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Goldfrank's Toxicologic Emergencies, 11e

Chapter 67: Chapter 67: AntipsychoticsAntipsychotics David N. Juurlink

FIGURE 67–1.FIGURE 67–1.

HISTORY AND EPIDEMIOLOGYHISTORY AND EPIDEMIOLOGY

The development of antipsychotic drugs dramatically altered the practice of psychiatry and eventually,medical care in general. Before the introduction of chlorpromazine in 1950, patients with schizophrenia weretreated with nonspecific sedatives such as barbiturates or chloral hydrate. Agitated patients were housed inlarge “mental institutions” and o�en placed in physical restraints, and thousands underwent surgicaldisruption of the connections between the frontal cortices and other areas of the brain (leucotomy). By 1955,approximately 500,000 patients with mental health disorders were institutionalized in the United States. Theadvent of antipsychotic drugs in the 1950s revolutionized the care of these patients. These drugs, originallytermed major tranquilizers and subsequently neuroleptics, dramatically reduced the characteristichallucinations, delusions, thought disorders and paranoia—the “positive” symptoms of schizophrenia.

Shortly a�er the introduction of these drugs, it became apparent that they were capable of causingsignificant toxicity a�er overdose, a common occurrence in patients with mental illness. Moreover, they werealso associated with a host of adverse e�ects during routine therapeutic use, particularly involving theendocrine and nervous systems. The latter includes the extrapyramidal syndromes (EPS), a constellation ofdisorders that are relatively common, sometimes irreversible, and occasionally life threatening.

The search for new drugs led to the development of multiple antipsychotics in several distinct chemicalclasses. These drugs exhibited varying potencies and markedly di�erent adverse e�ect profiles. The novelantipsychotic clozapine was first synthesized in 1959 but did not enter widespread clinical use until the early1970s. Clozapine was unusual because it conferred a relatively low risk of EPS and was o�en e�ective inpatients who had not responded well to other antipsychotics. Moreover, unlike other antipsychotic drugsavailable at the time, it o�en improved the “negative” symptoms of schizophrenia, such as avolition, alogia,and social withdrawal, symptoms that, although o�en 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 with stringent monitoring requirements.8,56

However, clozapine’s unique therapeutic and pharmacologic properties led to its characterization as anatypical antipsychotic, the forerunner and prototype of many other second-generation antipsychotics thathave now largely supplanted the earlier drugs in clinical practice.

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Most antipsychotic toxicity occurs through one of two mechanisms. A�er overdose, antipsychotic toxicity isdose dependent and reflects an extension of the drug’s e�ects on neurotransmitter systems and otherbiologic processes. The features of antipsychotic overdose are therefore generally predictable based on anunderstanding of the drug’s pharmacology. Unpredictable (idiosyncratic) adverse e�ects also occur in thecontext of therapeutic use. These toxicities result from individual susceptibility, which may in part have agenetic basis, and are less reliably correlated with the antipsychotic dose. In both types of toxicity, theseverity of illness ranges from minor to life threatening, depending on variety of other factors, includingconcomitant drug exposures, comorbidity, and access to medical care.

The true incidences of antipsychotic overdose and adverse e�ects are not known with certainty. Somepatients never seek medical attention, and others are misdiagnosed. Even among those who seek medicalattention and are correctly diagnosed, notification of poison control centers or other adverse event reportingsystems is discretionary and incomplete (Chap. 130). With these limitations in mind, a few observations canbe made.

In 2015, poison control centers in the United States were contacted about more than 2.17 million human

exposures involving potential poisons.92 Antipsychotic exposures are reported together with sedative–hypnotics, but these collectively represented 151,433 exposures (5.84% of all exposures). The vast majority ofpoison control center calls involving antipsychotic drugs pertain to intentional overdoses in patients 20 yearsor older, most of whom have a good outcome. However, these drugs were associated with more fatalitiesthan any other group (n = 401 deaths), although the extent to which they played a causal role in death isunclear. Importantly, poison control center data underestimate the annual incidence of poisoning andmortality associated with antipsychotic drugs and likely identify only a small minority of adverse drugreactions involving these drugs (Chap. 130).

Although all antipsychotics exhibit significant toxicity in overdose, a substantial body of clinical experienceand some observational data suggest that the low-potency, first-generation antipsychotics such asthioridazine, chlorpromazine, and mesoridazine are associated with greater toxicity than other

antipsychotics.18,20 Inferences regarding the relative toxicity of the antipsychotics derived from aggregated

data should be extrapolated to individual patients with caution.18,42

PHARMACOLOGYPHARMACOLOGY

ClassificationClassification

Antipsychotics are classified in several ways, according to their chemical structures, their receptor bindingprofiles, or as typical or atypical antipsychotics. Table 67–1 outlines the taxonomy of some of the morecommonly used antipsychotics. Classification by chemical structure was most useful before the 1970s, whenphenothiazines and butyrophenones constituted most of the antipsychotics in clinical use. At present,however, the spectrum of available antipsychotics and their structural heterogeneity renders this scheme oflittle use to clinicians. It is worth noting, however, that the phenothiazines exhibit a high degree of structural

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similarity to the tricyclic antidepressants (TCAs) (Fig. 67–1) and share many of their manifestations inoverdose. The phenothiazines are further classified according to the nature of the substituent on thenitrogen atom at position 10 of the center ring as aliphatic, piperazine, or piperidine compounds.

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TABLE 67–1

Classification of Commonly Used AntipsychoticsClassification of Commonly Used Antipsychotics

ClassificationClassification AntipsychoticAntipsychotic

UsualUsual

DailyDaily

AdultAdult

DoseDose

(mg)(mg)

Volume ofVolume of

DistributionDistribution

(L/kg)(L/kg)

Half-Half-

LifeLife

(Range,(Range,

h)h)

ProteinProtein

BindingBinding

(%)(%)

ActiveActive

MetaboliteMetabolite

TypicalsTypicals            

Butyrophenones Droperidol 1.25–30 2–3 2–10 85–90 N

  Haloperidol 1–20 18–30 14–41 90 Y

Diphenylbutylpiperidines

Pimozide 1–20 11–62 28–214 99 Y

PhenothiazinesPhenothiazines            

Aliphatic Chlorpromazine 100–800 10–35 18–30 98 Y

  Methotrimeprazine 2–50 23–42 17–78 NR Y

  Promazine 50–1,000 30–40 8–12 98 N

  Promethazine 25–150 9–25 9–16 93 Y

Piperazine Fluphenazine 0.5–20 220 13–58b 99 NR

  Perphenazine 8–64 10–35 8–12 >90 NR

  Prochlorperazine 10–150 13–32 17–27 >90 NR

  Trifluoperazine 4–50 NR 7–18 >90 Y

Piperidine Mesoridazine 100–400 3–6 2–9 98 Y

  Thioridazine 200–800 18 26–36 96 Y

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ClassificationClassification AntipsychoticAntipsychotic

UsualUsual

DailyDaily

AdultAdult

DoseDose

(mg)(mg)

Volume ofVolume of

DistributionDistribution

(L/kg)(L/kg)

Half-Half-

LifeLife

(Range,(Range,

h)h)

ProteinProtein

BindingBinding

(%)(%)

ActiveActive

MetaboliteMetabolite

  Pipotiazine 25–250

(monthly

IM

depot)

7.5 3–11 NR N

ThioxanthenesThioxanthenes Chlorprothixene 30–300 11–23 8–12 NR NR

  Flupentixol 3–6 7–8 7–36 NR NR

  Thiothixene 5–30 NR 12–36 >90 NR

  Zuclopenthixol 20–100 10 20 NR NR

AtypicalsAtypicals            

Benzamides Amisulpride 50–1,200 5.8 12 16 N

  Raclopride 3–6 1.5 12–24 NR N

  Remoxipride 150–600 0.7 3–7 80 Y

  Sulpiride 200–

1,200

0.6–2.7 4–11 14–40 N

Benzepines            

Dibenzodiazepine Clozapine 50–900 15–30 6–17 95 Y

Dibenzoxazepine Loxapinea 20–250 NR 2–8 90–99 Y

Thienobenzodiazepine

Olanzapine 5–20 10–20 21–54 93 N

Dibenzothiazepine Quetiapine 150–750 10 3–9 83 N

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aLoxapine’s atypical profile is lost at doses >50 mg/d; it is sometimes therefore categorized as a typical antipsychotic.

bFor hydrochloride salt; enanthate and decanoate have ranges of 3–4 days and 5–12 days, respectively.

