Chapter 180: Antipsychotics

INTRODUCTION

Developed starting in the 1950s, the typical antipsychotics are effective against the positive signs of psychosis (e.g., delusions, hallucinations, disorganized thought), but they provided no treatment for the negative signs (e.g., avolition, alogia, social withdrawal). In addition, numerous adverse side effects associated with these agents lead to poor patient compliance. The second-generation drugs, or atypical antipsychotics, have been available starting in the 1990s. These drugs are characterized by minimal extrapyramidal side effects when taken at effective dosages and have activity against the negative signs of schizophrenia (Table 180-1). Third-generation agents are being developed to minimize the adverse side effects seen with the first- and second-generation agents.

Antipsychotics were originally referred to as major tranquilizers, because of their ability to calm patients, but because they are not simply sedatives, this term is inappropriate. These drugs were also termed neuroleptics, which refers to their ability to slow movement. With the advent of the atypical antipsychotics, it became clear that antipsychotic properties do not necessarily parallel neuroleptic properties. For this reason, the preferred term is antipsychotics. Although antipsychotic is a useful term, these drugs are sometimes administered to treat other conditions, such as agitation, nausea and emesis, various headache conditions; to suppress hiccups; and to control various involuntary motor disorders, such as Tourette's syndrome, Huntington's chorea, and basal ganglia disorders.

PATHOPHYSIOLOGY

Currently more than 50 different antipsychotics are available worldwide. Classification by structure is difficult; a more useful method is classification according to their relative receptor-binding profiles (Table 180-2).¹ In overdose, the clinical toxicity is primarily an exaggerated effect of the pharmacologic activity.

Virtually all antipsychotics bind to (and inhibit) presynaptic and postsynaptic dopamine-2 (D₂) receptors in the CNS. When antipsychotic treatment is initiated, blockade of the D₂ receptor results in increased production and release of dopamine from the presynaptic cell. However, with continued use, depolarization inactivation occurs, and decreased production and release develop, along with continued postsynaptic receptor blockade.

The blockade of dopamine receptors in different regions of the brain produces varying effects. Blockade of D₂ receptors in the mesocortical and mesolimbic system is associated with antipsychotic efficacy, whereas D₂ receptor blockade in the area postrema (chemotactic trigger zone) is responsible for antiemetic activity. Aripiprazole is different for other antipsychotics; it is a partial D₂-agonist, with specific effects dependent on the concentration of dopamine. At low levels of dopamine, aripiprazole will stimulate the D₂ receptors, and at high levels of dopamine, aripiprazole will inhibit the D₂ receptors.

Blockade of the D₂ receptors in other regions of the brain produces many of the adverse effects associated with antipsychotics. Antagonism of the D₂ receptors in the tuberoinfundibular region is associated with hyperprolactinemia, which can cause galactorrhea, gynecomastia, and sexual dysfunction.¹ Blockade of the D₂ receptors in the nigrostriatal region is associated with the development of extrapyramidal symptoms. Agents with greater D₂ receptor affinity (e.g., haloperidol or fluphenazine) have a greater likelihood of inducing extrapyramidal symptoms, whereas agents with less receptor affinity (e.g., clozapine) are less likely to cause extrapyramidal symptoms. Blockade of the D₂ receptors in the anterior hypothalamus (preoptic area) can produce alterations in body temperature.

In addition to blocking dopamine receptors, many antipsychotics have activities at the α-adrenergic, muscarinic, histaminergic, and serotoninergic receptors. Antagonism of the α₁-adrenergic receptors leads to orthostatic hypotension and reflex tachycardia. Antagonism of the muscarinic receptors can produce anticholinergic symptoms, including hyperthermia, tachycardia, mydriasis, dry mucosal membranes, and urinary retention. Blockade of the histaminergic receptors primarily results in sedation.

Among the first-generation antipsychotics, potency is inversely related to the likelihood of sedation but directly correlated with extrapyramidal effects. Therefore, high-potency agents such as haloperidol, fluphenazine, and thiothixene are less sedating but more likely to cause extrapyramidal symptoms than are lower potency agents such as chlorpromazine and thioridazine.

