Antipsychotic Drugs: Adverse Effects

ADVERSE EFFECTS

Antipsychotic drugs are characterized by high thera-peutic indices with respect to mortality, but side effects occur routinely at therapeutic doses, mostly as exten- sions of pharmacological actions (Table 34.2). The char-acteristic neurological symptoms (discussed next) caused by these agents are particularly troublesome, of-ten limit the tolerated dose, and may interfere with the desired benefits and patient compliance.

Sedation

Sedation is common after use of all antipsychotic drugs and is especially notable with the low-potency phenoth-iazines; this is a result of their activity at α₁-adrenergic and H₁-histaminergic receptors. However, sedation de-creases during long-term treatment, and many patients become tolerant to this effect. Single daily doses given at bedtime minimize this problem.

Extrapyramidal Reactions

Two extrapyramidal conditions, acute dystonia and akathisia, occur early during treatment, while parkinson-ism tends to evolve gradually over days to weeks. All three reactions occur most commonly with the high-potency antipsychotics (Table 34.1) and are related to high D₂-receptor occupancy.Acute dystonia, which occurs in about 5% of patients on antipsychotic therapy, consists of uncontrollable movements and distortions of the face, head, and neck. It can be treated with centrally acting an-timuscarinic agents, such as benztropine, while antipsy-chotic therapy is temporarily discontinued. When this re-action subsides, the anticholinergic can be withdrawn.

The incidence of akathisia is about 20%; the syn-drome consists of intense motor restlessness and agi-tation that contribute to a behavioral deterioration. It is frequently unresponsive to anticholinergics and is more effectively treated with benzodiazepines and β-adrenergic antagonists, such as propranolol.

Signs of parkinsonism—akinesia, tremor, rigidity— can develop gradually, but this reaction usually re-sponds favorably to central antimuscarinic agents. As with dystonia, parkinsonism may subside, permitting withdrawal of the antimuscarinic drug.

Tardive dyskinesia is a late-occurring syndrome of abnormal movements of the face and tongue with wide-spread choreoathetosis. It is the most serious adverse effect of the antipsychotic drugs. It can be expected to occur in 20 to 40% of chronically treated patients; there is no established treatment, and reversibility may be limited. These reactions are more frequent and severe in the elderly.

Tardive dyskinesia is generally accepted to be a D₂ supersensitivity phenomenon, though research has not unequivocally established this postulate. An appropri-ate clinical response to these symptoms would be to re-duce the dose or discontinue the antipsychotic agent and then eliminate all drugs with central anticholinergic action, such as antidepressants. The rationale is to bal-ance the risks of continuing treatment in a patient with tardive dyskinesia with the benefits of antipsychotic ad-ministration. If these steps are not helpful, clozapine therapy can be considered, or diazepam can be em-ployed to enhance GABAergic activity. Prevention of this reaction is important. Generally, antipsychotics should be prescribed in minimally effective doses and their use reserved for time-limited treatment except in the treatment of chronic schizophrenic disorders.

The neuroleptic malignant syndrome is a rare med-ical emergency involving extrapyramidal symptoms that occurs in about 1% of patients receiving antipsychotics. The concern is not the incidence but that about 10% of these cases are fatal. The condition is marked by hyper-thermia or fever, diffuse muscular rigidity with severe extrapyramidal effects, autonomic dysfunction such as increased blood pressure and heart rate, and fluctuating levels of consciousness. Neuroleptic malignant syn-drome is most common in males, with about 80% of cases occurring in patients under 40 years of age. Treatment should include general supportive measures, such as rehydration and body cooling; antipsychotic therapy should be discontinued. Short-term therapy with dantrolene in combination with antiparkinson agents such as bromocriptine has been employed to control the muscular rigidity and hyperthermia.

Autonomic and Endocrine Effects

Most antipsychotics have both α-adrenergic and cholin-ergic antagonist activities, and blocking actions at hista-mine and serotonin receptors also contribute to the au-tonomic effects of some agents. Postural hypotension and depression of medullary cardiovascular centers re-sulting from α₁-adrenoceptor blockade is particularly troublesome in elderly or debilitated patients. β₂-Agonists, such as epinephrine, are contraindicated, as they may worsen the hypotension. The anticholinergic effects can be very bothersome but usually subside as tolerance to these effects occurs. Typically, autonomic signs can be controlled by adjustment of dose.

All antipsychotics except clozapine and perhaps olanzapine produce hyperprolactinemia by removing the inhibitory actions of dopamine on prolactin secre-tion. This results in amenorrhea, galactorrhea, and in-fertility in women and in loss of libido and impotence in men. Inhibition of the release of follicle-stimulating and luteinizing hormones may also play a role. In addition, weight gain is common, and food intake must be moni-tored.

Other Adverse Effects

Cholestatic jaundice is observed infrequently, usually during the first few weeks of treatment. This is thought to be a hypersensitivity reaction and is usually mild and self-limited. Cutaneous allergic reactions are occasion-ally reported. Both types of problems normally disap-pear upon changing to an antipsychotic from a different chemical class. Photosensitivity usually manifests as an acute hypersensitivity reaction to sun with sunburn or rash, but the condition is generally mild and does not re-quire dosage adjustment.

Opacities of the cornea and lens due to deposition of fine particulate matter are a common complication of chlorpromazine therapy but regress after drug with-drawal. The most serious ocular complication is pigmen-tary retinopathy associated with high-dose thioridazine administration; it is an irreversible condition leading to decreased visual acuity and possibly blindness.

Agranulocytosis is a potentially catastrophic idio-syncratic reaction that usually appears within the first 3 months of therapy. Although the incidence is extremely low (except for clozapine), mortality is high. Thus, any fever, sore throat, or cellulitis is an indication for dis-continuing the antipsychotic and immediately conduct-ing white blood cell and differential counts.

Contraindications for antipsychotic therapy are few; they may include Parkinson’s disease, hepatic fail-ure, hypotension, bone marrow depression, or use of CNS depressants. Overdoses of antipsychotics are rarely fatal, except for thioridazine, which is associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. For other agents gastric lavage should be attempted even if several hours have elapsed since the drug was taken, because gastroin-testinal motility is decreased and the tablets may still be in the stomach. Moreover, activated charcoal effec-tively binds most of these drugs and can be followed by a saline cathartic. The hypotension often responds to fluid replacement or pressor agents such as norepi-nephrine.