IM = intramuscular; N = no; NR = not reported; Y = yes.

Data from references 9, 11, 14, 39, 62, 70, and 86.

ClassificationClassification AntipsychoticAntipsychotic

UsualUsual

DailyDaily

AdultAdult

DoseDose

(mg)(mg)

Volume ofVolume of

DistributionDistribution

(L/kg)(L/kg)

Half-Half-

LifeLife

(Range,(Range,

h)h)

ProteinProtein

BindingBinding

(%)(%)

ActiveActive

MetaboliteMetabolite

IndolesIndoles            

Benzisoxazole Risperidone 2–16 0.7–2.1 3–20 90 Y

  Paliperidone 1–12 mg

(IM 25–

150

monthly)

7 23 74 N

  Iloperidone 12–14 30–36 18–33 96 Y

Imidazolidinone Sertindole 12–24 20–40 24–200 99 Y

Benzisothiazole Ziprasidone 40–160 2 4–10 99 N

  Lurasidone 20–160 80–90 29–37 99 Y

Dibenzo-oxepino

pyrroles

Asenapine 5–20 20–25 13–39 95 N

Quinolinones Aripiprazole 10–30 5 47–68 99 Y

FIGURE 67–1.FIGURE 67–1.

Structural similarity between phenothiazines and cyclic antidepressants.

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Of greater clinical utility is the classification of antipsychotics according to their binding a�inities for variousreceptors (Table 67–2). However, by far the most widely used classification system categorizes antipsychoticsas 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 totheir a�inity for the D2 receptor as either low potency (exemplified by thioridazine and chlorpromazine) or

high potency (exemplified by haloperidol).

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TABLE 67–2

Clinical and Toxicologic Manifestations of Selected AntipsychoticsClinical and Toxicologic Manifestations of Selected Antipsychotics

  

αα11--

AdrenergicAdrenergic

AntagonismAntagonism

MuscarinicMuscarinic

AntagonismAntagonism

Fast Sodium ChannelFast Sodium Channel

(I(INaNa) Blockade) Blockade

Delayed RectifierDelayed Rectifier

(I(IKrKr) Blockade) Blockade

Clinical e�ect Hypotension Central and

peripheral -

anticholinergic

e�ects

QRS complex

widening; myocardial

depression

QT interval

prolongation;

torsade de pointes

TypicalTypical        

Chlorpromazine

+++ ++ ++ ++

Fluphenazine – – + +

Haloperidol – – + ++

Loxapine +++ ++ ++ +

Mesoridazine +++ +++ +++ ++

Perphenazine + – + ++

Pimozide + – + ++

Thioridazine +++ +++ +++ +++

Trifluoperazine + – + ++

AtypicalAtypical        

Amisulpride – – – ++

Asenapine ++ – – –

Aripiprazole ++ – – –

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+ to ++ = e�ect present in increasing degree; -- = e�ect is absent; -- to + = presence of e�ect minimal or absent.

Data from references 19, 22, 51, 80, 112, and 114.

  

αα11--

AdrenergicAdrenergic

AntagonismAntagonism

MuscarinicMuscarinic

AntagonismAntagonism

Fast Sodium ChannelFast Sodium Channel

(I(INaNa) Blockade) Blockade

Delayed RectifierDelayed Rectifier

(I(IKrKr) Blockade) Blockade

Clozapine +++ +++ – +

Iloperidone +++ – – ++

Lurasidone – – – –

Olanzapine ++ +++ – –

Paliperidone ++ – – +

Quetiapine +++ +++ + – to +

Remoxipride – – – –

Risperidone ++ – – –

Sertindole + – – ++

Ziprasidone ++ – – +++

The concept of atypicality has evolved over time with the introduction of new antipsychoticss110,130 andconnotes di�erent features to pharmacologists and clinicians. From a clinical perspective, atypical (second-generation) antipsychotics treat both the positive and negative symptoms of schizophrenia, are less likelythan traditional drugs to produce EPS at clinically e�ective doses, and cause little or no elevation of the

serum prolactin concentration.66 From a pharmacologic perspective, many atypical antipsychotics alsoinhibit the activity of serotonin at the 5-HT2A receptor. Some antipsychotics are classified as third generation,

reflecting the property of antagonism (or partial antagonism) of D2 receptors with agonist at 5-HT1A

receptors.96

More than two dozen atypical antipsychotics are now in clinical use or under development. Despite theirconsiderably higher cost, they have largely supplanted traditional antipsychotics because of theire�ectiveness in treating the negative symptoms of schizophrenia and their somewhat more favorable

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adverse e�ect profile in addition to the perception that they cause fewer long-term adverse e�ects thanconventional 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.55 Controversy exists regarding thesuperiority of these drugs over first-generation antipsychotics, and it is worth noting that the use of thenewer antipsychotics for indications other than schizophrenia is extremely common, including their use asadjunctive treatment for depression, eating disorders, attention deficit hyperactivity disorder, insomnia,

posttraumatic stress disorder, personality disorders, and Tourette syndrome.81 However, the most extensiveo�-label use of atypical antipsychotics is for the management of agitation association with cognitiveimpairment in older adults.

Mechanisms of Antipsychotic ActionMechanisms of Antipsychotic Action

Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine

hypothesis.123 First advanced in 1967 and supported by in vivo data,1 this theory posits that the “positivesymptoms” of schizophrenia result from excessive dopaminergic signaling in the mesolimbic and

mesocortical pathways.88 This hypothesis arose in part from the observation that hallucinations anddelusions could be produced in otherwise normal individuals by drugs that augment dopaminergictransmission, such as cocaine and amphetamine, and that these e�ects could be blunted by dopamineantagonists.

There are at least five subtypes of dopamine receptors (D1 through D5), but schizophrenia principally involves

excess signaling at the D2 subtype,123 and antagonism of D2 neurotransmission is the sine qua non of

antipsychotic activity. Antipsychotics have di�erent binding profiles at this receptor, reflected by thedissociation constant (Kd), which in turn reflects release of the drug from the receptor. For example, the

receptor releases clozapine and quetiapine more rapidly than it does any other drugs.121,123

Dopamine receptors are present in many other areas of the central nervous system (CNS), including thenigrostriatal pathway (substantia nigra, caudate and putamen, which collectively govern the coordination ofmovement), tuberoinfundibular pathway, hypothalamus and pituitary, and area postrema of the medulla,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 e�ects of thesedrugs. For example, whereas D2 antagonism in the CTZ alleviates nausea and vomiting, 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.136,150

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

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therapeutic doses can be used to predict the adverse e�ect of each antipsychotic profile.22 For example,those that antagonize muscarinic receptors at clinically e�ective doses (most notably the aliphatic andpiperidine phenothiazines as well as clozapine, loxapine, olanzapine, and quetiapine) o�en produceanticholinergic e�ects during routine use and can produce pronounced anticholinergic manifestations a�eroverdose (Table 67–2). Similarly, blockade of peripheral α1-adrenergic receptors by the aliphatic and

piperidine phenothiazines, clozapine, risperidone, paliperidone, iloperidone, and others increases the risk ofpostural hypotension during therapy and clinically important hypotension a�er overdose. In contrast,haloperidol overdose, for example, is characterized by neither antimuscarinic e�ects nor hypotension.

