Clozapine
Clozaril
Second-Generation AntipsychoticGeneric availableTDM data
The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.
Compare Clozapine →FDA-Approved Indications
- Treatment-resistant schizophrenia (failure of standard antipsychotic treatment)
- Reducing risk of recurrent suicidal behavior in schizophrenia/schizoaffective disorder
Common Off-Label Uses
- Bipolar disorder (treatment-resistant)
- Psychosis in Parkinson's disease
- Aggression in intellectual disability
- Tardive dyskinesia
What Sets This Drug Apart
- Only antipsychotic with level-1 evidence for treatment-resistant schizophrenia (TRS); the only FDA-approved option after documented failure of 2 antipsychotics
- Only antipsychotic FDA-approved for reducing recurrent suicidal behavior in schizophrenia/schizoaffective disorder (InterSePT trial)
- Highest monitoring burden of any antipsychotic: mandatory REMS-based ANC monitoring (weekly x6mo, biweekly x6mo, then monthly), plus metabolic panel, troponin/ECG for myocarditis risk, LFTs,…
- Highest or co-highest metabolic burden among SGAs: weight gain 56% at 2 years, worst or second-worst triglyceride and glucose changes in NMA data
- Highest sedation of any antipsychotic (Leucht 2026 OR 6.37 vs placebo); somnolence 46% in controlled trials
- Paradoxical hypersalivation (31-48%) despite strong muscarinic antagonism (M4 partial-agonist mechanism); constipation carries risk of ileus/bowel obstruction
- Lowest EPS of any antipsychotic: akathisia and parkinsonism ~50% lower than placebo rates; prolactin-neutral
- CYP1A2 substrate — tobacco smoke decreases levels ~50%; smoking cessation requires dose reduction to prevent toxicity
Boxed Warning
WARNING: SEVERE NEUTROPENIA