Aripiprazole
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
- Aripiprazole
- Aripiprazole: From Antipsychotic Use (Schizophrenia and Bipolar I Disorder) to Major Affective Disorder
Aripiprazole: From Antipsychotic Use (Schizophrenia and Bipolar I Disorder) to Major Affective Disorder
One-Sentence Summary
Aripiprazole is an atypical antipsychotic already established in schizophrenia and bipolar disorder. The TxGNN model predicts it may be effective for major affective disorder (major depression). This is supported by 50 registered clinical trials (about 10 directly test aripiprazole in depression or bipolar depression, including several completed Phase 3 placebo-controlled studies) and 20 publications, mostly systematic reviews and meta-analyses. This looks like a label-adjacent use rather than a novel repurposing, and the source record should be checked against the regulatory label before any repurposing claim is made.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not stated in the SAHPRA record (indication text is empty). Established antipsychotic and mood-stabiliser use in schizophrenia and bipolar I disorder. |
| Predicted New Indication | Major affective disorder |
| TxGNN Prediction Score | 99.62% |
| Evidence Level | L1 |
| South Africa Market Status | Marketed |
| Number of SAHPRA Registrations | 1 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Aripiprazole is a partial agonist at dopamine D2/D3 and serotonin 5-HT1A receptors and an antagonist at 5-HT2A receptors. This profile is consistent with mood stabilisation in bipolar disorder and with boosting the effect of antidepressants in major depression. The DrugBank mechanism-of-action field is not populated for this record, so the description above comes from the pack’s mechanistic rationale.
Antipsychotic use in mood disorders is well recognised. A 2016 review notes that aripiprazole, quetiapine and olanzapine have received FDA approval as add-ons to antidepressants in major depressive disorder (PMID 25963405). Several later reviews position aripiprazole as one of the most widely studied augmentation agents in treatment-resistant depression (PMID 37149344).
The prediction is therefore reasonable, but it is not a novel discovery. The realistic question for South Africa is whether adjunctive use in depression is covered by the local registration and available in a suitable formulation.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00095823 | Phase 3 | Completed | 1200 | 14-week double-blind, placebo-controlled study of aripiprazole added to ongoing antidepressant therapy in MDD |
| NCT00876343 | Phase 3 | Completed | 586 | Placebo-controlled study of adjunctive aripiprazole with an SSRI or SNRI in MDD (pack grade A) |
| NCT02046564 | Phase 3 | Completed | 412 | Aripiprazole/sertraline combination (ASC-01) vs sertraline alone in patients responding incompletely to sertraline |
| NCT00683852 | Phase 3 | Completed | 225 | Reduced-dose aripiprazole vs placebo added to antidepressant therapy in MDD with inadequate response |
| NCT00882362 | Phase 3 | Completed | 155 | Long-term safety and efficacy of adjunctive aripiprazole with SSRI/SNRI in MDD |
| NCT01111552 | Phase 3 | Terminated | 237 | Oral aripiprazole/escitalopram combination in MDD with incomplete response; stopped early, so limited weight |
| NCT01111565 | Phase 3 | Terminated | 137 | Sister study of the aripiprazole/escitalopram combination in MDD; stopped early, so limited weight |
| NCT00080314 | Phase 3 | Completed | 400 | Flexible-dose aripiprazole (5-30 mg) vs placebo in bipolar I disorder with a major depressive episode |
| NCT03423680 | Phase 3 | Recruiting | 390 | Aripiprazole added to a mood stabiliser for a major depressive episode in bipolar I or II disorder |
| NCT07153406 | Phase 3 | Not yet recruiting | 220 | Esketamine vs aripiprazole, each with an SSRI/SNRI, in treatment-resistant MDD in patients over 60 |
Trials were selected by direct testing of aripiprazole in depression. Only some trials carry a completed relevance grading in the pack. Study results are not included in the data, only design and status. One trial, NCT00338273 (bipolar depression, Phase 3), was withdrawn with no enrolment.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38669232 | 2024 | Meta-analysis of RCTs | PLoS One | Efficacy and safety of aripiprazole or bupropion augmentation and switching in treatment-resistant depression or MDD |
| 34986373 | 2022 | Systematic review / network meta-analysis | J Affect Disord | Compares efficacy and discontinuation of augmentation agents in treatment-resistant depression |
| 38219278 | 2024 | Systematic review / network meta-analysis | Neuropsychopharmacol Rep | Brexpiprazole vs aripiprazole vs placebo in Japanese patients with MDD inadequately responsive to antidepressants |
| 37746943 | 2023 | Systematic review / network meta-analysis | Medicine | Ranks four atypical antipsychotics as add-on treatment for MDD |
| 35510505 | 2023 | Systematic review / meta-analysis | Psychol Med | Efficacy and tolerability of antipsychotics as monotherapy and adjunctive therapy in adult MDD |
| 35861202 | 2023 | Systematic review / meta-analysis | J Psychopharmacol | Augmentation and combination treatments for early-stage treatment-resistant depression |
| 34238049 | 2021 | Systematic review | J Psychopharmacol | Antidepressants plus second-generation antipsychotics vs esketamine vs lithium in major depression |
| 34167174 | 2021 | Systematic review / meta-analysis | Prim Care Companion CNS Disord | Long-term (6 months or more) adjunctive aripiprazole in MDD, with remission as the primary outcome |
| 37149344 | 2023 | Review | Psychiatr Clin North Am | Atypical antipsychotics, including aripiprazole, as the most widely studied augmentation agents in treatment-resistant depression |
| 36855876 | 2023 | Review | Am J Psychiatry | Where antipsychotics fit among treatments for treatment-resistant depression |
The retrieved set also contains bipolar genetics studies (GWAS) and unrelated reviews. These are not counted as supporting evidence.
South Africa Market Information
| Registration Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| Reg. No. 42/2.6.5/0179 | Abilify im 1.3ml vial | Injection | Not stated in the record |
Essential Medicines List (EML) status is not provided in the source data. The only registration in the record is an injectable product, whereas the depression trials above used oral aripiprazole. Whether an oral product is registered in South Africa is not shown in the data.
Safety Considerations
Please refer to the SAHPRA-approved Professional Information (PI) for safety information. Report adverse drug reactions to SAHPRA.
One signal from the retrieved literature: a systematic review of case reports describes impulsive-compulsive behaviours (such as problem gambling, hypersexuality and compulsive behaviours) linked to aripiprazole use or dose increases (PMID 38227009). No drug-interaction records were found for this drug in the source data.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Several completed Phase 3 placebo-controlled trials and multiple meta-analyses support adjunctive aripiprazole in major depression, so the evidence is strong (L1). However, the SAHPRA safety information is missing, the local indication text is empty, and the registered product is an injection, so use should stay within the approved label until these are resolved.
To proceed, the following is needed:
- The SAHPRA package insert (PI) for warnings and contraindications. This is currently a blocking gap.
- Confirmation of the approved indications for the South African registration, and whether adjunctive use in major depression is covered.
- Confirmation of whether oral aripiprazole products are registered in South Africa, since the depression evidence is for oral use.
- Mechanism-of-action data from DrugBank.
- A check of the source record against the regulatory label to decide whether this counts as repurposing at all.
Other predictions for this drug are weaker. Trichotillomania (score 99.26%) is at L3 with two small or upcoming trials, and aripiprazole has also been reported to cause hair-pulling, so its net benefit is unresolved. The remaining predictions (rare genetic syndromes, retinal dystrophy, hydranencephaly and others) are model-only (L5) with no supporting evidence and should be held.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.