Several antipsychotics also block voltage-gated fast sodium channels (INa). Although this e�ect is of little

consequence during therapy, in the setting of overdose this can slow cardiac conduction (phase 0depolarization) and impair myocardial contractility. This e�ect, most notable with the phenothiazines, isboth rate and voltage dependent and is therefore more pronounced at faster heart rates and less negative

transmembrane potentials.19 Blockade of the delayed rectifier potassium current (IKr) can produce

prolongation of the QT interval, creating a substrate for development of torsade de pointes.94 Prolongationof the QT interval is sometimes evident during maintenance therapy, particularly in patients with previouslyunrecognized repolarization abnormalities or additional risk factors for QT interval prolongation. This e�ectmay partially explain the dose-dependent increase in risk of sudden cardiac death among patients treated

with typical and atypical antipsychotic drugs.108,109

Several antipsychotics exhibit a relatively high degree of antagonism at the 5-HT2A receptor, which imparts

two important therapeutic properties: (1) greater e�ectiveness for the treatment of the negative symptomsof schizophrenia and (2) a significantly lower incidence of extrapyramidal side e�ects. Some antipsychoticsproduce unique e�ects through e�ects at other receptors. For example, loxapine and clozapine inhibit the

presynaptic reuptake of catecholamines and antagonize γ-aminobutyric acid (GABA)A receptors,129 which

may explain the apparent increase in the occurrence of seizures with overdose of these antipsychotics.105 Amore detailed description of the pharmacology of the most commonly used second-generationantipsychotics is warranted in light of their increasing role in therapy.

Clozapine, a dibenzodiazepine, binds to dopamine receptors (D1–D5) and serotonin receptors (5-HT1A/1C, 5-

HT2A/2C, 5-HT3, and 5-HT6) with moderate to high a�inity.8,106,114 It also antagonizes α1-adrenergic, α2-

adrenergic, and H1 histamine receptors. It has the highest binding a�inity of any atypical antipsychotic at M1

muscarinic receptors.113 Despite this feature, clozapine paradoxically activates the M4 genetic subtype of the

muscarinic receptor and frequently produces sialorrhea during therapy.112

Olanzapine, a thienobenzodiazepine, binds with high a�inity to serotonin (5-HT2A/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

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traditional antipsychotics.70,114 It is an exceptionally potent H1 antagonist, binding more avidly than

pyrilamine, which is a widely used antihistamine. It is also has a high a�inity for M1 receptors and is a

relatively weak α1 antagonist.

Risperidone, a benzisoxazole derivative, has high a�inity for several receptors, including serotonin receptors

(5-HT2A/2C), D2 receptors, and α1 and H1 receptors.70,112,114 It has no appreciable activity at M1 receptors. Its

primary metabolite (9-hydroxyrisperidone) is nearly equipotent as the parent compound at D2 and 5-

HT2Areceptors.70 Paliperidone is the major active metabolite of risperidone and is available orally and as a

long-acting parenteral preparation that exhibits a similar receptor binding profile.86

Quetiapine, a dibenzothiazepine, is a weak antagonist at D2, M1, and 5-HT1A receptors, but it is a potent

antagonist of α1-adrenergic and H1 receptors.70 At least 2 of its 11 metabolites are pharmacologically active,

but they circulate at low concentrations and likely contribute little to the quetiapine’s clinical e�ects. Aconsiderable proportion of fatalities involving antipsychotics reported to North American Poison Control

Centers involve quetiapine, usually in combination with other drugs.16

Ziprasidone, a benzothiazole derivative, is an antagonist at D2 and several serotonin (5-HT2A/2C, 5-HT1D, and

5-HT7) receptors, but it also displays agonist activity at 5-HT1Areceptors.70,71,114 Its α1 antagonist activity is

particularly strong, with a binding a�inity approximately one 10th that of prazosin. In addition, it is a strong

inhibitor of the delayed rectifier channel (IKr) and can significantly prolong repolarization.71,83

Lurasidone is an active metabolite of risperidone. It exhibits high a�inity for D2 and 5-HT2A receptors, as well

as for 5-HT1A and 5-HT7, but low a�inity α1 adrenergic receptors and no appreciable a�inity for muscarinic or

H1 receptors.86

Aripiprazole, a quinolinone derivative, is a novel antipsychotic that binds avidly to D2 and D3 receptors as

well as 5-HT1A, 5-HT2A, and 5-HT2B receptors.93,114 Some evidence suggests that its e�icacy in the treatment

of schizophrenia and its lower propensity for EPS relates to partial agonist activity at dopamine D2

receptors.91 Aripiprazole acts as a partial agonist at 5-HT1A receptors but is an antagonist at 5-HT2A receptors.

Its principal active metabolite, dehydroaripiprazole, has a�inity for D2 receptors and thus has pharmacologic

activity similar to that of the parent compound.93

Like aripiprazole, bifeprunox is a partial agonist at D2 and 5-HT1A receptors. It is characterized as a third-

generation antipsychotic and has no appreciable a�inity for serotonin 5-HT2A and 5-HT2C, muscarinic, or H1

receptors.31,96,122

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Amisulpride is a substituted benzamide derivative that preferentially blocks dopamine receptors in limbicrather than striatal structures. At low doses, it blocks presynaptic D2 and D3 receptors with high a�inity,

thereby accentuating dopamine release, and at high doses, it blocks postsynaptic D2 and D3 receptors. It has

no appreciable a�inity for serotonergic, histaminergic, adrenergic, and cholinergic receptors.86

Sertindole is a second-generation antipsychotic recently reintroduced into the market a�er being voluntarilywithdrawn in 1998 over concerns about its e�ects on the QT interval. It binds to striatal D2 receptors,

although less avidly than olanzapine, and exhibits antagonism at 5-HT2A and α1 adrenergic

receptors.68,102,128 It is estimated that between 3.1% and 7.8% of patients receiving sertindole develop QT

intervals greater than 500 ms.148

Asenapine is a second-generation antipsychotic administered sublingually because of its high first-passmetabolism. It acts as an antagonist at multiple dopamine, 5-HT, histamine, and α-adrenergic receptors but

has no appreciable activity at muscarinic receptors or on the QT interval.28,29

PHARMACOKINETICS AND TOXICOKINETICSPHARMACOKINETICS AND TOXICOKINETICS

With a few exceptions, the antipsychotics have similar pharmacokinetic characteristics regardless of theirchemical classification. Most are lipophilic; have a large volume of distribution; and with the exception ofasenapine, are generally well absorbed, although some antipsychotics with prominent anticholinergice�ects are likely to exhibit delayed absorption. Plasma concentrations generally peak within 2 to 3 hoursa�er a therapeutic dose but can be delayed a�er overdose.

Most antipsychotics are substrates for one or more isoforms of the hepatic cytochrome (CYP) enzyme system.For example, haloperidol, perphenazine, thioridazine, sertindole, and risperidone are extensivelymetabolized 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 influence the

tolerability and e�icacy of treatment with these antipsychotics during therapeutic use15,32,33,65,142 but areunlikely to significantly alter the severity of acute antipsychotic overdose.

Drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, and bupropion) can increase concentrations of theseantipsychotics, increasing the risk of adverse e�ects. In contrast, metabolism of clozapine and asenapine isprimarily mediated by CYP1A2, and increased clozapine concentrations follow exposure to CYP1A2 inhibitorssuch as fluvoxamine, macrolide, or fluoroquinolone antibiotics or upon smoking cessation because the

polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2.38 The kidneys play a relatively smallrole in the elimination of antipsychotics, and dose adjustment is generally not necessary for patients withchronic kidney disease.

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONSPATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS

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Table 67–3 lists the adverse e�ects of antipsychotics. Some of these e�ects develop primarily followingoverdose, but others occur during the course of therapeutic use.

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aAn exception is clozapine, which can cause sialorrhea.

