Clozapine

Class & Mechanism

Class: Second-generation (Atypical) antipsychotic.
Mechanism: Weak D2 receptor blockade, strong 5-HT2A receptor antagonism. Also acts on D4, alpha-adrenergic, histaminergic, and cholinergic receptors.

Treatment-resistant schizophrenia: Failure to respond to adequate doses of two different antipsychotics (at least one atypical), despite good compliance.
Suicide Risk: Specifically indicated for reducing the risk of recurrent suicidal behaviour in schizophrenia.
Aggression and Substance Misuse: May have unique benefits in reducing persistent aggression and cannabis use in schizophrenia patients.

Starting dose: 12.5 mg.
Dose is increased slowly (titrated) to minimize side effects like hypotension.
Plasma Monitoring: Useful to ensure adherence and optimize response.
- Minimum trough level: 200 µg/L (recommended for response).
- Upper limit: Levels above 500 µg/L may increase response but significantly increase side effect risk (e.g., seizures).

If response to clozapine is inadequate:

Antipsychotic Augmentation: Adding a second antipsychotic with high D2 affinity (e.g., amisulpride or aripiprazole). This is the only situation justifying polypharmacy.
Mood Stabilizers: Adding lamotrigine has some evidence.
ECT: May be used to augment clozapine in refractory cases.

Serious:
- ⚠️ Agranulocytosis: (0.8% incidence) Life-threatening reduction in white blood cell count (WBC).
- Myocarditis/Cardiomyopathy: Risk highest in first 2 months.
- Seizures: Dose-related (levels > 500 µg/L).
Common:
- Weight gain and metabolic syndrome (Highest risk among atypicals).
- Sialorrhea (Excessive salivation - often troublesome at night).
- Sedation (Very common).
- Constipation: High risk of paralytic ileus; often requires prophylactic laxatives.

Baseline: Full blood count (FBC), electrocardiogram (ECG), and echocardiogram.
Initial Phase: FBC monitored weekly for 18 weeks.
Maintenance Phase: FBC monitored 4-weekly thereafter.
Action: Discontinue if total WBC < 3.0 x 10⁹/L or neutrophil count < 1.5 x 10⁹/L.

Availability: Available in government hospitals in Sri Lanka. Used as the gold standard for resistant cases.

⚠️ EXAM DETAIL: Clozapine is the only drug with proven superior efficacy for treatment-resistant schizophrenia.
⚠️ EXAM DETAIL: Reduced risk of suicide is a specific indication for clozapine.
⚠️ EXAM DETAIL: Constipation is a common but potentially fatal side effect (ileus).