such as paroxetine, fluoxetine, and bupropion) can increase the concentrations of these antipsychotics and increase the risk of adverse effects. In contrast, metabolism of clozapine is primarily mediated by CYP1A2, and increased clozapine concentrations can result following exposure to CYP1A2 inhibitors such as fluvoxamine, macrolide and fluoroquinolone antibiotics, as well as after smoking cessation, because smoking induces CYP1A2.³⁵ The kidney plays a relatively small role in the elimination of antipsychotics, and dose adjustment is generally not necessary for patients with kidney disease.

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.

Adverse Effects During Therapeutic Use

The Extrapyramidal Syndromes.

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-HT_2A 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.

Acute dystonia.

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

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

Treatment of acute dystonia.

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.

Akathisia.

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.

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.

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

Treatment of akathisia.

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

Parkinsonism.

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

Treatment of drug-induced parkinsonism.

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

Tardive dyskinesias.

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

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

Treatment of tardive dyskinesia.

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.

Neuroleptic malignant syndrome.

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.

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-HT_2A receptors seem to be associated with a lower incidence of NMS.⁴

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.

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

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.

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.

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.

Treatment of neuroleptic malignant syndrome: General measures.

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.

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

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.

Treatment of neuroleptic malignant syndrome: Pharmacologic measures.

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.

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.

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.

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.

Electroconvulsive therapy.

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

Adverse Effects on Other Organ Systems.

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).

Acute Overdose

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.

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.

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.

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 (I_Na). Prolongation of the QT interval results from blockade of the delayed rectifier potassium current (I_Kr), 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

The diagnosis of antipsychotic poisoning is supported by the clinical history, the physical examination, and a limited number of adjunctive tests. Both the clinical and ECG findings are nonspecific and can occur following overdose of several different drug classes, including CAs, skeletal muscle relaxants, carbamazepine, and first-generation antihistamines such as diphenhy­dramine. Moreover, the absence of typical ECG changes does not exclude a significant antipsychotic ingestion, particularly in the initial phase of an overdose, and at least one additional ECG should be performed in the ­subsequent 2 to 3 hours.

Abdominal radiography may reveal radioopacities in the gastrointestinal tract, as some solid dosage forms of phenothiazines are radiopaque. However, these tests are neither sensitive nor specific, and they are not routinely recommended.

Serum concentrations of antipsychotics are not widely available, do not correlate well with clinical signs and symptoms, and do not help guide therapy. Comprehensive urine drug screens using high-performance liquid chromatography, gas chromatography–mass spectrometry, or tandem mass spectrometry may indicate the presence of antipsychotics, but these tests are available at only a few hospitals and in most instances provide only a qualitative result. Blood and urine immunoassays for CAs may yield a false-positive result in the presence of phenothiazines.^5,99

The care of a patient with an antipsychotic overdose should proceed with the recognition that other drugs, particularly other psychotropics, may have been coingested and can confound both the clinical presentation and management. Regularly encountered coingestants include other psychotropic drugs such as antidepressants, sedative-hypnotics, anticholinergics, valproic acid, and lithium, as well as ethanol and nonprescription analgesics such as acetaminophen and aspirin.

Supportive care is the cornerstone of treatment for patients with antipsychotic overdose. Supplemental oxygen should be administered if hypoxia is present. Patients with altered mental status should receive thiamine and naloxone, along with parenteral dextrose if hypoglycemia present. Intubation and ventilation are rarely required for patients with single drug ingestions but may be necessary for patients with very large overdoses of antipsychotics or ingestion of other CNS depressants. All symptomatic patients should undergo continuous cardiac monitoring. In addition, an ECG should be recorded upon presentation and reliable venous access obtained. Asymptomatic patients with a normal ECG obtained 6 hours after overdose are at exceedingly low risk of complications and no longer require cardiac monitoring. Symptomatic patients and those with an abnormal ECG should have continuous monitoring for a minimum of 24 hours.

Gastrointestinal Decontamination

Gastrointestinal decontamination with activated charcoal (1 g/kg by mouth or nasogastric tube) should be considered for patients who present within a few hours of a large or multidrug overdose. Although this intervention is time sensitive, many antipsychotics exhibit significant antimuscarinic activity and slow gastric emptying, thereby increasing the likelihood that activated charcoal will be beneficial. Although it is unknown whether activated charcoal improves clinically important outcomes, a Bayesian analysis of pharmacokinetic data from a series of quetiapine overdoses concluded that activated charcoal use led to a 35% reduction in the fraction of quetiapine absorbed.⁵⁰ Orogastric lavage and whole-bowel irrigation likely will not improve clinical outcomes and should not be routinely employed in the management of antipsychotic overdose.