TABLE 67–3

Adverse E�ects of AntipsychoticsAdverse E�ects of Antipsychotics

Central nervous system Somnolence, progressing to coma

Respiratory depression with loss of airway reflexes

Hyperthermia

Seizures

Extrapyramidal syndromes

Central anticholinergic syndrome

Cardiovascular  

Clinical Tachycardia

Hypotension (orthostatic or resting)

Myocardial depression

Electrocardiographic QRS complex prolongation

Right deviation of terminal 40 ms of frontal plane axis

QT interval prolongation

Torsade de pointes

Nonspecific repolarization changes

Endocrine Amenorrhea, oligomenorrhea, or metrorrhagia

Breast tenderness and galactorrhea

Gastrointestinal Impaired peristalsis

Dry moutha

Genitourinary Urinary retention

Ejaculatory dysfunction

Priapism

Ophthalmic Mydriasis or miosis; visual blurring

Dermatologic Impaired sweat production

Cutaneous vasodilation

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Adverse E�ects During Therapeutic UseAdverse E�ects During Therapeutic Use

The Extrapyramidal SyndromesThe Extrapyramidal Syndromes

The EPSs (Table 67–4) are a group of disorders that share the common feature of abnormal muscularactivity. Among the typical antipsychotics, the incidence of EPS appears to be highest with the more potentantipsychotics such as haloperidol and flupenthixol and lower with less potent antipsychotics such aschlorpromazine and thioridazine. Atypical antipsychotics are associated with an even lower incidence ofEPS. Although the physiologic mechanisms for this observation are not fully understood, several hypotheseshave been put forth, including 5-HT2A antagonism, rapid dissociation from the D2 receptor, and a lower

degree of nigrostriatal dopaminergic hypersensitivity during chronic use.66,67,84 However, it is important tonote that EPS occur during treatment with any antipsychotic, regardless of typicality or potency.

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Data from references 104 and 136.

TABLE 67–4

The Extrapyramidal SyndromesThe Extrapyramidal Syndromes

DisorderDisorder

Time ofTime of

MaximalMaximal

RiskRisk

FeaturesFeaturesPostulatedPostulated

MechanismMechanismSuggested TreatmentsSuggested Treatments

Akathisia Hours to

days

Restlessness and general

unease; inability to sit still

Mesocortical

D2 antagonism

Dose reduction, trial of

alternate drug, propranolol,

benzodiazepines,

anticholinergics

Dystonia Hours to

days

Sustained, involuntary

muscle contraction, including

torticollis, blepharospasm,

oculogyric crisis

Imbalance of

dopaminergic

or cholinergic

transmission

Anticholinergics,

benzodiazepines

Neuroleptic

malignant

syndrome

2–10

days

Many (Table 67–5): altered

mental status, motor

symptoms, hyperthermia,

autonomic instability,

catatonia, mutism

D2 antagonism

in striatum,

hypothalamus,

and

mesocortex

Cooling, benzodiazepines,

supportive care,

bromocriptine,

amantadine, or other

direct-acting dopamine

agonist

Parkinsonism Weeks Bradykinesia, rigidity,

shu�ling gait, masklike

facies, resting tremor

Postsynaptic

striatal D2

antagonism

Dose reduction,

anticholinergics, dopamine

agonists

Tardive

dyskinesia

3

months

to years

Late-onset involuntary

choreiform movements,

buccolinguomasticatory

movements

Excess

dopaminergic

activity

Recognize early and stop

o�ending drug; addition of

other antipsychotic;

cholinergics

Acute DystoniaAcute Dystonia

Acute dystonia is a movement disorder characterized by sustained involuntary muscle contractions, o�eninvolving the muscles of the head and neck, including the extraocular muscles and the tongue, but

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occasionally involving the extremities. These contractions are sometimes referred to as limited reactions,reflecting their transient nature rather than their severity. All of the currently available antipsychotics are

associated with the development of acute dystonic reactions.136 Spasmodic torticollis, facial grimacing,protrusion of the tongue, and oculogyric crisis are among the more common manifestations. Laryngealdystonia is a rare but potentially life-threatening variant that is easily misdiagnosed because it presents with

throat pain, dyspnea, stridor, and dysphonia rather than the more characteristic features of dystonia.40

Acute dystonia typically develops within a few hours of starting of treatment but may be delayed in onset forseveral days. Le� untreated, dystonia resolves slowly over several days a�er the o�ending antipsychotic iswithdrawn. Risk factors for acute dystonia include male gender, young age (children are particularly

susceptible), a previous episode of acute dystonia, and recent cocaine use.137,150 Although the reaction o�enappears dramatic and sometimes is mistaken for seizure activity, it is rarely life threatening. Of note,xenobiotics other than antipsychotics sometimes cause acute dystonia, particularly metoclopramide, the

antidepressants, some antimalarials, histamine H2 receptor antagonists, anticonvulsants, and cocaine.137

Treatment of Acute DystoniaTreatment of Acute Dystonia

Acute dystonia is generally more distressing than serious, but rare cases compromise respiration,

necessitating supplemental oxygen and, occasionally, assisted ventilation.40,137 The response to parenteralanticholinergics is generally rapid and dramatic, and benztropine is recommended as the first-line treatment(2 mg intravenously or intramuscularly in adults or 0.05 mg/kg in children). Diphenhydramine is o�en morereadily available, and it is also reasonable to use (50 mg intravenously or intramuscularly in adults, or 1mg/kg in children). Parenteral benzodiazepines such as lorazepam (0.05–0.10 mg/kg intravenously orintramuscularly) or diazepam (0.1 mg/kg intravenously) can be used for patients who do not respond toanticholinergics but can also be e�ective as initial therapy. It is important to recognize that additional dosesof anticholinergics are o�en necessary because the duration of action of most antipsychotics exceeds that of

either benztropine or diphenhydramine.30 We recommend that patients in whom acute dystonia jeopardizesrespiration be observed for at least 12 to 24 hours a�er initial resolution.

AkathisiaAkathisia

Akathisia (from the Greek phrase “not to sit”) is characterized by a feeling of restlessness, anxiety, or sense ofunease, o�en in conjunction with the objective finding of an inability to remain still. Patients with akathisiafrequently appear uncomfortable or fidgety. They typically rock back and forth while standing or repeatedlycross and uncross their legs while seated. Akathisia is sometimes misinterpreted as a manifestation of theunderlying psychiatric disorder rather than an adverse e�ect of drug therapy.

Akathisia is common and o�en reduces adherence to therapy. Like acute dystonia, akathisia tends to occurrelatively early in the course of treatment and coincides with peak antipsychotic concentrations in

plasma.150 The incidence appears highest with typical, high-potency antipsychotics and lowest with atypicalantipsychotics. Although most cases develop within days to weeks a�er initiation of treatment or an increasein 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.84,136 Interestingly, a similar phenomenon is

described in patients a�er the initiation of treatment with antidepressants, particularly the selective

serotonin reuptake inhibitors.7,78

Treatment of AkathisiaTreatment of Akathisia

Akathisia can be di�icult to treat. A reduction in the antipsychotic dose is a reasonable initial intervention. Ifthis fails or is impractical, substitution of another (generally atypical) antipsychotic drug or treatment withlipophilic β-adrenergic antagonists such as propranolol lessen akathisia. In the absence of good data, the

choice of intervention should be guided by individual patient considerations.76,104 Benzodiazepines produceshort-term relief, and anticholinergics such as benztropine or procyclidine lessen akathisia in some patientsbut are more likely to be e�ective for akathisia induced by antipsychotics with little or no intrinsic

anticholinergic activity.21,77

ParkinsonismParkinsonism

Antipsychotics occasionally produce a parkinsonian syndrome characterized by rigidity, akinesia orbradykinesia, and postural instability. It is similar to idiopathic Parkinson disease, although the classic “pill-

rolling” tremor is o�en less pronounced.104 The syndrome typically develops during the first few months oftherapy, particularly with high-potency antipsychotics. It is more common among older women, and in somepatients, it represents iatrogenic unmasking of latent Parkinson disease. Parkinsonism results from

antagonism of postsynaptic D2 receptors in the striatum.136

Treatment of Drug-Induced ParkinsonismTreatment of Drug-Induced Parkinsonism

The risk of drug-induced parkinsonism is minimized by using the lowest e�ective dose of antipsychotic. Theaddition of an anticholinergic o�en attenuates symptoms at the expense of additional side e�ects. Thisstrategy is o�en e�ective in younger patients, although the routine use of prophylactic anticholinergics is notrecommended. A dopamine agonist such as amantadine is sometimes added, particularly in older patientswho may be less tolerant of anticholinergics, but this may aggravate the underlying psychiatric disturbance

and is not generally recommended.82

Tardive DyskinesiasTardive Dyskinesias

The term tardive dyskinesia was coined in 1952 to describe the delayed onset of persistent orobuccal

masticatory movements occurring in a three women a�er several months of antipsychotic therapy.136 Theadjective tardive, meaning delayed, was used to distinguish these movement disorders from theParkinsonian movements described earlier. The incidence of tardive dyskinesia in younger patients isapproximately 3% to 5% per year but rises considerably with age. A prospective study of older patientstreated with high-potency typical antipsychotics identified a 60% cumulative incidence of tardive dyskinesia

a�er 3 years of treatment.61 Potential risk factors for tardive dyskinesia include alcohol use, a�ective

disorder, prior electroconvulsive therapy, diabetes mellitus, and various genetic factors.136

