Clozapine

Clozapine blocks D1, D2, D3 and D5 receptors only weakly and D4 receptors strongly, with potent α-adrenergic, muscarinic, H1 and serotonin blockade. Its mechanism is unknown, though D2 and 5-HT2A antagonism has been proposed. It causes few extrapyramidal effects and little or no rise in prolactin.

Like other second-generation antipsychotics: Most second-generation antipsychotics block dopamine D2 receptors together with serotonin 5-HT2A receptors, though exactly how they work is unclear; aripiprazole instead is a partial agonist at D2 receptors. As a group they cause fewer extrapyramidal effects than first-generation drugs, but many also block H1, α1 or muscarinic receptors, and weight gain with raised glucose and lipids is common.

• Check the absolute neutrophil count before starting and regularly throughout; risk peaks in the first 18 weeks, and a low baseline count bars starting.
• Watch for myocarditis, most often in the first two months: chest pain, fast heart rate, fever or breathlessness need urgent review.
• Ask about bowel habit and treat constipation promptly, as gut hypomotility can progress to ileus.
• Titrate slowly, since orthostatic hypotension, bradycardia, fainting and seizures are most likely early on.

Good to know: Kept for schizophrenia that has not responded to other antipsychotics because of its risks of severe neutropenia and seizures; it causes few movement side effects.

Easily mixed up with first-generation antipsychotics and lithium.