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 were treated with nonspecific sedatives such as barbiturates or chloral hydrate. 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 mental health disorders were institutionalized in the United States. The advent of antipsychotic drugs 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 were capable of causing significant toxicity after overdose, a common occurrence in patients with mental illness. Moreover, they were also associated with a host of adverse effects during routine therapeutic use, particularly 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 in several distinct chemical classes. These drugs exhibited varying potencies and markedly different adverse effect profiles. The novel antipsychotic clozapine was first synthesized in 1959 but did not enter widespread clinical use until the early 1970s. Clozapine was unusual because it conferred a relatively low risk of EPS and was often effective in patients who had not responded well to other antipsychotics. Moreover, unlike other antipsychotic drugs available at the time, it often improved the “negative” symptoms of schizophrenia, such as avolition, alogia, and social withdrawal, symptoms that, although 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 with stringent monitoring requirements.8,56 However, clozapine’s unique therapeutic and pharmacologic properties 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 drugs in clinical practice.
Most antipsychotic toxicity occurs through one of two mechanisms. After overdose, antipsychotic toxicity is dose dependent and reflects an extension of the drug’s effects on neurotransmitter systems and other biologic processes. The features of antipsychotic overdose are therefore generally predictable based on an understanding of the drug’s pharmacology. Unpredictable (idiosyncratic) adverse effects also occur in the context of therapeutic use. These toxicities result from individual susceptibility, which may in part have a genetic basis, and are less reliably correlated with the antipsychotic dose. In both types of toxicity, the severity of illness ranges from minor to life threatening, depending on variety of other factors, including concomitant drug exposures, comorbidity, and access to medical care.
The true incidences of antipsychotic overdose and adverse effects are not known with certainty. Some patients never seek medical attention, and others are misdiagnosed. Even among those who seek medical attention and are correctly diagnosed, notification of poison control centers or other adverse event reporting systems is discretionary and incomplete (Chap. 130). With these limitations in mind, a few observations can be 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 of poison control center calls involving antipsychotic drugs pertain to intentional overdoses in patients 20 years or older, most of whom have a good outcome. However, these drugs were associated with more fatalities than any other group (n = 401 deaths), although the extent to which they played a causal role in death is unclear. Importantly, poison control center data underestimate the annual incidence of poisoning and mortality associated with antipsychotic drugs and likely identify only a small minority of adverse drug reactions involving these drugs (Chap. 130).
Although all antipsychotics 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.18,20 Inferences regarding the relative toxicity of the antipsychotics derived from aggregated data should be extrapolated to individual patients with caution.18,42
Antipsychotics are classified in several ways, according to their chemical structures, their receptor binding profiles, or as typical or atypical antipsychotics. Table 67–1 outlines the taxonomy of some of the more commonly used antipsychotics. Classification by chemical structure was most useful before the 1970s, when phenothiazines 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 of little use to clinicians. It is worth noting, however, that the phenothiazines exhibit a high degree of structural similarity to the tricyclic antidepressants (TCAs) (Fig. 67–1) and share many of their manifestations in overdose. The phenothiazines are further classified according to the nature of the substituent on the nitrogen atom at position 10 of the center ring as aliphatic, piperazine, or piperidine compounds.
TABLE 67–1Classification of Commonly Used Antipsychotics ||Download (.pdf) TABLE 67–1 Classification of Commonly Used Antipsychotics
|Classification ||Antipsychotic ||Usual Daily Adult Dose (mg) ||Volume of Distribution (L/kg) ||Half-Life (Range, h) ||Protein Binding (%) ||Active Metabolite |
|Typicals || || || || || || |
| 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 |
|Phenothiazines || || || || || || |
| 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 |
| ||Pipotiazine ||25–250 (monthly IM depot) ||7.5 ||3–11 ||NR ||N |
|Thioxanthenes ||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 |
|Atypicals || || || || || || |
| 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 |
|Indoles || || || || || || |
| 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 |
Structural similarity between phenothiazines and cyclic antidepressants.
Of greater clinical utility is the classification of antipsychotics according to their binding affinities for various receptors (Table 67–2). 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).