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Several distinct tardive syndromes are recognized, including the classic orobuccal lingual masticatorystereotypy, chorea, dystonia, myoclonus, blepharospasm, and tics. It is generally accepted that the atypicalantipsychotics are associated with a lower incidence of tardive dyskinesia and other drug-related movementdisorders. However, whether this is true of all atypical antipsychotics is unclear. Among the atypicalantipsychotics, 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 are uncertain.132,133,136

Treatment of Tardive DyskinesiaTreatment of Tardive Dyskinesia

Tardive dyskinesia is highly resistant to the usual pharmacologic treatments for movement disorders. Arecent systematic review of various treatment options concluded that none was supported by goodevidence, including dose reduction, switching between antipsychotics, anticholinergics, benzodiazepines, β-

adrenergic antagonists, buspirone, calcium channel blockers, or vitamin E.12 Consequently, no firm guidancecan be o�ered regarding the management of tardive dyskinesia, which should be guided by individualpatient considerations. Despite the absence of good data, a recent review proposed strategies formanagement of tardive dyskinesia, beginning with primary prevention (avoidance of antipsychotic therapy

where possible and use of the lowest e�ective dose).141 Tetrabenazine, an inhibitor of vesicular monoaminetransporter type 2 (VMAT2), was suggested as the first-line treatment, although it is expensive and may cause

somnolence, depression, or parkinsonism.4 Valbenazine, a recently approved VMAT2 inhibitor with a longer

half-life, appears to be better tolerated than tetrabenazine.59 For focal tardive dyskinesia (cervical ororomandibular, for example), the same review suggested botulinum toxin injections.

Neuroleptic Malignant SyndromeNeuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a potentially life-threatening emergency. First described in 1960 in

patients treated with haloperidol, this syndrome is now associated with virtually every antipsychotic.35 The

reported incidence of NMS ranges from 0.2% to 1.4% of patients receiving antipsychotics,2,24,131 but lesssevere episodes may go undiagnosed or unreported. As a result, much of what is known about theepidemiology and treatment of NMS is speculative and based on case reports and case series. Most cases of

NMS are diagnosed in young adulthood, with the frequency of diagnosis diminishing gradually therea�er.46

The pathophysiology of NMS is incompletely understood but involves abrupt reductions in centraldopaminergic neurotransmission in the striatum and hypothalamus, altering the core temperature “set

point”48 and leading to impaired thermoregulation and other manifestations of autonomic dysfunction.

Blockade of striatal D2 receptors contributes to muscle rigidity and tremor.13,26,138 In some cases, a direct

e�ect on skeletal muscle may play a role in the pathogenesis of hyperthermia, but the thermodysregulation

of NMS is principally a centrally mediated phenomenon.48 Altered mental status is multifactorial and reflectsone or more of hypothalamic and spinal dopamine receptor antagonism, a genetic predisposition, or the

direct e�ects of hyperthermia and other drugs.50 Although NMS most o�en occurs during treatment with aD2 receptor antagonist, withdrawal of dopamine agonists sometimes produces an indistinguishable

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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,43 or

bromocriptine.13 The resulting disorder is sometimes referred to as the Parkinsonian-hyperpyrexia

syndrome, and mortality rates of up to 4% are reported.95 Hospitalization for aspiration pneumonia, acommon occurrence in older patients with Parkinson disease, is a particularly high-risk setting for thiscomplication and is particularly dangerous because the cardinal manifestations of NMS are easilymisattributed to the combined e�ects of pneumonia and the underlying movement disorder.

The vast majority of NMS cases occur in the context of therapeutic use of antipsychotics rather than a�eroverdose. Postulated risk factors for the development of NMS include young age, male gender, extracellularfluid volume contraction, use of high-potency antipsychotics, depot preparations, cotreatment with lithium,

multiple drugs in combination, and rapid dose escalation.2,25,75,97 One large observational study97 suggeststhat treatment with high-potency first-generation antipsychotics is associated with a more than 20-foldincrease in the risk of NMS, although this may partly reflect heightened suspicion of the disorder in patientsreceiving those drugs. The mortality rate of NMS associated with first-generation antipsychotics is estimated

at approximately 16%, and the rate associated with second-generation antipsychotics is estimated at 3%.135

The manifestations of NMS include the tetrad of altered mental status, muscular rigidity (classicallydescribed as “lead pipe”), hyperthermia, and autonomic dysfunction. These findings appear in anysequence, although a review of 340 NMS cases found that mental status changes and rigidity usually

preceded the development hyperthermia and autonomic instability.139 Occasionally, rigidity is not present

when creatine kinase concentrations are elevated but emerges therea�er.98 Signs typically evolve over aperiod of several days, with the majority occurring within 2 weeks of antipsychotic initiation. However, it isimportant to recognize that NMS occurs even a�er prolonged use of an antipsychotic, particularly a�er adose increase, the addition of another antipsychotic, or the development of intercurrent illness. It is alsoworth noting that the clinical course of NMS o�en fluctuates, sometimes waxing and waning dramaticallyover a few hours.

There are no universally accepted criteria for the diagnosis of NMS, and more than a dozen sets of criteria

have been proposed.3,24,37,75 The operating characteristics of these criteria have not been formallyevaluated, in part because of the absence of a gold standard. An international group published the results of

a Delphi consensus panel regarding the diagnosis of NMS (Table 67–5).47 A recent validation exercisesuggested that an aggregate cuto� score of 74 (of a possible 100) was associated with the highest degree ofagreement between expert-generated criteria and Diagnostic and Statistical Manual of Mental Disorders,

fourth edition, text revision, criteria (sensitivity, 69.6%; specificity, 90.7%).49 However, the authors cautionthat in the absence of a biological reference standard, this scoring system should be used adjunctively withcurrent clinical standards for the diagnosis of NMS.

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DBP = diastolic blood pressure; SBP = systolic blood pressure.

Data from Fryml L, Williams KR, Pelic CG, et al. The role of amantadine withdrawal in 3 cases of treatment-refractory

altered mental status. J Psychiatr Pract. 2017 May;23(3):191-199.

