Antipsychotic Drugs

Antipsychotic drugs treat schizophrenia and other psychotic disorders, bipolar mania, and as adjuncts in depression, with short-term use for agitation, delirium and some neuropsychiatric symptoms. They control positive symptoms and reduce relapse, but have little effect on negative and cognitive symptoms.

Mechanism. They block or partially agonise dopamine D2 receptors in the mesolimbic tract. About 60 to 80% occupancy gives antipsychotic effect, and over 80% causes extrapyramidal effects. Second generation agents also antagonise 5-HT2A receptors, and aripiprazole-like drugs are D2 partial agonists. Receptor effects at histamine, muscarinic and adrenergic receptors explain sedation, weight gain and hypotension.

Classification. First generation (haloperidol, chlorpromazine), second generation (olanzapine, risperidone, quetiapine, clozapine), and partial agonists (aripiprazole, brexpiprazole, cariprazine). Clozapine is reserved for treatment-resistant illness.

Adverse effect profiles. Extrapyramidal effects are highest with high-potency first generation drugs and risperidone, and lowest with clozapine and quetiapine. Metabolic effects are highest with clozapine and olanzapine, intermediate with quetiapine and risperidone, and lowest with aripiprazole, lurasidone and ziprasidone. Hyperprolactinaemia is highest with risperidone, paliperidone and amisulpride. Sedation is highest with clozapine, chlorpromazine, quetiapine and olanzapine. QT prolongation is highest with thioridazine, ziprasidone and amisulpride.

Efficacy. Most agents have similar efficacy for positive symptoms, with clozapine superior in resistant illness and olanzapine and amisulpride slightly superior to others.

Formulations. Oral, short-acting intramuscular, and long-acting injections (fluphenazine, haloperidol, flupentixol, zuclopenthixol, risperidone, paliperidone, olanzapine, aripiprazole).

• Schizophrenia first episode: one antipsychotic at a low to moderate dose, chosen by side effect profile and patient preference; assess response at 2 weeks (early improvement predicts outcome) and 4 to 6 weeks.
• Treatment resistance: failure of two antipsychotics at an adequate dose for at least 6 weeks each, after confirming adherence, leads to clozapine.
• Continuation: at least 1 to 2 years after a first episode, and longer after relapses. Stop slowly if stopping.
• Long-acting injection: when adherence is poor or the patient prefers.
• Mania: an antipsychotic (olanzapine, risperidone, quetiapine, aripiprazole, haloperidol) with or without a mood stabiliser.
• Dementia: avoid unless severe distress or risk, at the lowest dose for under 6 weeks, because of increased mortality and stroke.

Special groups. Pregnancy: use the lowest effective dose and avoid abrupt cessation; monitor glucose with olanzapine and quetiapine. Breastfeeding: avoid clozapine; olanzapine and quetiapine give low infant exposure. Children: specialist use. Older adults: start at 25 to 50% of the adult dose. Kidney impairment: reduce amisulpride, paliperidone and risperidone. Liver impairment: reduce doses.

Regional: haloperidol, chlorpromazine, fluphenazine decanoate and risperidone are most available. Khat or cannabis-related psychosis may need short courses only. Ritonavir raises levels of aripiprazole, quetiapine and risperidone.

Adverse effects. Acute dystonia, akathisia, parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinaemia (galactorrhoea, amenorrhoea, sexual dysfunction, bone loss), weight gain, diabetes and dyslipidaemia, QT prolongation, sedation, orthostatic hypotension, anticholinergic effects, and raised venous thromboembolism risk.

Baseline and follow-up. Weight, waist, blood pressure, fasting glucose or HbA1c and lipids at baseline; weight at 4, 8 and 12 weeks; glucose and lipids at 12 weeks, then yearly. Prolactin if symptoms. ECG with cardiac risk or QT drugs. Movement disorder scale every 6 to 12 months.

Neuroleptic malignant syndrome. Fever, rigidity, altered consciousness, autonomic instability and raised creatine kinase. Stop the drug, cool, hydrate, and use benzodiazepines; dantrolene or bromocriptine in severe cases.

Interactions. QT-prolonging drugs (macrolides, quinolones, ondansetron, methadone, quinine, lumefantrine), CYP2D6 inhibitors, carbamazepine and rifampicin (lower levels), and alcohol and sedatives.

Referral and escalation. Treatment resistance, neuroleptic malignant syndrome, severe movement disorder, or marked metabolic change.