TABLE 67–2Clinical and Toxicologic Manifestations of Selected Antipsychotics ||Download (.pdf) TABLE 67–2 Clinical and Toxicologic Manifestations of Selected Antipsychotics
The concept of atypicality has evolved over time with the introduction of new antipsychoticss110,130 and connotes different features to pharmacologists and clinicians. From a clinical perspective, atypical (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.66 From a pharmacologic perspective, many atypical antipsychotics also inhibit 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 their considerably higher cost, they 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.55 Controversy exists regarding the superiority of these drugs over first-generation antipsychotics, and it is worth noting that the use of the newer antipsychotics for indications other than schizophrenia is extremely common, including their use as adjunctive treatment for depression, eating disorders, attention deficit hyperactivity disorder, insomnia, posttraumatic stress disorder, personality disorders, and Tourette syndrome.81 However, the most extensive off-label use of atypical antipsychotics is for the management of agitation association with cognitive impairment in older adults.
Mechanisms 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 “positive symptoms” of schizophrenia result from excessive dopaminergic signaling in the mesolimbic and mesocortical pathways.88 This hypothesis arose in part from the observation that hallucinations and delusions could be produced in otherwise normal individuals by drugs that augment 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,123 and antagonism of D2 neurotransmission is the sine qua non of antipsychotic activity. Antipsychotics have different binding profiles at this receptor, reflected by the dissociation 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 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 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 effects of these drugs. 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 therapeutic doses can be used to predict the adverse effect of each antipsychotic profile.22 For example, those 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 effects during routine use and can produce pronounced anticholinergic manifestations after overdose (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 of postural hypotension during therapy and clinically important hypotension after overdose. In contrast, haloperidol overdose, for example, is characterized by neither antimuscarinic effects nor hypotension.
Several antipsychotics also block voltage-gated fast sodium channels (INa). 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.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 Prolongation of the QT interval is sometimes evident during maintenance therapy, particularly in patients with previously unrecognized repolarization abnormalities or additional risk factors for QT interval prolongation. This effect may 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 effectiveness for the treatment of the negative symptoms of schizophrenia and (2) a significantly lower incidence of extrapyramidal side effects. Some antipsychotics produce unique effects through effects 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 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, binds to dopamine receptors (D1–D5) and serotonin receptors (5-HT1A/1C, 5-HT2A/2C, 5-HT3, and 5-HT6) with moderate to high affinity.8,106,114 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.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 affinity 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 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 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-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 effects. A considerable 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 affinity 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 affinity for D2 and 5-HT2A receptors, as well as for 5-HT1A and 5-HT7, but low affinity α1 adrenergic receptors and no appreciable affinity 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 efficacy 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 affinity 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 affinity for serotonin 5-HT2A and 5-HT2C, muscarinic, or H1 receptors.31,96,122
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 with high affinity, thereby accentuating dopamine release, and at high doses, it blocks postsynaptic D2 and D3 receptors. It has no appreciable affinity for serotonergic, histaminergic, adrenergic, and cholinergic receptors.86
Sertindole is a second-generation antipsychotic 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 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-pass metabolism. 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 TOXICOKINETICS
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 with the exception of asenapine, are generally well absorbed, although some antipsychotics with prominent anticholinergic effects are likely to exhibit delayed absorption. Plasma concentrations generally peak within 2 to 3 hours after a therapeutic dose but can be delayed after 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 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 influence the tolerability and efficacy of treatment with these antipsychotics during therapeutic use15,32,33,65,142 but are unlikely to significantly alter the severity of acute antipsychotic overdose.
Drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, and bupropion) can increase concentrations of these antipsychotics, increasing the risk of adverse effects. In contrast, metabolism of clozapine and asenapine is primarily mediated by CYP1A2, and increased clozapine concentrations follow exposure to CYP1A2 inhibitors such 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 small role in the elimination of antipsychotics, and dose adjustment is generally not necessary for patients with chronic kidney disease.
PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS
Table 67–3 lists the adverse effects of antipsychotics. Some of these effects develop primarily following overdose, but others occur during the course of therapeutic use.
TABLE 67–3Adverse Effects of Antipsychotics ||Download (.pdf) TABLE 67–3 Adverse Effects of Antipsychotics
|Central nervous system || |
Somnolence, progressing to coma
Respiratory depression with loss of airway reflexes
Central anticholinergic syndrome
|Cardiovascular || |
| Clinical || |
Hypotension (orthostatic or resting)
| 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 || |
|Genitourinary || |
|Ophthalmic ||Mydriasis or miosis; visual blurring |
|Dermatologic || |
Impaired sweat production
Adverse Effects During Therapeutic Use
The Extrapyramidal Syndromes
The EPSs (Table 67–4) are a 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 flupenthixol 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, 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 to note that EPS occur during treatment with any antipsychotic, regardless of typicality or potency.