Antagonism of the serotonin receptors is associated with a reduced likelihood of inducing extrapyramidal symptoms.² Because serotonin receptor antagonism inhibits dopamine release in the nigrostriate and prefrontal cortex, blockade of the serotonin subtype 2A (5-HT_2A) receptors is associated with increased efficacy in treatment of negative symptoms, while providing reduced risk of extrapyramidal symptoms. Agents that are partial 5-HT_1A receptor agonists, such as ziprasidone and aripiprazole, have similar effects.

PHARMACOKINETICS

Most of the antipsychotics have similar pharmacokinetic profiles. After oral administration, absorption occurs rapidly, the drugs undergo significant first-pass metabolism, and peak plasma concentrations typically occur within 1 to 6 hours. Following IM injection, peak plasma concentrations typically occur within 60 minutes for immediate-release products, but can be delayed up to 1 day with depot preparations. Nearly all antipsychotics have high protein binding and a large volume of distribution. Metabolism is primarily through the cytochrome P-450 enzyme system, with isoenzymes 2D6, 1A2, and 3A4 accounting for the majority of drug metabolism. Because of the near-complete hepatic metabolism of these drugs, renal impairment rarely requires dosage adjustments (noTable exceptions include sulpiride and remoxipride).

CLINICAL FEATURES

Isolated overdose of antipsychotics is rarely fatal, and most patients develop only mild to moderate symptoms.^3,4,5,6 Toxicity is largely a function of the dose ingested, habituation, comorbid conditions, and age. Following overdose, CNS depression is frequent but is less severe in patients receiving long-term therapy, because tolerance to the sedative effects develops after days to weeks of regular use. CNS effects range from lethargy, ataxia, dysarthria, and confusion to coma with respiratory depression in cases of severe overdose.^5,6 The ingestion of a single pill of some of the atypical or typical antipsychotics can cause significant CNS and respiratory depression in young children.⁷ Respiratory depression is more common in multidrug overdoses.

Paradoxical agitation and delirium may occur in mixed overdoses, especially those involving agents with antimuscarinic properties. Seizures occur in approximately 1% of individuals after overdose, with the incidence higher for loxapine and clozapine. Gastric pharmacobezoars have been reported with quetiapine extended-release overdose.⁸

Many of the antipsychotics have antimuscarinic properties (Table 180-2). Thus, patients can manifest signs or symptoms that are consistent with antimuscarinic toxicity, including tachycardia, dry mucous membranes, dry skin, mydriasis, decreased bowel sounds, urinary retention, agitation, delirium, and hyperthermia. Due to the α-adrenergic antagonism of many of these agents, mydriasis expected with pure anticholinergic agents is less likely to be present.

The most common cardiovascular manifestations of antipsychotic overdose are sinus tachycardia and orthostatic hypotension. ECG changes include prolongation of the PR, QRS, and QT intervals, depressed ST segments, T-wave abnormalities (widening, flattening),⁹ and increased U-wave amplitude. Ventricular dysrhythmias are rare,⁷ with the exception of amisulpride (not available in the United States) overdoses.¹⁰

DIAGNOSIS

Routine laboratory analysis should include a CBC, basic chemistry tests, and a pregnancy test for women of childbearing age. Obtain an ECG to assess the conduction intervals. Obtain a CBC for a patient with a fever while taking clozapine or chlorpromazine, even if in therapeutic amounts.

TREATMENT

Treatment for patients with antipsychotic poisoning is largely supportive.^3,4,5,6 For patients who are known to have ingested or are suspected of having ingested a significant amount, establish IV access and monitor cardiac rhythm. Patients with respiratory depression should receive ventilatory support. Patients with depressed consciousness should receive oxygen supplementation, continuous pulse oximetry, assessment of blood glucose, and consideration for administration of naloxone and thiamine. Seizures should be treated with a benzodiazepine such as lorazepam.

Treat hypotension with aggressive fluid resuscitation. Adults without previously known or suspected cardiac disease should receive at least 1 to 2 L of isotonic crystalloid. Children should receive 20 to 40 mL/kg. If hypotension persists, direct-acting α-adrenergic agonists, such as phenylephrine or norepinephrine, are the preferred vasopressors for treatment. Dopamine, an indirect-acting vasopressor, is not recommended as a first-line agent for treatment of hypotension following an antipsychotic overdose.

