Can aripiprazole (Abilify) be used as adjunctive therapy for an adult with a single‑episode major depressive disorder (ICD‑10 F32.9) after an inadequate trial of an antidepressant?

Aripiprazole for Major Depressive Disorder (DSM-5 F32.9)

Yes, aripiprazole (Abilify) is FDA-approved and strongly recommended as adjunctive therapy for adults with major depressive disorder who have shown inadequate response to at least one antidepressant trial. 1, 2, 3

Evidence Basis for Aripiprazole Augmentation

The American College of Physicians identifies aripiprazole as a superior choice for augmentation therapy in treatment-resistant major depressive disorder, based on high-quality evidence showing remission rates of 55.4% versus 34.0% with placebo (p=0.031). 1

• Aripiprazole is the first atypical antipsychotic approved by the FDA specifically as adjunctive therapy for major depressive disorder in adults. 2, 3
• Two large, well-designed pivotal trials demonstrated that 6 weeks of adjunctive aripiprazole (2-20 mg/day) significantly improved Montgomery-Åsberg Depression Rating Scale (MADRS) scores compared to placebo when added to ongoing antidepressant therapy. 3, 4
• Improvements in MADRS scores favored aripiprazole from 1-2 weeks onward, with benefits maintained regardless of the specific antidepressant used, patient age, or baseline depression severity. 3

When to Initiate Aripiprazole Augmentation

Before adding aripiprazole, you must verify that the patient has completed an adequate trial of at least one antidepressant—defined as 6-8 weeks at maximum tolerated dose with documented adherence. 1

• The American College of Physicians emphasizes that augmentation should only follow confirmation of inadequate response to proper antidepressant monotherapy. 1
• Starting doses range from 2-5 mg/day, with titration up to 15 mg/day based on response and tolerability. 2, 3

Expected Outcomes and Monitoring

• Response rates (≥50% improvement in MADRS) and remission rates (MADRS ≤10) are significantly higher with aripiprazole augmentation compared to continuing antidepressant monotherapy alone. 3, 4
• Clinical improvement may be evident as early as 1-2 weeks after initiation. 3
• Evaluate treatment response at 6-8 weeks using standardized depression scales (MADRS or equivalent) to determine whether to continue, adjust dose, or consider alternative strategies. 1

Safety Profile and Adverse Effects

Akathisia is the most common adverse event, occurring in approximately 17-26% of patients, though most cases are mild to moderate and rarely lead to discontinuation. 4, 5

• Other common adverse effects include weight gain (minimal trend over 6 weeks), sedation, and extrapyramidal symptoms. 4
• In older adults (ages 50-67), aripiprazole demonstrated similar efficacy to younger patients, with akathisia occurring in 17.1% of older patients versus 26.0% in younger patients. 5
• Mandatory monitoring includes assessment for akathisia, extrapyramidal symptoms, weight, metabolic parameters (glucose and lipids), and movement disorders at 2-4 week intervals. 6

Critical Pitfalls to Avoid

• Do not initiate aripiprazole without first confirming an inadequate 6-8 week trial of antidepressant monotherapy at adequate doses. 1
• Do not use aripiprazole as monotherapy for major depressive disorder—it is approved only as adjunctive therapy to ongoing antidepressants. 2, 3
• If akathisia emerges, reduce the aripiprazole dose rather than discontinuing immediately, as most cases respond to dose adjustment. 7
• Monitor for serotonin syndrome when combining aripiprazole with serotonergic antidepressants, watching for agitation, confusion, tremor, hyperthermia, and autonomic instability. 6

Alternative Augmentation Strategies

If aripiprazole is contraindicated or not tolerated, the American College of Physicians provides moderate-quality evidence supporting these alternatives: 1

• Bupropion augmentation (150-300 mg/day added to ongoing SSRI) shows comparable efficacy to switching strategies and has lower discontinuation rates than buspirone. 8
• Cognitive-behavioral therapy added to pharmacotherapy produces superior functional outcomes and lower relapse rates compared to medication alone. 8
• Switching to a different second-generation antidepressant (e.g., from SSRI to SNRI or bupropion) yields similar response rates to augmentation strategies. 8

Long-Term Management

• Once remission is achieved with aripiprazole augmentation, continue combination therapy for at least 4-9 months for a first depressive episode, or at least 12 months for recurrent depression. 8
• Long-term tolerability data from 52-week open-label extension studies support sustained use when clinically indicated. 4