TABLE 67–4The Extrapyramidal Syndromes ||Download (.pdf) TABLE 67–4 The Extrapyramidal Syndromes
|Disorder ||Time of Maximal Risk ||Features ||Postulated Mechanism ||Suggested 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, shuffling 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 offending drug; addition of other antipsychotic; cholinergics |
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 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. Laryngeal dystonia 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 for several days. Left untreated, dystonia resolves slowly over several days after 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.137,150 Although the reaction often appears 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 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 parenteral anticholinergics 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 often more readily available, and it is also reasonable to use (50 mg intravenously or intramuscularly in adults, or 1 mg/kg in children). Parenteral benzodiazepines such as lorazepam (0.05–0.10 mg/kg intravenously or intramuscularly) or diazepam (0.1 mg/kg intravenously) can be used for patients who do not respond to anticholinergics but can also be effective as initial therapy. It is important to recognize that additional doses of anticholinergics are often 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 jeopardizes respiration be observed for at least 12 to 24 hours after initial resolution.
Akathisia (from the Greek phrase “not to sit”) is characterized by a feeling of restlessness, anxiety, or sense of unease, often in conjunction with the objective finding of an inability to remain still. Patients with akathisia frequently appear uncomfortable or fidgety. They typically rock back and forth while standing or repeatedly cross and uncross their legs while seated. Akathisia is sometimes misinterpreted as a manifestation of the underlying psychiatric disorder rather than an adverse effect of drug therapy.
Akathisia is common and often reduces adherence to therapy. Like acute dystonia, akathisia tends to occur relatively 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 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.84,136 Interestingly, a similar phenomenon is described in patients after the initiation of treatment with antidepressants, particularly the selective serotonin reuptake inhibitors.7,78
Akathisia can be difficult to treat. A reduction in the antipsychotic dose is a reasonable initial intervention. If this fails or is impractical, substitution of another (generally atypical) antipsychotic drug or treatment with lipophilic 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 produce short-term relief, and anticholinergics such as benztropine or procyclidine lessen akathisia in some patients but are more likely to be effective for akathisia induced by antipsychotics with little or no intrinsic anticholinergic activity.21,77
Antipsychotics occasionally produce a parkinsonian syndrome characterized by rigidity, akinesia or bradykinesia, and postural instability. It is similar to idiopathic Parkinson disease, although the classic “pill-rolling” tremor is often less pronounced.104 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 represents iatrogenic unmasking of latent Parkinson disease. Parkinsonism results from antagonism of postsynaptic D2 receptors in the striatum.136
Treatment of Drug-Induced Parkinsonism
The risk of drug-induced parkinsonism is 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 is often effective in younger patients, although the routine use of prophylactic anticholinergics is not recommended. A dopamine agonist such as amantadine is sometimes added, particularly in older patients who may be less tolerant of anticholinergics, but this may aggravate the underlying psychiatric disturbance and is not generally recommended.82
The term tardive dyskinesia was coined in 1952 to describe the delayed onset of persistent orobuccal masticatory movements occurring in a three women after several months of antipsychotic therapy.136 The adjective tardive, meaning delayed, was used to distinguish these movement disorders from the Parkinsonian movements described earlier. 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.61 Potential risk factors for tardive dyskinesia include alcohol use, affective disorder, prior electroconvulsive therapy, diabetes mellitus, and various genetic factors.136
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 are uncertain.132,133,136
Treatment of Tardive Dyskinesia
Tardive dyskinesia is highly resistant to the usual pharmacologic treatments for movement disorders. A recent systematic review of various treatment options concluded that none was supported by good evidence, including dose reduction, switching between antipsychotics, anticholinergics, benzodiazepines, β-adrenergic antagonists, buspirone, calcium channel blockers, or vitamin E.12 Consequently, no firm guidance can be offered regarding the management of tardive dyskinesia, which should be guided by individual patient considerations. Despite the absence of good data, a recent review proposed strategies for management of tardive dyskinesia, beginning with primary prevention (avoidance of antipsychotic therapy where possible and use of the lowest effective dose).141 Tetrabenazine, an inhibitor of vesicular monoamine transporter 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 or oromandibular, for example), the same review suggested botulinum toxin injections.