Patients with a QT_c interval of >500 milliseconds are at increased risk for torsade de pointes.^11,12 Assuming there are no contraindications to magnesium supplementation, and regardless of the serum magnesium level, adults with a QT_c interval of >500 milliseconds should receive magnesium sulfate, 2 grams IV over 10 minutes.⁵ Patients with torsade de pointes should receive 2 grams of magnesium sulfate as a bolus, followed by an infusion of 2 to 4 milligrams/min, regardless of the magnesium concentration. Overdrive pacing can also be useful, especially in cases that prove refractory to magnesium.¹³

Patients with an intraventricular conduction delay (e.g., prolonged QRS complex) and ventricular arrhythmias should be treated with sodium bicarbonate, 1 to 2 mEq/kg IV bolus, followed by intermittent boluses or a continuous infusion. Lidocaine is an accepTable alternative or second-line agent for ventricular dysrhythmias. Do not use types Ia (e.g., quinidine, procainamide), Ic (e.g., propafenone), III (e.g., amiodarone), and IV antiarrhythmics in patients with cardiac conduction disturbances or ventricular arrhythmias, because their use can potentiate such cardiotoxicity. Consider intravenous lipid emulsion for severe quetiapine overdoses with cardiovascular instability refractory to conventional therapy.^14,15,16

DISPOSITION AND FOLLOW-UP

Following ingestion, observe the patient for at least 6 hours. Because of the potential for orthostatic hypotension, obtain orthostatic pulse and blood pressures prior to disposition. The patient can be judged free of toxicity if there are no mental status changes, pulse and blood pressure abnormalities, orthostatic hypotension, and QT_c interval prolongation after 6 hours of observation from the time of ingestion.¹⁷ Patients with evidence of toxicity (e.g., sinus tachycardia or QT interval prolongation) should be admitted to a monitored bed for observation. Patients who develop severe symptoms (e.g., seizure, respiratory depression, hypotension, acidosis) during the observation period in the ED should be admitted to an intensive care unit.

ADVERSE EFFECTS OF THERAPEUTIC DOSING

CARDIOVASCULAR

Both atypical and typical antipsychotics can affect myocardial conduction and repolarization. At therapeutic dosages, this is usually evidenced by prolongation of the QT interval. Of the typical agents, thioridazine, pimozide, and IV haloperidol cause the greatest degree of QT prolongation.^11,18 The prescribing information for haloperidol contains a warning that QT interval prolongation and torsade de pointes can occur, especially when administered IV or in doses higher than typically used. The warning advises caution when treating patients who have other QT interval–prolonging conditions or are taking drugs known to prolong the QT interval. This warning also emphasizes that haloperidol is not approved for IV administration and that electrocardiographic monitoring is recommended if IV haloperidol is given. Among the atypical antipsychotics, ziprasidone, sertindole, and amisulpride are associated with the greatest degree of QT prolongation in therapeutic dosing.^11,18

EXTRAPYRAMIDAL SYMPTOMS

Extrapyramidal symptoms result from D₂ receptor blockade in the basal ganglia (nigrostriatal region). Although high-potency typical agents cause the highest rate of extrapyramidal symptoms, all antipsychotic agents are capable of producing these symptoms.¹⁹ Blockade of the 5-HT_2C receptors may contribute to the induction of extrapyramidal symptoms as well by inhibiting dopamine release in the nigrostriatal and mesolimbic pathways. Many of the atypical antipsychotic agents bind to the 5-HT_2C receptors.

Extrapyramidal symptoms can be classified into three major patterns: (1) early-onset reversible syndromes, (2) delayed-onset reversible syndromes, and (3) potentially irreversible syndromes. The early-onset reversible syndromes typically start within hours to days and include acute dystonia and akathisia. The delayed-onset reversible syndromes occur days to weeks after the antipsychotic is started and include parkinsonism and neuroleptic malignant syndrome. The potentially irreversible syndromes typically begin months to years after therapy is started and include focal perioral tremor and tardive dyskinesia.

