Clozapine
| Evidence Level: L2 | Predicted Indications: 9 |
Table of Contents
Clozapine: Manic bipolar affective disorder
One-Sentence Summary
Clozapine is an atypical antipsychotic with a broad receptor-blocking profile, marketed in Canada under 17 valid licences. The TxGNN model predicts it may be effective for manic bipolar affective disorder, with 1 directly relevant Phase 2 trial (NCT00029458) and a systematic review and meta-analysis of clozapine in bipolar disorder supporting this direction (evidence level L2).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Manic bipolar affective disorder |
| TxGNN Prediction Score | 0.9995 |
| Evidence Level | L2 |
| Canada Market Status | Marketed (marketed DINs: 17 of 17) |
| Number of DINs | 17 (marketed: 17) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data are not available in the data compiled for this report. From the published literature, clozapine blocks several receptors, including dopamine D2/D4, serotonin 5-HT2A, muscarinic and adrenergic receptors. This broad profile plausibly contributes to antimanic and mood-stabilizing effects, particularly when mania does not respond to conventional treatment.
Many patients with mania do not respond adequately to standard therapy or cannot tolerate effective doses. This is the clinical gap that the completed Phase 2 double-blind study (NCT00029458) was designed to address. A systematic review and meta-analysis (PMID 32182485) also assessed clozapine in bipolar disorder. It found clozapine similar to other antipsychotics in manic episodes and better in treatment-resistant bipolar disorder, based on three small comparative studies.
The evidence is limited to a small Phase 2 trial and small comparative studies, and no Phase 3 trial specific to mania is available.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00029458 | Phase 2 | Completed | 42 | Double-blind study of clozapine efficacy and safety in treatment-resistant mania (manic phase of bipolar disorder); directly relevant but small |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 32182485 | 2020 | Systematic review/Meta-analysis | Journal of psychiatric research | Assessed clinical efficacy and adverse effects of clozapine in bipolar disorder; clozapine similar to other antipsychotics in manic episodes and better in treatment-resistant bipolar disorder |
| 25346322 | 2015 | Systematic review | Bipolar Disorders | Efficacy and safety of clozapine in treatment-resistant bipolar disorder |
| 41192460 | 2025 | Cohort/Real-world effectiveness | The Lancet Psychiatry | Transdiagnostic effectiveness and safety of clozapine across psychotic, affective and personality disorders versus other antipsychotics |
| 33460070 | 2020 | Review | Acta Psychiatrica Scandinavica | Evidence-based treatment options for bipolar mania, including choice of mood stabilizer and antipsychotic |
| 16432528 | 2006 | Review | Molecular Psychiatry | Treatment-resistant bipolar disorder in acute manic or depressive episodes and maintenance treatment |
| 11280956 | 2001 | Review | Bulletin of the Menninger Clinic | Treatment-resistant bipolar disorder; newer treatments rest mostly on case reports and case series |
| 33719158 | 2021 | Review | Bipolar Disorders | Overview of current knowledge on clozapine for bipolar disorder and future directions |
| 41262335 | 2025 | Modelling study | Drug Design, Development and Therapy | Clozapine drug interactions and individualized dosing in bipolar disorder |
| 10682225 | 2000 | Case series | Clinical Neuropharmacology | 36 patients given combined ECT and clozapine; 67% benefited and the combination was mostly well tolerated |
Canada Market Information
Clozapine has 17 valid single-ingredient licences in Canada. The local records contain no approved-indication text or dosage-form details. Main authorizations:
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 00894737 | CLOZARIL | Not recorded | Not recorded |
| 00894745 | CLOZARIL | Not recorded | Not recorded |
| 02490668 | CLOZARIL | Not recorded | Not recorded |
| 02490676 | CLOZARIL | Not recorded | Not recorded |
| 02248035 | AA-CLOZAPINE | Not recorded | Not recorded |
Safety Considerations
- Drug Interactions: 100 interactions were found in the interaction screening. Major-level examples include bupropion, morphine and potassium citrate. Moderate-level examples include metformin, pioglitazone, other antidiabetic agents (acarbose, alogliptin, canagliflozin), anticholinergic agents (atropine, hyoscyamine, glycopyrronium), famotidine, cimetidine and omeprazole.
- Conditions of concern (not label text): Relationship data list conditions in which clozapine may be problematic, including neutropenia, agranulocytosis, leukopenia, epilepsy, liver disease, diabetes mellitus and diabetic ketoacidosis, hyperglycemia, coronary artery disease, stroke, cardiac conduction disease, orthostatic hypotension, angle-closure glaucoma, paralytic ileus and respiratory failure.
- Literature-reported safety themes: Safety reviews and the bipolar literature highlight agranulocytosis (blood count monitoring), myocarditis and cardiomyopathy, seizures and metabolic syndrome.
Please refer to the package insert for full warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: A completed Phase 2 double-blind trial and a systematic review and meta-analysis directly address clozapine in mania and treatment-resistant bipolar disorder. This supports evidence level L2. However, there is no Phase 3 trial, the studies are small, and clozapine carries serious risks that need strict monitoring.
To proceed, the following is needed:
- Package insert warnings and contraindications from Health Canada
- Detailed mechanism-of-action data
- Confirmation of the results of NCT00029458 and larger controlled trials in mania
- A safety monitoring plan covering neutrophil counts, cardiac effects, seizure risk and metabolic parameters, together with a review of interacting medicines
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.