Aripiprazole

Evidence Level: L5

Predicted Indications: 8

Aripiprazole

Pharmacist Assessment Report

Aripiprazole: Gaze palsy, familial horizontal, with progressive scoliosis

One-Sentence Summary

Aripiprazole is an atypical antipsychotic that acts as a dopamine D2/D3 and serotonin 5-HT1A partial agonist.

Quick Overview

Item	Content
Original Indication	Not recorded in the local data
Predicted New Indication	Gaze palsy, familial horizontal, with progressive scoliosis
TxGNN Prediction Score	0.9960
Evidence Level	L5
Canada Market Status	Marketed (marketed DINs on record: at least 20)
Number of DINs	at least 20
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. Rather than fully blocking or fully stimulating these receptors, it adjusts dopaminergic and serotonergic activity up or down depending on the existing tone. Formal mechanism-of-action data were not available in the data compiled for this report, so this description reflects the established pharmacology summarized in the repurposing rationale.

Major depressive disorder often responds only partially to serotonergic antidepressants. Adding a drug that modulates dopamine and serotonin signalling in mood circuits is a plausible way to improve response. This is the logic behind the adjunctive-treatment trials listed below, and the reviews and network meta-analyses in the literature table discuss atypical antipsychotics, including aripiprazole, as augmentation options in treatment-resistant depression.

Guardrails suggested by the rationale: monitor for akathisia, metabolic effects and impulse-control adverse events.

Clinical Trial Evidence

The data include 36 trials. The table lists the 10 most relevant ones, prioritizing completed, controlled studies directly testing aripiprazole in major depressive disorder.

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 treatment
NCT00095758	Phase 3	Completed	1151	14-week double-blind, placebo-controlled adjunctive aripiprazole study in major depressive disorder
NCT00683852	Phase 3	Completed	225	Double-blind, placebo-controlled study of reduced-dose aripiprazole added to antidepressant therapy
NCT00876343	Phase 3	Completed	586	Placebo-controlled study of aripiprazole added to an SSRI or SNRI
NCT00105196	Phase 3	Completed	349	14-week double-blind, placebo-controlled adjunctive study after incomplete response to an antidepressant
NCT01421342	Phase 3	Completed	1522	VA VAST-D: aripiprazole augmentation vs bupropion augmentation vs switching to bupropion in treatment-resistant depression
NCT00095745	Phase 3	Completed	1002	52-week open-label safety and tolerability study of adjunctive aripiprazole
NCT00882362	Phase 3	Completed	155	Long-term safety and efficacy of aripiprazole added to an SSRI or SNRI
NCT01111539	Phase 3	Terminated	211	Aripiprazole/escitalopram combination vs comparator; terminated early, limiting interpretation
NCT01488266	Not applicable	Unknown	90	Aripiprazole augmentation vs switching antidepressant class in partially responsive depression

Literature Evidence

The data include 20 publications. The table lists the 10 most relevant, prioritizing systematic reviews and network meta-analyses.

PMID	Year	Type	Journal	Key Findings
42090141	2026	Systematic review / network meta-analysis	JAMA Psychiatry	Adjunctive antipsychotics in major depressive disorder; notes that the US FDA has approved 5 atypical antipsychotics for this use
42283956	2026	Network meta-analysis	Advances in Therapy	Compares efficacy and safety of atypical antipsychotics used as adjunctive treatment in major depressive disorder
39739012	2025	Systematic review / network meta-analysis	Neuropsychopharmacology	Relative effectiveness of antidepressant treatments in treatment-resistant depression
34986373	2022	Systematic review / network meta-analysis	Journal of Affective Disorders	Compares efficacy and discontinuation of augmentation agents in treatment-resistant depression
35861202	2023	Systematic review / meta-analysis	Journal of Psychopharmacology	Augmentation and combination treatments for early-stage treatment-resistant depression
34238049	2021	Comparative analysis	Journal of Psychopharmacology	Antidepressants plus second-generation antipsychotics vs esketamine vs lithium in major depression
21154393	2010	Cochrane review	Cochrane Database of Systematic Reviews	Second-generation antipsychotics for major depressive disorder and dysthymia
37149344	2023	Review	Psychiatric Clinics of North America	Antidepressants and atypical antipsychotics, with aripiprazole among the best-studied augmentation agents in treatment-resistant depression
36855876	2023	Review	American Journal of Psychiatry	Where antipsychotics fit among treatment-resistant depression therapies
25963405	2016	Review	Asia-Pacific Psychiatry	Notes that aripiprazole is among the antipsychotics with FDA approval as adjunctive treatment in major depressive disorder, effective at subantipsychotic doses

One additional meta-analysis on aripiprazole or bupropion augmentation (PMID 38669232) carries a retraction notice and is therefore not relied on.

Canada Market Information

Twenty single-ingredient licences are currently valid. The licence records available are partial, and no dosage form or indication text is recorded. Five are listed below.

DIN	Product Name	Dosage Form	Approved Indication
02322412	ABILIFY	Not recorded	Not recorded
02554569	ABILIFY ASIMTUFII	Not recorded	Not recorded
02472228	NRA-ARIPIPRAZOLE	Not recorded	Not recorded
02488051	ARIPIPRAZOLE	Not recorded	Not recorded
02473704	SANDOZ ARIPIPRAZOLE	Not recorded	Not recorded

Safety Considerations

Contraindications flagged in related drug-disease records (these are not label text; verify against the Canadian product monograph): orthostatic hypotension, epilepsy, hyperglycemia and diabetes, diabetic ketoacidosis, neutropenia, agranulocytosis and leukopenia, hyperlipidemia, obesity, myocardial infarction and coronary artery disease, heart conduction disease, neuroleptic malignant syndrome, and cerebrovascular disorder.

Drug Interactions: 100 interactions were found. Among those displayed, one is rated Major: bupropion. Most others are rated Moderate, including antidiabetic agents (metformin, pioglitazone, alogliptin, canagliflozin, acarbose, chlorpropamide, acetohexamide, albiglutide), anticholinergics (atropine, hyoscyamine, clidinium), CYP-inhibiting drugs (clarithromycin, cimetidine), and others such as epinephrine, famotidine, loperamide, aprepitant, cisapride and clotrimazole.

Please also refer to the package insert for full safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Several completed, large, double-blind, placebo-controlled Phase 3 trials directly test aripiprazole added to antidepressants in major depressive disorder, and recent network meta-analyses support the approach. Known risks (akathisia, metabolic effects, impulse-control problems) call for monitoring.

To proceed, the following is needed:

Health Canada product monograph warnings and contraindications, which are missing from the compiled data
Formal mechanism-of-action data
Review of the Major-level interaction with bupropion and of the metabolic and cardiovascular contraindication signals
Confirmation of the approved indications on the Canadian licences, since no indication text is recorded
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.