Pharmacology · Second-generation antipsychotics
Clozapine !
The most effective antipsychotic for treatment-resistant schizophrenia; it can cause severe neutropenia, so blood counts are checked.
Updated 2026-11-01
The figure shows risperidone in the human D2 receptor; clozapine binds the same site more weakly (no clozapine-bound D2 structure exists). Clozapine acts on many receptors (D4, 5-HT2A, H1, M1, α1).
Mechanism of action
Clozapine is a weak D2 antagonist with strong 5-HT2A, H1, muscarinic and α1 blockade and actions at many other receptors. Low D2 occupancy explains almost no extrapyramidal effects and no rise in prolactin; why it works when other drugs fail is not fully known. It also reduces suicidal behaviour in schizophrenia.
- Clozapine weakly blocks D2 and strongly blocks 5-HT2A
- Psychosis improves, even when other drugs failed
- Low D2 occupancy: almost no extrapyramidal effects
- H1, M1 and α1 block: sedation, weight gain, hypotension
Pharmacokinetics
- Absorption
- Taken by mouth (tablets, orally disintegrating tablets, suspension)
- Metabolism
- Liver, mainly CYP1A2 (also CYP3A4 and CYP2D6); smoking induces CYP1A2 and lowers levels, so stopping smoking can raise them
Indications
- Treatment-resistant schizophrenia
- Reducing recurrent suicidal behaviour in schizophrenia or schizoaffective disorder
Adverse effects
Common
- Sedation and dizziness
- Hypersalivation (drooling), especially at night
- Tachycardia
- Constipation
- Weight gain, high glucose and high lipids
- Transient fever early in treatment
Contraindications
- A low neutrophil count before starting (treatment is not started)
- Previous clozapine-induced myocarditis or severe neutropenia (usually no rechallenge)
- Hypersensitivity to clozapine
Key interactions
- Fluvoxamine and other strong CYP1A2 inhibitors (also ciprofloxacin)
- Much higher clozapine levels and toxicity
- Smoking (and stopping smoking)
- Smoking induces CYP1A2 and lowers levels; quitting can raise them sharply
- Carbamazepine
- Avoided: adds bone-marrow risk and lowers clozapine levels
- Other anticholinergic drugs
- More constipation and ileus
What is monitored
- Absolute neutrophil count before starting and regularly during treatment
- Fever, sore throat or other signs of infection (neutropenia check)
- Chest pain, tachycardia, breathlessness early in treatment (myocarditis)
- Bowel habit (constipation)
- Weight, glucose and lipids
- Blood pressure and heart rate during titration
Administration and safety
- Started low and increased slowly; after even a short interruption it is restarted from a low dose because of hypotension and syncope
- Not dispensed or continued without a current neutrophil result
Nursing care
- Checks the neutrophil count is current before each supply and reports any fever or sore throat at once
- Asks daily about bowel movements; encourages fluids, fibre and activity
- Takes lying and standing blood pressure during titration
- Asks about smoking changes, which can alter clozapine levels
- Records weight, waist, glucose and lipids at baseline and during treatment
Pregnancy and breastfeeding
Newborns exposed in the third trimester may have extrapyramidal or withdrawal symptoms (agitation, abnormal tone, tremor, feeding problems); use weighs benefit and risk.
Test yourself
Think of the answer, then tap the question to see it.
When is clozapine used in schizophrenia?
When the illness has not responded adequately to standard antipsychotics (treatment-resistant), and to reduce recurrent suicidal behaviour.
A patient on clozapine has fever and sore throat. What must be ruled out first?
Severe neutropenia (agranulocytosis), with an urgent neutrophil count.
Why can clozapine levels rise when a patient stops smoking?
Tobacco smoke induces CYP1A2, which metabolises clozapine; when smoking stops, the induction fades and levels rise.
Which cardiac complication is watched for in the first weeks of clozapine?
Myocarditis (and cardiomyopathy): chest pain, tachycardia, breathlessness, fever or ECG changes.
Related drugs
← Back to the class: Second-generation antipsychotics
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - CLOZAPINE tablet (DailyMed (U.S. National Library of Medicine), 2026); Clozapine: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); eEML - Electronic Essential Medicines List (World Health Organization, 2025); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 19 (McGraw Hill, 2023).
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Representative model, for educational purposes only.