TABLE 67–5

Suggested Diagnostic Criteria for the Neuroleptic Malignant SyndromeSuggested Diagnostic Criteria for the Neuroleptic Malignant Syndrome

CriterionCriterionPriorityPriority

ScoreScore

Exposure to a dopamine antagonist or withdrawal of a dopamine agonist in previous 72 hours 20

Hyperthermia (>100.4oF or 38.0oC on at least two occasions, measured orally 18

Rigidity 17

Mental status alteration (reduced or fluctuating level of consciousness) 13

Creatine kinase elevation (at least four times the upper limit of normal) 10

Sympathetic nervous system lability, defined as at least two of: 10

Blood pressure elevation (SBP or DBP ≥25% above baseline)  

Blood pressure fluctuation (≥20% DBP change or ≥25% SBP change in 24 hours)  

Diaphoresis  

Urinary incontinence  

Hypermetabolic state (defined as heart rate increase ≥25% above baseline and respiratory rate

increase ≥50% above baseline)

5

Negative workup for other toxic, metabolic, infectious, or neurologic causes 7

It may be di�icult to distinguish NMS from other toxin-induced hyperthermia syndromes, such as thoseassociated with anticholinergics (antimuscarinics) (Chap. 49) and the serotonergics (Chap. 69), all of whichshare common features of elevated temperature, altered mental status, and neuromuscular abnormalities.The most important di�erentiating feature is the medication history, with dopamine antagonists,antimuscarinic drugs, and direct or indirect serotonin agonists (o�en in combination) as the most likely

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etiologies, respectively. The time course of the illness also helps to di�erentiate among the disorders.Whereas serotonin toxicity and the antimuscarinic syndrome tend to develop rapidly a�er exposure tocausative xenobiotics, NMS typically develops more gradually, o�en waxing and waning over several days ormore. Occasionally, clinicians must attempt to di�erentiate NMS from other disorders in the absence of a

reliable medication history. The physical examination is of some utility in this regard.103 Although NMS isclassically characterized by “lead-pipe” rigidity, the presence of ocular or generalized clonus is moresuggestive of serotonin toxicity, particularly when accompanied by shivering and hyperreflexia, findings nottypical of NMS. Because skeletal muscle contraction occurs through nicotinic rather than muscarinictransmission, patients with the antimuscarinic syndrome generally have few muscular abnormalities.However, such patients are sometimes resistant to physical restraint, giving the appearance of increasedmuscle tone.

Treatment of Neuroleptic Malignant Syndrome: General MeasuresTreatment of Neuroleptic Malignant Syndrome: General Measures

Treatment recommendations are largely based on general physiologic principles, case reports, and caseseries. Therapy should be individualized according to the severity and duration of illness and the modifying

influences of comorbidity.13,111,140 The provision of good supportive care is the cornerstone for treatment ofNMS. It is essential to recognize the condition as an emergency and to withdraw the o�ending xenobioticimmediately. When NMS ensues a�er abrupt discontinuation of a dopamine agonist such as levodopa, thedrug should be reinstituted promptly. Most patients with suspected NMS should be admitted to an intensivecare unit. Supplemental oxygen should be administered, and assisted ventilation is necessary in cases ofrespiratory failure, which result from one or more of central hypoventilation, loss of protective airwayreflexes, rigidity of the chest wall muscles or oversedation.

The hyperthermia associated with NMS is multifactorial in origin and, when present, warrants aggressivetreatment. Antipyretics are not e�ective. Immersion of patients with severe drug-induced hyperthermia

(>106°F) in an ice-water bath has been shown to rapidly lower body temperature (Chaps. 29 and 75).74

Despite the absence of good data in patients with NMS, we recommend ice-water immersion in patients withsevere hyperthermia given the urgency with which it should be corrected. Other strategies include activecooling blankets; the placement of ice packs in the groin and axillae; or evaporative cooling, which can beaccomplished by removing the patient’s clothing and exposing the patient to cooled water or towelsimmersed in ice water while maintaining continuous air circulation with the use of fans. Although o�en

used,145 these approaches are inferior to ice water immersion and are not recommended unless immersionis impractical or unsafe.

Hypotension should be treated initially with isotonic crystalloid followed by vasopressors if necessary.Maintenance of intravascular volume and adequate renal perfusion are recommended to reduce theincidence of myoglobinuric acute kidney injury in patients with high creatine kinase concentrations.Tachycardia does not require specific treatment, but hemodynamically significant bradycardia necessitatestranscutaneous or transvenous pacing. Venous thromboembolism is a major cause of morbidity andmortality in patients with NMS, and prophylactic doses of low-molecular-weight heparin are reasonable inpatients who likely will be immobilized for more than 12 to 24 hours.

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Pharmacologic Treatment of Neuroleptic Malignant SyndromePharmacologic Treatment of Neuroleptic Malignant Syndrome

Benzodiazepines are the most widely used pharmacologic adjuncts for treatment of NMS and arerecommended as first line-therapy. Dantrolene and bromocriptine are not well studied, and their

incremental benefit over good supportive care is debated.111,116 Benzodiazepines are frequently used in themanagement of NMS because of their rapid onset of action, which is particularly important when patientsare agitated or restless. They attenuate the sympathetic hyperactivity that characterizes NMS by facilitatingGABA-mediated chloride transport and producing neuronal hyperpolarization, in a fashion analogous to their

beneficial e�ects in cocaine toxicity.50 The primary disadvantage of benzodiazepines is that they will cloudthe assessment of the patient’s mental status.

Dantrolene reduces skeletal muscle activity by inhibiting ryanodine receptor type 1 calcium release

channels, interfering with calcium release from the sarcoplasmic reticulum.69 In theory, this should reducebody temperature and total oxygen consumption and lessen the risk of myoglobinuric acute kidney injury.The role of dantrolene in NMS is controversial because the available literature is limited to case reports andcase series with varying conclusions. Moreover, unlike malignant hyperthermia (in which the use ofdantrolene is unquestioned), the muscle rigidity of NMS is principally a centrally mediated process.Nevertheless, several reports describe rapid, dramatic reductions in rigidity and temperature a�er its

administration.17,53,72 Dantrolene is not recommended as a routine treatment in patients with NMS but isreasonable in those with prominent muscular rigidity or rhabdomyolysis, in light of its potential benefits and

relative safety.13 It can be given by mouth or nasogastric tube (50–100 mg/d) or by intravenous (IV) infusion(2–3 mg/kg/d, or up to 10 mg/kg/d in severe cases). Bromocriptine is a centrally acting dopamine agonistgiven orally or by nasogastric tube at dosages of 2.5 to 10 mg three or four times daily. The rationale for itsuse rests in the belief that reversal of antipsychotic-related striatal D2 antagonism will ameliorate the

manifestations of NMS. It is recommended in patients with moderate to severe NMS, but other dopamine

agonists anecdotally associated with success may be used instead, including ropinirole, levodopa,100,127 and

amantadine.44,60,131 Of note, dopaminergics are associated with exacerbation of underlying psychiatricillness.

When these medications are used, they should be tapered slowly a�er the patient improves to minimize thelikelihood of recrudescent NMS. In severe cases with prominent rigidity it is reasonable to use dantroleneand a dopamine agonist should be used in combination with benzodiazepines.

Electroconvulsive TherapyElectroconvulsive Therapy

Electroconvulsive therapy (ECT) is reported to dramatically improve the manifestations of NMS, presumablyby enhancing central dopaminergic transmission. In one report, five patients received an average of 10 ECT

treatments, and resolution generally occurred a�er the third or fourth session.99 Whether this resultrepresents a true e�ect of ECT or simply the natural course of NMS with good supportive care alone is notclear. As with drug therapies for NMS, the e�ectiveness of ECT remains unproven, but its use seemsreasonable in patients with severe, persistent, or treatment-resistant NMS as well as those with residual

catatonia or psychosis a�er resolution of other manifestations.13,100

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Adverse E�ects on Other Organ SystemsAdverse E�ects on Other Organ Systems

Sedation, dry mouth, and urinary retention occur commonly with antipsychotics, particularly during theinitial period of therapy. These e�ects occur most commonly with antipsychotics that exhibit antihistaminicand antimuscarinic activity. All antipsychotics lower the seizure threshold, but seizures are uncommonduring therapeutic use. Because hypothalamic dopamine inhibits hypophyseal prolactin release,hyperprolactinemia and galactorrhea can occur. All antipsychotics are associated with a host of metabolicderangements, including weight gain, dyslipidemia, and steatohepatitis. The metabolic syndrome appears

most commonly in association with clozapine, olanzapine, and chlorpromazine therapy.34 Rare but dramatic

instances of glucose intolerance, including fatal cases of diabetic ketoacidosis, are also described.6,54,107,134

The mechanism of this is incompletely understood, but it is not adequately explained by the weight gainassociated with antipsychotic therapy because glucose disturbances o�en develop shortly a�er therapy is

instituted. The risk of hyperglycemia appears greatest during the initial weeks of antipsychotic therapy.79

Other idiosyncratic reactions reported with use of antipsychotics include photosensitivity, skin pigmentationand cholestatic hepatitis (particularly with the phenothiazines), myocarditis, and agranulocytosis (the latter

occurs with many antipsychotics, most notably clozapine, occurring in up to 2% of patients).90 Most of theseconditions result from an immunologically based hypersensitivity reaction and develop during the firstmonth of therapy. Finally, an increasing number of reports associate antipsychotic drugs with venous

thromboembolism.52,63 This may partially explain the high incidence of thromboembolic disease found inpatients with NMS (see later).

