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 profile (dopamine, serotonin, muscarinic, histaminergic and adrenergic antagonism). The TxGNN model predicts it may be effective for manic bipolar affective disorder, with 1 completed Phase 2 trial and a 2020 systematic review and meta-analysis directly addressing this direction. The evidence level is 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 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not formally recorded in the data compiled for this report. Based on known pharmacology, clozapine antagonises D2/D4 dopamine receptors, 5-HT2A serotonin receptors, and muscarinic, histaminergic and adrenergic receptors. This broad profile is consistent with antimanic and mood-stabilising effects, particularly in treatment-resistant mania.
Many patients with mania do not respond adequately to conventional treatment or cannot tolerate therapeutic doses of standard agents. Clozapine has been explored as an alternative in this group, and the antipsychotic class already plays an established role in acute mania. This supports the plausibility of the model’s very high score, although the score itself is a computational prediction and not clinical proof.
Clinical Trial Evidence
Only one registered trial directly studies the predicted disease itself (manic phase of bipolar disorder):
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00029458 | Phase 2 | Completed | 42 | Double-blind study of clozapine efficacy and safety in treatment-resistant mania; results not provided in the data compiled for this report |
No Phase 3 trial of clozapine specific to mania is listed, which is why the evidence level is L2 rather than L1.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 32182485 | 2020 | Systematic review/Meta-analysis | J Psychiatr Res | Assessed clinical efficacy and adverse effects of clozapine in bipolar disorder; small comparative studies suggested similar efficacy to other antipsychotics in manic episodes and better outcomes in treatment-resistant bipolar disorder |
| 25346322 | 2015 | Systematic review | Bipolar Disord | Efficacy and safety of clozapine in treatment-resistant bipolar disorder |
| 41192460 | 2025 | Cohort/Effectiveness study | Lancet Psychiatry | Transdiagnostic effectiveness and safety of clozapine versus other antipsychotics, including affective disorders |
| 33460070 | 2020 | Review | Acta Psychiatr Scand | Evidence-based treatment options for bipolar mania, including choice of antipsychotic |
| 33719158 | 2021 | Review | Bipolar Disord | Overview of current knowledge and open questions for clozapine in bipolar disorder |
| 16432528 | 2006 | Review | Mol Psychiatry | Treatment-resistant bipolar disorder in acute and maintenance phases |
| 41262335 | 2025 | Pharmacokinetic/dosing study | Drug Des Devel Ther | Clozapine drug interactions and individualised dosing in bipolar disorder |
| 10682225 | 2000 | Case series/Review | Clin Neuropharmacol | 36 patients treated with combined ECT and clozapine; 67% benefited and the combination was generally well tolerated |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 10288L | Clopine 200 | Tablet 200 mg | Not stated in the data compiled for this report |
Cytotoxicity
Not applicable: clozapine is not an antineoplastic drug.
Safety Considerations
- Contraindication-related conditions (from drug-disease relationship data, not label text): epilepsy, liver disease, neutropenia, agranulocytosis, leukopenia, diabetes mellitus and diabetic ketoacidosis, hyperglycaemia, orthostatic hypotension, coronary artery disease, heart conduction disease, sudden cardiac arrest, stroke and cerebrovascular disorders, pulmonary embolism, respiratory failure, angle-closure glaucoma, paralytic ileus and benign prostatic hyperplasia.
- Drug Interactions: 100 interactions were recorded. Major-level examples include bupropion, morphine and potassium citrate. Moderate-level examples include metformin, other glucose-lowering agents (acarbose, pioglitazone, alogliptin, canagliflozin), famotidine, cimetidine, omeprazole, epinephrine and several anticholinergic agents (atropine, hyoscyamine, glycopyrronium).
- Literature-reported risks: agranulocytosis requiring absolute neutrophil count monitoring, metabolic effects, cardiotoxicity (myocarditis, cardiomyopathy) and seizures.
Please refer to the TGA-approved Product Information (PI) for full warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: A completed Phase 2 double-blind trial in treatment-resistant mania and a 2020 systematic review and meta-analysis directly support the prediction (evidence level L2). There is no Phase 3 trial specific to mania, and clozapine carries serious risks that require strict monitoring.
To proceed, the following is needed:
- Published results of NCT00029458 and confirmation of efficacy in a larger, adequately powered randomised trial in mania
- Clozapine’s approved indication and safety text from the TGA Product Information
- A monitoring plan covering neutrophil counts, metabolic and cardiac risk, and seizure risk
- A review of the large drug-interaction burden for the intended patient population
- Detailed mechanism of action data
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.