Neuroleptic 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 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 on case reports and case series. Most cases of NMS are diagnosed in young adulthood, with the frequency of diagnosis diminishing gradually thereafter.46
The pathophysiology of NMS is incompletely understood but involves abrupt reductions in central dopaminergic 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 effect 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 reflects one or more of hypothalamic and spinal dopamine receptor antagonism, a genetic predisposition, or the direct effects of hyperthermia and other drugs.50 Although NMS most often occurs during treatment with a D2 receptor antagonist, withdrawal of dopamine agonists sometimes produces 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,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, 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 after 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.2,25,75,97 One large observational study97 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 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 (classically described as “lead pipe”), hyperthermia, and autonomic dysfunction. These findings appear in any sequence, 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 thereafter.98 Signs typically evolve over a period of several days, with the majority occurring within 2 weeks of antipsychotic initiation. However, it is important to recognize that NMS occurs even after prolonged use of an antipsychotic, particularly after a dose increase, the addition of another antipsychotic, or the development of intercurrent illness. It is also worth noting that the clinical course of NMS often fluctuates, sometimes waxing and waning dramatically over 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 formally evaluated, 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 exercise suggested that an aggregate cutoff score of 74 (of a possible 100) was associated with the highest degree of agreement 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 caution that in the absence of a biological reference standard, this scoring system should be used adjunctively with current clinical standards for the diagnosis of NMS.
TABLE 67–5Suggested Diagnostic Criteria for the Neuroleptic Malignant Syndrome ||Download (.pdf) TABLE 67–5 Suggested Diagnostic Criteria for the Neuroleptic Malignant Syndrome
|Criterion ||Priority Score |
|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 difficult to distinguish NMS from other toxin-induced hyperthermia syndromes, such as those associated with anticholinergics (antimuscarinics) (Chap. 49) and the serotonergics (Chap. 69), all of which share common features of elevated temperature, altered mental status, and neuromuscular abnormalities. The most important differentiating feature is the medication history, with dopamine antagonists, antimuscarinic drugs, and direct or indirect serotonin agonists (often in combination) as the most likely etiologies, respectively. The time course of the illness also helps to differentiate among the disorders. Whereas serotonin toxicity and the antimuscarinic syndrome tend to develop rapidly after exposure to causative xenobiotics, NMS typically develops more gradually, often waxing and waning over several days or more. Occasionally, clinicians must attempt to differentiate 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 is classically characterized by “lead-pipe” rigidity, the presence of ocular or generalized clonus is more suggestive of serotonin toxicity, particularly when accompanied by shivering and hyperreflexia, findings not typical of NMS. Because skeletal muscle contraction occurs through nicotinic rather than muscarinic transmission, patients with the antimuscarinic syndrome generally have few muscular abnormalities. However, such patients are sometimes 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.13,111,140 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 xenobiotic immediately. When NMS ensues after abrupt discontinuation of a dopamine agonist such as levodopa, the drug should be reinstituted promptly. Most patients with suspected NMS should be admitted to an intensive care unit. Supplemental oxygen should be administered, and assisted ventilation is necessary in cases of respiratory failure, which result from one or more of central hypoventilation, loss of protective airway reflexes, rigidity of the chest wall muscles or oversedation.
The hyperthermia associated with NMS is multifactorial in origin and, when present, warrants aggressive treatment. Antipyretics are not effective. 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 with severe hyperthermia given the urgency with which it should be corrected. Other strategies include 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 continuous air circulation with the use of fans. Although often used,145 these approaches are inferior to ice water immersion and are not recommended unless immersion is 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 the incidence of myoglobinuric acute kidney injury in patients with high creatine kinase concentrations. Tachycardia does not require specific treatment, but hemodynamically significant bradycardia necessitates transcutaneous or transvenous pacing. Venous thromboembolism is a major cause of morbidity and mortality in patients with NMS, and prophylactic doses of low-molecular-weight heparin are reasonable in patients who likely will be immobilized for more than 12 to 24 hours.
Pharmacologic Treatment of Neuroleptic Malignant Syndrome
Benzodiazepines are the most widely used pharmacologic adjuncts for treatment of NMS and are recommended 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 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.50 The primary disadvantage of benzodiazepines is that they will cloud the 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 reduce body 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 and case series with varying conclusions. Moreover, unlike malignant hyperthermia (in which the use of dantrolene is unquestioned), the muscle rigidity of NMS is principally a centrally mediated process. Nevertheless, several reports describe rapid, dramatic reductions in rigidity and temperature after its administration.17,53,72 Dantrolene is not recommended as a routine treatment in patients with NMS but is reasonable 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 agonist given orally or by nasogastric tube at dosages of 2.5 to 10 mg three or four 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. 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 psychiatric illness.
