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[Pharmacology](https://durgical.com/en/pharmacology/) · [Second-generation antipsychotics](https://durgical.com/en/pharmacology/classes/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

- Class: [Second-generation antipsychotics](https://durgical.com/en/pharmacology/classes/second-generation-antipsychotics/)
- Receptor: Dopamine D2 receptor
- ATC code: N05AH02
- WHO Model List of Essential Medicines

◎**Dopamine D2 receptor**Clozapine

ⓘ 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).

**Target in 3D:** Dopamine D2 receptor. PDB structure 6CM4 (RCSB PDB, public domain). [View the structure at RCSB PDB](https://www.rcsb.org/structure/6CM4) · Drag to rotate · pinch to zoom

## 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

### Serious (rare, important)

- Severe neutropenia (agranulocytosis) with life-threatening infections (boxed warning)
- Orthostatic hypotension, bradycardia, syncope and cardiac arrest, mostly during titration or when restarting
- Dose-related seizures
- Myocarditis and cardiomyopathy
- Severe constipation up to paralytic ileus
- Higher mortality in older people with dementia-related psychosis (boxed warning)

## 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.

## Memory aid

Clozapine's «4 Cs + S»: Count (neutrophils), Convulsions, Cardiac (myocarditis), Constipation, plus Saliva.

## 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.

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## Related drugs

- [Olanzapine](https://durgical.com/en/pharmacology/olanzapine/)
- [Quetiapine](https://durgical.com/en/pharmacology/quetiapine/)

[← Back to the class: Second-generation antipsychotics](https://durgical.com/en/pharmacology/classes/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](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=883b5d43-0339-7dc1-f775-93791fb9b978) (DailyMed (U.S. National Library of Medicine), 2026); [Clozapine: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a691001.html) (MedlinePlus (U.S. National Library of Medicine), 2026); [eEML - Electronic Essential Medicines List](https://list.essentialmeds.org/?query=clozapine) (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.

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