Brexpiprazole
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Brexpiprazole: From Schizophrenia and Depressive Disorders to Neurotic Depression
One-Sentence Summary
Brexpiprazole is an atypical antipsychotic originally used for schizophrenia and as an add-on treatment in major depressive disorder and anxiety disorder. The TxGNN model's top-ranked prediction is dysthymic disorder, but this has no supporting studies. The best-supported prediction is neurotic depression (rank 5), which has 0 registered clinical trials and 20 publications, all of them indirect (they study major depressive disorder, not this label).
Note: The top-ranked prediction (dysthymic disorder) has no clinical trials or literature. The sections below follow that prediction, as required by the report format. Neurotic depression and melancholia are discussed where relevant because they are the only predictions with literature.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Schizophrenia; major depressive disorder (adjunctive); anxiety disorder (approved indication text is not available in the Singapore licence records) |
| Predicted New Indication | Dysthymic disorder |
| TxGNN Prediction Score | 98.53% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 6 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Published reviews describe brexpiprazole as a serotonin-dopamine activity modulator. It is a partial agonist at 5-HT1A and D2 receptors and a potent antagonist at 5-HT2A and noradrenergic α1B/α2C receptors.
Dysthymic disorder is a chronic, milder form of depression closely related to major depressive disorder, where brexpiprazole is already used as an add-on to antidepressants. This makes the prediction biologically coherent. However, the model score is the only support: no trials or publications were found specifically for dysthymic disorder.
Other predictions fall into two groups:
- Plausible, depression/anxiety spectrum: agoraphobia, neurotic disorder, neurotic depression and melancholia. Their high scores likely reflect overlap with the approved indications.
- No evident mechanistic link: benign paroxysmal torticollis of infancy, Keppen-Lubinsky syndrome, Ohdo syndrome, inherited retinal dystrophy and congenital isolated ACTH deficiency. These appear to be network-level associations only. For benign paroxysmal torticollis, antipsychotic-related dystonia and extrapyramidal effects are an added safety concern.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
No literature was found for dysthymic disorder. The table below shows the most relevant publications retrieved for the related predictions neurotic depression and melancholia. They address major depressive disorder and treatment-resistant depression, so the evidence is indirect.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26301701 | 2015 | RCT | J Clin Psychiatry | Phase 3 placebo-controlled study of adjunctive brexpiprazole 2 mg in MDD with inadequate response to antidepressants |
| 42090141 | 2026 | Network meta-analysis | JAMA Psychiatry | Adjunctive atypical antipsychotics in MDD; five agents are FDA-approved for this use |
| 42283956 | 2026 | Network meta-analysis | Adv Ther | Efficacy and safety of lumateperone versus other approved adjunctive atypical antipsychotics in MDD |
| 34986373 | 2022 | Network meta-analysis | J Affect Disord | Comparison of augmentation agents in treatment-resistant depression |
| 38924903 | 2024 | Network meta-analysis | Psychiatry Res | Eight enhanced therapies for treatment-resistant depression |
| 34238049 | 2021 | Network meta-analysis | J Psychopharmacol | Antidepressant plus second-generation antipsychotic vs. esketamine vs. lithium in major depression |
| 39424742 | 2024 | Open-label study | CNS Drugs | Long-term safety and efficacy of adjunctive brexpiprazole 2 mg in Japanese patients with MDD |
| 37149344 | 2023 | Review | Psychiatr Clin North Am | Antidepressants and atypical antipsychotics in treatment-resistant depression |
| 36855876 | 2023 | Review | Am J Psychiatry | Role of antipsychotics in the evolving treatment-resistant depression landscape |
| 28228056 | 2017 | Review (drug profile) | Ann Pharmacother | Pharmacology and clinical data for brexpiprazole in schizophrenia and MDD |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15764P | REXULTI Film-Coated Tablets 3 mg | Film-coated tablet | Not available in the records |
| SIN15768P | REXULTI Film-Coated Tablets 0.25 mg | Film-coated tablet | Not available in the records |
| SIN15767P | REXULTI Film-Coated Tablets 0.5 mg | Film-coated tablet | Not available in the records |
| SIN15766P | REXULTI Film-Coated Tablets 1 mg | Film-coated tablet | Not available in the records |
| SIN15763P | REXULTI Film-Coated Tablets 4 mg | Film-coated tablet | Not available in the records |
A sixth licence (SIN15765P, 2 mg) is also valid. All six registrations are single-ingredient oral tablets.
Safety Considerations
- Drug Interactions: 100 interactions were found in the interaction database. Examples of those rated Major: bupropion, aprepitant, morphine, lorcaserin, cimetidine, clarithromycin and clotrimazole. Examples rated Moderate include antidiabetic drugs (metformin, pioglitazone, acarbose, alogliptin, canagliflozin, dapagliflozin), anticholinergics (atropine, hyoscyamine, clidinium), epinephrine and loperamide.
- Other considerations: Antipsychotics can cause dystonia and extrapyramidal effects, which is relevant to the movement-disorder prediction (benign paroxysmal torticollis of infancy).
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The top prediction, dysthymic disorder, rests on the model score alone (L5), with no trials or publications. Neurotic depression and melancholia reach L3 only through indirect MDD evidence, including one phase 3 RCT of adjunctive brexpiprazole in MDD, and are best treated as research questions rather than repurposing candidates.
To proceed, the following is needed:
- Package insert warnings and contraindications from the Singapore regulator (HSA), which are required before safety screening can proceed
- Approved indication text for the Singapore licences
- Mechanism of action data from DrugBank
- Direct evidence for dysthymic disorder, such as a literature search or a trial
- Verification of how "neurotic depression" and "melancholia" map to the approved MDD indication, and subtype-specific analyses of existing MDD trials
- A review of the major interactions (bupropion, CYP-inhibiting drugs) for the intended patient population
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.