When these medications are used, they should be tapered slowly after the patient improves to minimize the likelihood of recrudescent NMS. In severe cases with prominent rigidity it is reasonable to use dantrolene and a dopamine agonist should be used in combination with benzodiazepines.
Electroconvulsive therapy (ECT) is 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.99 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 effectiveness of ECT remains unproven, but its use seems reasonable in patients with severe, persistent, or treatment-resistant NMS as well as those with residual catatonia or psychosis after resolution of other manifestations.13,100
Adverse Effects on Other Organ Systems
Sedation, dry mouth, and urinary retention occur commonly with antipsychotics, particularly during the initial period of therapy. These effects occur most commonly with antipsychotics that exhibit antihistaminic and antimuscarinic activity. All antipsychotics lower the seizure threshold, but seizures are uncommon during therapeutic use. Because hypothalamic dopamine inhibits hypophyseal prolactin release, hyperprolactinemia and galactorrhea can occur. All antipsychotics are associated with a host of metabolic derangements, 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 gain associated with antipsychotic therapy because glucose disturbances often develop shortly after 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 pigmentation and 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 these conditions result from an immunologically based hypersensitivity reaction and develop during the first month 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 in patients with NMS (see later).
Antipsychotic overdose produces a spectrum of toxic manifestations involving multiple organ systems, but the most serious toxicity involves the CNS and cardiovascular system. 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.
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 significant respiratory 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 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, as well as 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, with some antipsychotics, a compensatory response to hypotension. Bradycardia is distinctly uncommon, and although it may be a preterminal finding, its presence should prompt a search for alternative causes, including in ingestion of negative chronotropic drugs such as β-adrenergic antagonists, calcium channel blockers, cardioactive steroids, and opioids. Hypotension is a common 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 exhibiting similarities to those of cyclic antidepressant toxicity (Chaps 15 and 68). These include prolongation of the QRS complex and a rightward deflection of the terminal 40 ms of the QRS complex, typically manifesting as a tall, broad terminal positive deflection of the QRS complex in lead aVR. These changes reflect blockade of the inward sodium current (INa). Prolongation of the QT interval results from blockade of the delayed rectifier potassium current (IKr), creating a substrate for development of torsade de pointes 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
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 shared by other drug classes, including TCAs, 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 early after overdose, and at least one additional ECG is recommended in the following 2 to 3 hours.
Abdominal radiography sometimes reveals densities in the gastrointestinal tract because some solid dosage forms of phenothiazines are radiopaque. However, these tests are neither sensitive nor specific, and they are not recommended in the absence of another indication.
Plasma 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 can detect antipsychotics, but these tests are available at only a few hospitals and in most instances provide only a qualitative result and are not recommended. Urine immunoassays for TCAs occasionally produce a false-positive result in the presence of phenothiazines.5,115
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, opioids, anticholinergic agents, 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. Intubation and ventilation are rarely required for patients with single xenobiotic ingestions but may be necessary for patients with very large overdoses of antipsychotics or coingestion of other CNS depressants. Patients with altered mental status should receive thiamine, as well as parenteral dextrose if hypoglycemia is present. Naloxone is recommended based on clinical grounds (Antidotes in Depth: A4). All symptomatic patients should undergo continuous cardiac monitoring. An ECG should be recorded upon presentation and reliable venous access obtained. Asymptomatic patients with a normal ECG 6 hours after overdose are at exceedingly low risk of complications and generally do not require ongoing cardiac monitoring. Symptomatic patients and those with an abnormal ECG should have continuous monitoring for a minimum of 24 hours.
Gastrointestinal decontamination with activated charcoal (1 g/kg by mouth or nasogastric tube) is recommended for patients who present within a few hours of a large or multidrug overdose and have no contraindications. 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,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 lavage and whole-bowel irrigation likely will not improve clinical outcomes and should be used rarely in the management of patients with antipsychotic overdose.
