A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with haloperidol.

Clozapine is associated with a dose-dependent seizure risk at a rate higher than that seen with most other antipsychotic drugs. In a review of 1418 patients treated with clozapine, the cumulative seizure risk was estimated to be 10 percent after 3.8 years of treatment. Higher doses of clozapine were associated with a greater rate of seizures:

• 600 mg/day or more – 4.4%
• 300 to 600 mg/day – 2.7%
• 300 mg/day or less – 1.0%

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain.

• Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes
• Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics
• Weight Gain: Weight gain has been observed with atypical antipsychotic use. Monitor weight.