Acute dystonia is a hyperkinetic movement disorder characterized by intermittent, uncoordinated, involuntary contractions of the muscles of the face, tongue, neck, trunk, or extremities. Clinical manifestations include tongue protrusions, facial grimacing, trismus, oculogyric crisis, blepharospasm, opisthotonus, tortipelvis, and abnormal postures and gait. Although distressing to patients, these effects are not life threatening.

Akathisia is a subjective sensation of motor restlessness. It typically occurs within minutes to days of initiating or increasing the dose of an antipsychotic.^20,21 Occasionally, akathisia can be misinterpreted as increasing agitation related to an underlying psychiatric condition and can thereby prompt additional medication administration. Although akathisia is more likely to occur with the use of high-potency D₂ receptor antagonists, it can occur with large doses, rapid escalation of doses, or parenteral administration of all antipsychotics.²²

The treatment of akathisia or acute dystonia includes the administration of diphenhydramine, 25 to 50 milligrams, or benztropine, 1 to 2 milligrams, either orally or parenterally, with parenteral administration preferred in severe cases. Benzodiazepines may serve as adjunctive therapy or can be used primarily if there is a concern about the administration of anticholinergic agents. Because of the prolonged effects of the dystonia-inducing agent, oral therapy with either diphenhydramine or benztropine should be continued for approximately 2 days after parenteral treatment.

Parkinsonism typically occurs weeks to months after initiation of therapy. It is characterized by cogwheel-type muscle rigidity, pill-rolling tremor, mask facies, shuffling gait, bradykinesia or akinesia, and cognitive impairment. It occurs in up to 13% of patients receiving long-term antipsychotic therapy. Treatment of drug-induced parkinsonism may involve lowering the dosage of a typical antipsychotic, changing to an atypical agent, adding an anticholinergic agent such as diphenhydramine or benztropine, or adding an agent that enhances dopaminergic activity (e.g., amantadine).

Perioral lip tremor, termed the rabbit syndrome, is an uncommon late-onset extrapyramidal adverse effect of antipsychotics. Tardive dyskinesia is a late-onset extrapyramidal syndrome that can range from reversible to partially reversible to irreversible. Clinical observation suggests that if patients take these drugs long enough, the majority develop the disorder. Tardive dyskinesia is characterized by painless, stereotyped, repetitive movements of the orofacial structures. There can be occasional tongue protrusion, lip smacking, facial grimacing, and choreoathetosis of the trunk and limbs. Although tardive dyskinesia can occur with any antipsychotic agent, it is more common with the typical agents. In young patients, the observed annual occurrence rate of tardive dyskinesia is about 3% to 5% with the typical antipsychotics. In elderly patients, tardive dyskinesia can develop in up to 25% during the first year of haloperidol therapy. The occurrence rate for tardive dyskinesia with the atypical agents is about one tenth that with the first-generation antipsychotics.

Because the symptoms of tardive dyskinesia may be irreversible, the best treatment is the use of steps to minimize its occurrence.¹⁹ Early detection and prompt withdrawal of the antipsychotic increase the likelihood of complete recovery. Unlike with drug-induced parkinsonism, anticholinergic agents exacerbate tardive dyskinesia and should not be used.

OTHER ADVERSE EFFECTS

Therapeutic use of atypical antipsychotics is linked with the development of type 2 diabetes mellitus and diabetic ketoacidosis.^{19,23,24,25,26} There is some suggestion that the risk is greatest with olanzapine.²⁷ Atypical antipsychotics are associated with weight gain and intra-abdominal obesity, abnormal glucose regulation, and insulin resistance.²⁸ Nonalcoholic steatohepatitis has been reported with the therapeutic use of risperidone and olanzapine, and pancreatitis has been associated with the use of clozapine. Hyperprolactinemia is more common with the typical antipsychotics, but can occur with the atypical antipsychotics as well, manifesting as menstrual disturbances and galactorrhea in females and gynecomastia in males.²⁹ Amisulpride, paliperidone, and risperidone are the most likely of the atypical antipsychotics to induce hyperprolactinemia.

Phenothiazines are associated with leukopenia in up to 0.8% and agranulocytosis in 0.05% of patients.³⁰ Several atypical antipsychotics have also been associated with agranulocytosis, with the highest incidence in patients taking clozapine, in whom leukopenia occurs in 3% and agranulocytosis in 0.8%. Due to these adverse effects, clozapine can only be prescribed within a strictly monitored program.