Treatment of Cardiovascular Complications

Vital signs should be monitored closely. Hypotension may result from peripheral α-adrenergic blockade and is most likely to occur with older, low potency antipsychotics such as thioridazine.⁷⁶ The hypotension should be treated initially with appropriate titration of 0.9% sodium chloride solution (30–40 mL/kg). If vasopressors are required, direct-acting agonists such as norepinephrine or phenylephrine are preferred over dopamine, which is an indirect agonist and likely will be ineffective. Vasopressin or its analogs may also be used, although direct-acting vasopressors should be used with great caution in patients who have coingested a negative inotropic drug such as a β-adrenergic antagonist or calcium channel blocker. Continuous blood pressure monitoring may be warranted in such cases.

Progressive widening of the QRS complex is uncommon and reflects sodium channel blockade and slowing of phase 0 depolarization in the His-Purkinje system. This may be associated with reduced cardiac output and malignant ventricular dysrhythmias. Much of what is known about the treatment of sodium channel blocker toxicity derives from the cyclic antidepressant literature. Treatment recommendations are extended to sodium-channel-blocking antipsychotic drugs by analogy. Sodium bicarbonate (1–2 mEq/kg) is the first-line therapy for ventricular dysrhythmias and should be considered for patients with dysrhythmias or QRS widening >0.12 msec. The rationale for this strategy is based upon the treatment of cyclic antidepressant overdose (Antidotes in Depth: A5). At least two mechanisms underlie the beneficial effects of sodium bicarbonate. First, the degree of sodium channel blockade is partially overcome by an increase in extracellular sodium. Indeed, hypertonic saline alone may be beneficial. Second, the binding of these drugs to the sodium channel is pH dependent, with less extensive binding at higher pH.

Repeated boluses of bicarbonate can be given to achieve a target blood pH of 7.5, although many toxicologists recommend continuous infusions.¹⁰⁹ If the patient is intubated, hyperventilation also can be used but is not comparably efficacious. If significant conduction abnormalities or ventricular dysrhythmias persist despite the use of sodium bicarbonate, lidocaine (1–2 mg/kg followed by continuous infusion) is a reasonable second-line antidysrhythmic. Although lidocaine is also a sodium channel antagonist, it exhibits rapid on/off sodium channel binding with preferential binding in the inactivated state and may lessen the cardiotoxicity associated with antipsychotic drug overdose.¹⁰⁸ Class IA antidysrhythmics (procainamide, disopyramide, and quinidine), class IC antidysrhythmics (propafenone, encainide, and flecainide), and class III antidysrhythmics (amiodarone, sotalol and bretylium) can aggravate cardiotoxicity and should not be used. When administering sodium bicarbonate to patients with antipsychotic overdose, caution must be taken to avoid hypokalemia, as many of these antipsychotics block cardiac potassium channels thereby prolonging the QT interval. Hypokalemia can exacerbate this blockade, potentially leading to torsade de pointes, particularly in overdoses involving amisulpride or ziprasidone.

Sinus tachycardia related to anticholinergic activity should not be treated unless it is associated with active ischemia, which, although uncommon, may complicate antipsychotic overdose in patients with existing coronary disease. Should symptomatic sinus tachycardia occur, a short-acting β-adrenergic antagonist such as esmolol may be preferable. Prolongation of the QT interval requires no specific treatment other than monitoring and correction of potential contributing causes such as hypokalemia and ­hypomagnesemia. Torsade de pointes should be treated with cardioversion followed by IV magnesium sulfate, taking care to prevent hypotension, which is dose- and rate-dependent. Overdrive pacing with isoproterenol or transcutaneous or transvenous pacing should be considered if the patient does not respond to magnesium sulfate, although in theory this therapy may worsen the rate-dependent sodium channel blockade.

Many antipsychotics, including olanzapine, quetiapine, and sertindole, exhibit a high degree of lipophilicity in addition to significant cardiovascular toxicity. Recently, considerable enthusiasm has emerged for the use of high-dose intravenous fat emulsion therapy for patients with significant overdoses of drugs displaying these characteristics. The rationale for this therapy rests, in part, in the concept that highly lipophilic drugs will selectively partition into the exogenous fat, thereby minimizing toxicity at the biophase. This treatment has been extensively studied in animal models of bupivacaine toxicity,^33,125,126 but published experience with antipsychotics is limited to a handful of case reports.^39,72,133 Dosing for fat “rescue” is not well established, but a popular protocol involves 20% lipid emulsion given as a bolus (1.5 mL/kg) followed by an infusion of 0.25 mL/kg/min for 30 to 60 minutes, with adjustment of therapy according to the individual response (Antidotes in Depth: A20). Extracorporeal circulatory support has been associated with survival in severe quetiapine overdose and may be an option in selected centers.⁶²