Acute OverdoseAcute Overdose

Antipsychotic overdose produces a spectrum of toxic manifestations involving multiple organ systems, butthe most serious toxicity involves the CNS and cardiovascular system. Some of these manifestations arepresent to a minor degree during therapeutic use, although they tend to be most pronounced during theearly period of therapy and dissipate with continued use.

Depressed level of 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 significantrespiratory depression is uncommon in the absence of other factors. Many antipsychotics, including several

of the atypicals, are potent muscarinic antagonists and produce anticholinergic features in overdose.10,22,27

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 maybe 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 ofimpaired sweating, as well as increased heat production in agitated patients. Hyperthermia should alwaysprompt a search for other features of NMS. Tachycardia is a common finding in patients with antipsychoticoverdose and reflects reduced vagal tone and, with some antipsychotics, a compensatory response to

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hypotension. Bradycardia is distinctly uncommon, and although it may be a preterminal finding, its presenceshould prompt a search for alternative causes, including in ingestion of negative chronotropic drugs such asβ-adrenergic antagonists, calcium channel blockers, cardioactive steroids, and opioids. Hypotension is acommon feature of antipsychotic overdose and is generally caused by peripheral α1-adrenergic blockade

and, particularly with the phenothiazines, reduced myocardial contractility.

The electrocardiographic (ECG) manifestations of antipsychotic overdoses vary, sometimes exhibitingsimilarities to those of cyclic antidepressant toxicity (Chaps 15 and 68). These include prolongation of theQRS complex and a rightward deflection of the terminal 40 ms of the QRS complex, typically manifesting as atall, broad terminal positive deflection of the QRS complex in lead aVR. These changes reflect blockade of theinward 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 and other ventricular

dysrhythmias.94 This situation is sometimes evident during maintenance therapy and may underlie the

apparent increase in sudden cardiac death among users of antipsychotic drugs.108,109

DIAGNOSTIC TESTSDIAGNOSTIC TESTS

The diagnosis of antipsychotic poisoning is supported by the clinical history, the physical examination, and alimited number of adjunctive tests. Both the clinical and ECG findings are nonspecific and shared by otherdrug classes, including TCAs, skeletal muscle relaxants, carbamazepine, and first-generation antihistaminessuch as diphenhydramine. Moreover, the absence of typical ECG changes does not exclude a significantantipsychotic ingestion, particularly early a�er overdose, and at least one additional ECG is recommended inthe following 2 to 3 hours.

Abdominal radiography sometimes reveals densities in the gastrointestinal tract because some solid dosageforms of phenothiazines are radiopaque. However, these tests are neither sensitive nor specific, and they arenot recommended in the absence of another indication.

Plasma concentrations of antipsychotics are not widely available, do not correlate well with clinical signs andsymptoms, and do not help guide therapy. Comprehensive urine drug screens using high-performance liquidchromatography, gas chromatography–mass spectrometry, or tandem mass spectrometry can detectantipsychotics, but these tests are available at only a few hospitals and in most instances provide only aqualitative result and are not recommended. Urine immunoassays for TCAs occasionally produce a false-

positive result in the presence of phenothiazines.5,115

MANAGEMENTMANAGEMENT

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 presentationand management. Regularly encountered coingestants include other psychotropic drugs such as

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antidepressants, sedative–hypnotics, opioids, anticholinergic agents, valproic acid, and lithium, as well asethanol and nonprescription analgesics such as acetaminophen and aspirin.

Supportive care is the cornerstone of treatment for patients with antipsychotic overdose. Supplementaloxygen should be administered if hypoxia is present. Intubation and ventilation are rarely required forpatients with single xenobiotic ingestions but may be necessary for patients with very large overdoses ofantipsychotics or coingestion of other CNS depressants. Patients with altered mental status should receivethiamine, as well as parenteral dextrose if hypoglycemia is present. Naloxone is recommended based onclinical grounds (Antidotes in Depth: A4). All symptomatic patients should undergo continuous cardiacmonitoring. An ECG should be recorded upon presentation and reliable venous access obtained.Asymptomatic patients with a normal ECG 6 hours a�er overdose are at exceedingly low risk of complicationsand generally do not require ongoing cardiac monitoring. Symptomatic patients and those with an abnormalECG should have continuous monitoring for a minimum of 24 hours.

Gastrointestinal DecontaminationGastrointestinal Decontamination

Gastrointestinal decontamination with activated charcoal (1 g/kg by mouth or nasogastric tube) isrecommended for patients who present within a few hours of a large or multidrug overdose and have nocontraindications. Although this intervention is time sensitive, many antipsychotics exhibit significantantimuscarinic activity and slow gastric emptying, thereby increasing the likelihood that activated charcoalwill be beneficial. Although it is unknown whether activated charcoal improves clinically important -

outcomes,64 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.57 Orogastric lavageand whole-bowel irrigation likely will not improve clinical outcomes and should be used rarely in themanagement of patients with antipsychotic overdose.

Treatment of Cardiovascular ComplicationsTreatment of Cardiovascular Complications

Vital signs should be monitored closely. Hypotension most o�en results from peripheral α-adrenergic

blockade and is most likely to occur with older, low-potency antipsychotics such as thioridazine.91

Hypotension should be treated initially with appropriate titration of 0.9% sodium chloride. If vasopressorsare required, direct-acting agonists such as norepinephrine or phenylephrine are recommended overdopamine, which is an indirect agonist and likely will be ine�ective. Vasopressin or its analogs should beused with great caution in patients who have coingested a negative inotropic drug such as a β-adrenergicantagonist or calcium channel blocker. Continuous blood pressure monitoring may be warranted in suchcases.

Progressive prolongation of the QRS complex is uncommon and reflects sodium channel blockade andslowing of phase 0 depolarization in the His-Purkinje system. This is usually associated with reduced cardiacoutput and malignant ventricular dysrhythmias. Much of what is known about the treatment of sodiumchannel blocker toxicity derives from the cyclic antidepressant literature, with treatment recommendations

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extended to sodium channel blocking antipsychotic drugs by analogy. Sodium bicarbonate (1–2 mEq/kg) isthe first-line therapy for ventricular dysrhythmias and is recommended for patients with dysrhythmias orQRS complex greater than 0.12 seconds (Antidotes in Depth: A5 and Chap. 68). At least two mechanismsunderlie the beneficial e�ects of sodium bicarbonate, sodium channel blockade is partially overcome by anincrease in extracellular sodium, and the binding of antipsychotics to the sodium channel is less extensivebinding at higher pH values.

Repeated boluses of bicarbonate are recommended to achieve a target blood pH of no greater than 7.5,

although we recommend continuous infusions.125 If the patient is intubated, hyperventilation isrecommended only if sodium bicarbonate is unavailable. If significant conduction abnormalities orventricular dysrhythmias persist despite the use of sodium bicarbonate, lidocaine (1–2 mg/kg, followed bycontinuous infusion) is a reasonable second-line antidysrhythmic. Although lidocaine is also a sodiumchannel blocker, it exhibits rapid on/o� sodium channel binding with preferential binding in the inactivated

state and reportedly lessens the cardiotoxicity associated with antipsychotic drug overdose.124 Class IAantidysrhythmics (procainamide, disopyramide, and quinidine), class IC antidysrhythmics (propafenone,encainide, and flecainide), and class III antidysrhythmics (amiodarone, sotalol, and bretylium) can aggravatecardiotoxicity and are contraindicated. When administering sodium bicarbonate to patients withantipsychotic overdose, caution must be taken to avoid hypokalemia because many of these antipsychoticsblock cardiac potassium channels, thereby prolonging the QT interval. Hypokalemia and hypomagnesemiaexacerbate this blockade, potentially leading to torsade de pointes and other lethal dysrhythmias,particularly in patients with overdoses involving amisulpride or ziprasidone.