Seizures have been associated with several antipsychotics, primarily chlorpromazine, loxapine, and clozapine.^31,32,33 The risk of seizure appears to be dose dependent.

Neuroleptic malignant syndrome is a rare but potentially fatal idiosyncratic complication of antipsychotic drug therapy.^34,35 Neuroleptic malignant syndrome is not the result of overdose. It most often occurs shortly after the start of therapy or after a dosage adjustment, and the antipsychotic serum concentration is usually within the therapeutic range. Neuroleptic malignant syndrome is associated with all the typical antipsychotics and most of the commonly available atypical antipsychotics, including aripiprazole, clozapine, olanzapine, risperidone, and ziprasidone.^36,37 The incidence is about 1 to 2 cases per 10,000 patients treated.³⁵

Neuroleptic malignant syndrome typically develops over a period of 1 to 3 days and is characterized by the tetrad of fever, muscular rigidity, autonomic dysfunction, and altered mental status (including lethargy, agitation, mutism, or coma). The rigidity is typically described as lead-pipe and cogwheel rigidity, similar to that observed with parkinsonism.

Major diagnostic criteria for neuroleptic malignant syndrome are fever and muscle rigidity (Table 180-3). An international consensus panel includes two criteria that embody important concepts about this syndrome: (1) recent dopamine antagonist exposure or dopamine agonist withdrawal, and (2) negative evaluation for other causes.³⁸ Common laboratory abnormalities include elevated creatine kinase level, leukocytosis, elevated levels of hepatic transaminases, hypernatremia or hyponatremia, metabolic acidosis, myoglobinuria, elevated BUN and creatinine levels, and decreased serum iron level.³⁹

Treatment is primarily supportive.^34,35,40,41 Withdraw any antipsychotics and potentiating drugs, such as anticholinergics, antihistamines, or lithium. Consider and evaluate for other medical conditions that can present in a similar manner, including CNS infection, other drug-induced hyperthermic syndromes, serotonin syndrome, anticholinergic poisoning, and sympathomimetic toxicity.^40,41 Reduce the patient's temperature with external cooling measures; pharmacologic antipyretics such as acetaminophen are not beneficial in lowering the temperature associated with this syndrome. Sedation is very important to decrease agitation and sympathetic activity; a benzodiazepine, such as lorazepam, is recommended.^34,40,41

Airway and breathing difficulties should be anticipated, and patients with excessive secretions, dysphagia, decreased airway reflexes, acidosis, or hypoxia should be intubated. In addition, strongly consider intubating patients with fever and rigidity, because muscular paralysis reduces the muscle contraction and thereby reduces the fever. When patients with neuroleptic malignant syndrome are intubated, nondepolarizing agents (e.g., rocuronium) are preferred over depolarizing agents (e.g., succinylcholine).

Complications from profound muscle rigidity are responsible for most deaths in neuroleptic malignant syndrome. Prompt reduction in muscle rigidity can be expected to minimize the occurrence of complications such as rhabdomyolysis, renal failure, respiratory failure, disseminated intravascular coagulation, and cardiovascular collapse. The role of specific pharmacotherapy is unclear. For each therapy reported effective, none has clearly been shown to be superior to supportive care alone.^34,40,41

Pharmacologic therapies described in case reports and series include amantadine, bromocriptine, and dantrolene. Dantrolene (1.0 to 2.5 milligrams/kg IV load, followed by 1 milligram/kg IV every 6 hours) should primarily be used for more severe cases of neuroleptic malignant syndrome in which the rigidity is pronounced. Dantrolene should not be used concurrently with calcium, because this increases the risk of cardiovascular collapse.⁶ Bromocriptine, a centrally acting dopamine agonist, can reduce fever and muscle rigidity in neuroleptic malignant syndrome and possibly shorten the duration.⁴² This drug is only available in an oral preparation and may require administration by a nasogastric tube. Adverse sides effects of hypotension, vomiting, and worsening of psychosis are limiting factors to the routine use of bromocriptine.⁴¹

Acknowledgment: The authors would like to thank Dr. Richard A. Harrigan and Dr. William J. Brady, who authored this chapter in previous editions.