Treatment of Cardiovascular Complications
Vital signs should be monitored closely. Hypotension most often 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 vasopressors are required, direct-acting agonists such as norepinephrine or phenylephrine are recommended over dopamine, which is an indirect agonist and likely will be ineffective. Vasopressin or its analogs 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 prolongation of the QRS complex is uncommon and reflects sodium channel blockade and slowing of phase 0 depolarization in the His-Purkinje system. This is usually 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, with treatment recommendations extended to sodium channel blocking antipsychotic drugs by analogy. Sodium bicarbonate (1–2 mEq/kg) is the first-line therapy for ventricular dysrhythmias and is recommended for patients with dysrhythmias or QRS complex greater than 0.12 seconds (Antidotes in Depth: A5 and Chap. 68). At least two mechanisms underlie the beneficial effects of sodium bicarbonate, sodium channel blockade is partially overcome by an increase in extracellular sodium, and the binding of antipsychotics to the sodium channel is less extensive binding 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 is recommended only if sodium bicarbonate is unavailable. 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 blocker, it exhibits rapid on/off sodium channel binding with preferential binding in the inactivated state and reportedly lessens the cardiotoxicity associated with antipsychotic drug overdose.124 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 are contraindicated. When administering sodium bicarbonate to patients with antipsychotic overdose, caution must be taken to avoid hypokalemia because many of these antipsychotics block cardiac potassium channels, thereby prolonging the QT interval. Hypokalemia and hypomagnesemia exacerbate 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 active ischemia, which, although uncommon, may complicate antipsychotic overdose in patients with existing coronary disease. If symptomatic sinus tachycardia requires emergent treatment, a short-acting β-adrenergic antagonist such as esmolol is recommended. Prolongation of the QT interval requires no specific treatment other than monitoring and correction of potential contributing causes such as hypokalemia and hypomagnesemia. After torsade de pointes has resolved spontaneously resolved or after cardioversion, intravenous magnesium sulfate is recommended to lessen the likelihood of recurrence, taking care to prevent hypotension, which is dose and rate dependent. Overdrive pacing with isoproterenol or transcutaneous 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 patients with significant cardiac toxicity from lipophilic drugs (Antidotes in Depth: A23). The rationale for this therapy rests, 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 result, it is reasonable to give ILE only in cases of not rapidly treatable cardiovascular collapse after antipsychotic 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 is associated 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
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 xenobiotics. When treatment is necessary, benzodiazepines such as lorazepam or diazepam generally suffice, although phenobarbital is a reasonable second-line therapy. Although phenytoin is part of the standard algorithm for status epilepticus, it is of limited effectiveness for xenobiotic-induced seizures.126 Patients with refractory seizures should respond to propofol infusion or general anesthesia. Finally, seizures abruptly lower serum pH and thereby increase the cardiotoxicity of antipsychotics by enhancing binding to the sodium channel; therefore, an ECG should be obtained after 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: A11) can safely and effectively 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 it should be used with caution. It should not be used in patients with ventricular dysrhythmias, any degree of heart block, or prolongation of the QRS complex. If physostigmine is used, it is recommended to be given in 0.5-mg increments every 3 to 5 minutes, with close observation. 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 is a reasonable alternative to glycopyrrolate but it crosses the blood–brain barrier and is likely to aggravate 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, and 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) are reasonable alternatives to physostigmine for patients able to take medications orally.58,89,101
No pharmacologic rationale supports the use of multiple-dose charcoal or manipulation of urinary pH to increase 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 most antipsychotics 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 other xenobiotics amenable to extracorporeal removal.
Over the past decade, the atypical antipsychotics have largely supplanted traditional antipsychotics, which were 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 of therapy or after overdose. Of the various toxicities that arise during therapeutic use, NMS is the most dangerous. Its manifestations are protean, and it may be difficult to recognize. Altered mental status, muscle rigidity, hyperthermia, and autonomic instability are its hallmarks, but the diagnosis should be considered in any unwell patient treated with antipsychotics, particularly in the 2 weeks after a change in therapy or in a patient with another stressor such as severe intercurrent illness or general anesthesia. Treatment of NMS is largely supportive and often involves the use of benzodiazepines. Dopamine agonists such as bromocriptine and ropinirole are recommended in patients with moderate to severe NMS, while dantrolene is recommended only in those with severe muscle rigidity or rhabdomyolysis. Electroconvulsive therapy is anecdotally 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 the diagnosis of, particularly in conjunction with typical ECG findings of sodium channel blockade and QT interval prolongation, although these vary considerably among the available antipsychotic drugs.
Most fatalities after 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 ILE or extracorporeal life support, although these interventions are not well studied in the context of antipsychotic drug overdose.
Frank LoVecchio and Neal Lewin contributed to this chapter in a previous edition.
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