Sinus tachycardia related to anticholinergic activity should not be treated unless it is associated with activeischemia, which, although uncommon, may complicate antipsychotic overdose in patients with existingcoronary disease. If symptomatic sinus tachycardia requires emergent treatment, a short-acting β-adrenergicantagonist such as esmolol is recommended. Prolongation of the QT interval requires no specific treatmentother than monitoring and correction of potential contributing causes such as hypokalemia andhypomagnesemia. A�er torsade de pointes has resolved spontaneously resolved or a�er cardioversion,intravenous magnesium sulfate is recommended to lessen the likelihood of recurrence, taking care toprevent hypotension, which is dose and rate dependent. Overdrive pacing with isoproterenol ortranscutaneous or transvenous pacing is recommended if the patient does not respond to magnesium;however, magnesium is preferred because pacing may worsen rate-dependent sodium channel blockade.

Most antipsychotics exhibit a high degree of lipophilicity in addition to significant cardiovascular toxicity.Considerable enthusiasm has emerged for the use of intravenous lipid emulsion (ILE) therapy for patientswith significant cardiac toxicity from lipophilic drugs (Antidotes in Depth: A23). The rationale for this therapyrests, in part, in the concept that highly lipophilic drugs selectively partition into the exogenous lipid,minimizing toxicity at the biophase. This treatment has been extensively studied in animal models of

bupivacaine toxicity,36,143,144 but published experience with antipsychotic drugs is limited to a handful of

case reports.41,85,87,151 Recently published evidence-based recommendations on the use of ILE in acute

poisoning note the very low quality of evidence supporting the intervention for most poisonings.45 As a

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result, it is reasonable to give ILE only in cases of not rapidly treatable cardiovascular collapse a�erantipsychotic overdose. Dosing for ILE is not well established, but a reasonable protocol begins with 20%lipid emulsion given as a bolus of 1.5 mL/kg (Antidotes in Depth: A23). Extracorporeal circulatory support isassociated with survival in severe quetiapine overdose; however, this is only an option in selected centers.This intervention, when available, in critically ill patients unresponsive to other therapies is reasonable but

therefore not routinely recommended at this time.73

Treatment of SeizuresTreatment of Seizures

Seizures associated with antipsychotic overdose are generally short-lived and o�en require nopharmacologic treatment. Multiple or refractory seizures should prompt a search for other causes, includinghypoglycemia and ingestion of other proconvulsant xenobiotics. When treatment is necessary,benzodiazepines such as lorazepam or diazepam generally su�ice, although phenobarbital is a reasonablesecond-line therapy. Although phenytoin is part of the standard algorithm for status epilepticus, it is of

limited e�ectiveness for xenobiotic-induced seizures.126 Patients with refractory seizures should respond topropofol infusion or general anesthesia. Finally, seizures abruptly lower serum pH and thereby increase thecardiotoxicity of antipsychotics by enhancing binding to the sodium channel; therefore, an ECG should beobtained a�er resolution of seizure activity.

Treatment of the Central Antimuscarinic SyndromeTreatment of the Central Antimuscarinic Syndrome

Many of the older and newer generation antipsychotics have pronounced anticholinergic properties. Casereports and observational studies suggest that the cholinesterase inhibitor physostigmine (Antidotes inDepth: A11) can safely and e�ectively ameliorate the agitated delirium associated with the central

antimuscarinic (anticholinergic) syndrome by indirectly increasing synaptic acetylcholine levels.26,118-120

Although benzodiazepines control agitation, they further impair alertness, obfuscating the assessment of

mental status and increasing the risk of complications.23

Physostigmine has been used successfully in patients with antipsychotic overdose,23,117,120,146,147 but itshould be used with caution. It should not be used in patients with ventricular dysrhythmias, any degree ofheart block, or prolongation of the QRS complex. If physostigmine is used, it is recommended to be given in0.5-mg increments every 3 to 5 minutes, with close observation. If bradycardia, bronchospasm, orbronchorrhea develops, these can be treated with glycopyrrolate 0.2 to 0.4 mg IV. Atropine is o�en morewidely available and is a reasonable alternative to glycopyrrolate but it crosses the blood–brain barrier and islikely to aggravate delirium. The e�ects of physostigmine are transient, typically ranging in duration from 30to 90 minutes, and additional doses are o�en necessary. Of note, physostigmine does not prevent othercomplications of antipsychotic overdose, particularly those involving the cardiovascular system.

Other commonly used cholinesterase inhibitors, such as edrophonium, neostigmine, and pyridostigmine,should not be used to treat anticholinergic delirium because they do not cross the blood–brain barrier. Casereports involving other anticholinergics suggest that cholinesterase inhibitors used for treatment of

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dementia (eg, tacrine, donepezil, and galantamine) are reasonable alternatives to physostigmine for patients

able to take medications orally.58,89,101

Enhanced EliminationEnhanced Elimination

No pharmacologic rationale supports the use of multiple-dose charcoal or manipulation of urinary pH toincrease the clearance of antipsychotics. One volunteer study found that urinary acidification may increase

remoxipride elimination,149 but this practice is impractical and possibly dangerous. Because mostantipsychotics exhibit large volumes of distribution and extensive protein binding (Table 67–1),extracorporeal removal is unwarranted and should be performed only if the patient has coingested otherxenobiotics amenable to extracorporeal removal.

SUMMARYSUMMARY

Over the past decade, the atypical antipsychotics have largely supplanted traditional antipsychotics, whichwere associated with greater toxicity in overdose and a higher incidence of extrapyramidal reactions.Consequently, atypical antipsychotics are now implicated in the majority of overdoses.

With both typical and atypical antipsychotics, significant toxicity can occur either during the course oftherapy or a�er overdose. Of the various toxicities that arise during therapeutic use, NMS is the mostdangerous. Its manifestations are protean, and it may be di�icult to recognize. Altered mental status, musclerigidity, hyperthermia, and autonomic instability are its hallmarks, but the diagnosis should be considered inany unwell patient treated with antipsychotics, particularly in the 2 weeks a�er a change in therapy or in apatient with another stressor such as severe intercurrent illness or general anesthesia. Treatment of NMS islargely supportive and o�en involves the use of benzodiazepines. Dopamine agonists such as bromocriptineand ropinirole are recommended in patients with moderate to severe NMS, while dantrolene isrecommended only in those with severe muscle rigidity or rhabdomyolysis. Electroconvulsive therapy isanecdotally associated with dramatic clinical improvement.

The principal manifestations of antipsychotic overdose involve the CNS and cardiovascular system.Depressed mental status, hypotension, and anticholinergic signs are nonspecific features that support thediagnosis of, particularly in conjunction with typical ECG findings of sodium channel blockade and QTinterval prolongation, although these vary considerably among the available antipsychotic drugs.

Most fatalities a�er antipsychotic overdose occur in cases involving coingestion of other CNS depressants orcardiotoxic medications.

Supportive care is the mainstay of therapy for patients with antipsychotic overdose, although selective use ofnonspecific antidotes, such as activated charcoal, sodium bicarbonate, or physostigmine, may improveoutcomes in selected patients. Particularly severe or refractory cardiovascular toxicity may warrant a trial ofILE or extracorporeal life support, although these interventions are not well studied in the context ofantipsychotic drug overdose.

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13. 

AcknowledgmentsAcknowledgments

Frank LoVecchio and Neal Lewin contributed to this chapter in a previous edition.

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