Treatment of Seizures

Seizures associated with antipsychotic overdose are generally short lived and often require no pharmacologic treatment. Multiple or refractory seizures should prompt a search for other causes, including hypoglycemia and ingestion of other proconvulsant medications. When treatment is necessary, benzodiazepines such as lorazepam or diazepam generally suffice, although phenobarbital may be necessary. Although phenytoin is part of the standard algorithm for status epilepticus, it is of limited effectiveness for xenobiotic-induced seizures; barbiturates such as phenobarbital or thiopental are preferred. Refractory seizures should respond to propofol infusion or general anesthesia. Seizures complicated by hyperthermia are considerably more ominous and warrant aggressive lowering of body temperature with aggressive rapid cooling measures. Finally, seizures can abruptly lower serum pH and may abruptly increase the cardiotoxicity of these drugs by enhancing binding to the sodium channel; therefore, an ECG should be obtained following resolution of seizure activity.

Treatment of the Central Antimuscarinic Syndrome

Many of the older and newer-generation antipsychotics have pronounced anticholinergic properties. Case reports and observational studies suggest that the cholinesterase inhibitor physostigmine (Antidotes in Depth: A9) can safely and effectively ameliorate the agitated delirium associated with the central anticholinergic syndrome by indirectly increasing synaptic acetylcholine concentraions.^{25,102, 103, and 104} Doses of 1 to 2 mg are usual, administered cautiously after ensuring QRS widening is not present. Although benzodiazepines will control agitation, they will further impair alertness, obfuscating the assessment of mental status and increasing the risk of complications.²²

Physostigmine has been used successfully in patients with antipsychotic overdose,^{22,101,104,128,129} but it should be used with caution. It should not be used in patients with dysrhythmias, any degree of heart block, or widening of the QRS complex. If physostigmine is used, it should be given in 0.5 mg increments slowly every 3 to 5 minutes, with close observation of the patient. If bradycardia, bronchospasm, or bronchorrhea develops, these can be treated with glycopyrrolate 0.2 to 0.4 mg IV. Atropine is often more widely available and could be used, but it crosses the blood–brain barrier and may aggravate any associated delirium. The effects of physostigmine are transient, typically ranging in duration from 30 to 90 minutes, and additional doses are often necessary. Of note, physostigmine does not prevent other complications of antipsychotic overdose, particularly those involving the cardiovascular system.

Other commonly used cholinesterase inhibitors, such as edrophonium, neostigmine, or pyridostigmine, should not be used to treat anticholinergic delirium because they do not cross the blood–brain barrier. Case reports involving other anticholinergics suggest that cholinesterase inhibitors used for treatment of dementia (eg, tacrine, donepezil, and galantamine) may be alternatives to physostigmine for patients able to take medications orally.^51,74,85

Enhanced Elimination

No pharmacologic rationale supports the use of multiple-dose activated charcoal or manipulation of urinary pH to increase the clearance of antipsychotics. One volunteer study found that urinary acidification may increase remoxipride elimination,¹³¹ but this practice is impractical and possibly dangerous. Because most antipsychotics exhibit large volumes of distribution and extensive protein binding (Table 70–1), extracorporeal removal is unwarranted and should be considered only if the patient has coingested other xenobiotics amenable to extracorporeal removal.

• Over the past decade, atypical antipsychotics have supplanted traditional antipsychotic drugs, which were associated with greater toxicity in overdose and a higher incidence of extrapyramidal symptoms. Consequently, atypical antipsychotics are now implicated in the majority of overdoses.

• With all antipsychotics, significant toxicity can occur either during the course of therapy or following overdose.

• Of the various toxicities that arise during therapeutic use, NMS is the most dangerous. It may be difficult to recognize, but should be considered in any unwell patient treated with antipsychotics, particularly in the 2 weeks following a change in therapy or in a patient with severe intercurrent illness.

• The principal manifestations of antipsychotic overdose involve the CNS and cardiovascular system. Depressed mental status, hypotension, and anticholinergic signs are nonspecific features that support the diagnosis of antipsychotic overdose, particularly in conjunction with typical ECG findings of sodium channel blockade and QT interval prolongation. Most fatalities following antipsychotic overdose occur in cases involving coingestion of other CNS depressants or cardiotoxic medications.

• Supportive care is the mainstay of therapy for patients with antipsychotic overdose, although selective use of nonspecific antidotes, such as activated charcoal, sodium bicarbonate, or physostigmine may improve outcomes in selected patients. Particularly severe or refractory cardiovascular toxicity may warrant a trial of lidocaine or intravenous lipid emulsion, although these interventions are not well studied in this setting.

Acknowledgments

Frank LoVecchio, MD, and Neal A. Lewin, MD, contributed to this chapter in previous editions.

References