In an adult with major depressive disorder who has failed an adequate dose and duration of antidepressant monotherapy, what is the most evidence‑based medication for augmentation?

Best Medication for Antidepressant Augmentation in Major Depressive Disorder

For adults with major depressive disorder who have failed adequate antidepressant monotherapy, aripiprazole is the single best-supported augmentation medication, based on the most recent high-quality evidence showing it doubles remission rates (36.8% vs 18.9%) with acceptable tolerability. 1

Evidence Hierarchy for Augmentation Strategies

The 2023 American College of Physicians systematic review establishes that augmentation with bupropion SR or buspirone demonstrates efficacy equivalent to switching antidepressants, supported by moderate-certainty evidence from the STAR*D trial. 2 Critically, bupropion SR augmentation carries a significantly lower discontinuation rate due to adverse events (12.5%) compared with buspirone (20.6%, P < 0.001). 2

However, when prioritizing the single most recent and highest-quality study, the 2009 double-blind, placebo-controlled trial (N=349 randomized patients with confirmed inadequate antidepressant response) demonstrated that aripiprazole augmentation achieved:

• Mean MADRS improvement of -10.1 versus -6.4 with placebo (P<0.001) 1
• Remission rate of 36.8% versus 18.9% with placebo (P<0.001) 1
• High completion rate (83%) with low discontinuation due to adverse events (6.2%) 1

This represents the third consecutive positive trial without a failed trial, establishing aripiprazole as the most robustly validated augmentation agent. 1

Practical Implementation Algorithm

First-Line Augmentation Choice

• Initiate aripiprazole 2-5 mg daily, titrating to 5-15 mg/day based on response and tolerability (typical effective range 2-20 mg/day), while continuing the current antidepressant at therapeutic dose. 1

• Alternative first-line option: Add bupropion SR 150 mg once daily for 3-4 days, then increase to 150 mg twice daily if aripiprazole is contraindicated (seizure history, eating disorder) or if metabolic concerns preclude antipsychotic use. 2, 3

Monitoring Requirements

• Assess response at 2 weeks for early improvement, then definitively at 6-8 weeks using validated scales (PHQ-9, HAM-D, MADRS). 2, 4

• For aripiprazole: Monitor weight, fasting glucose, and lipid profile at baseline and quarterly to detect metabolic dysregulation, though aripiprazole carries lower metabolic risk than olanzapine or quetiapine. 4, 5

• For bupropion: Screen for emerging anxiety, agitation, or insomnia, which occur more commonly than with aripiprazole augmentation. 2

Second-Line Augmentation Options

If aripiprazole or bupropion fail or are not tolerated:

• Quetiapine extended-release 150-300 mg at bedtime is FDA-approved for depression augmentation and may be preferred when insomnia is prominent, though it carries higher metabolic risk than aripiprazole. 5, 6

• Lithium 300-600 mg daily (target level 0.6-0.8 mEq/L) has historical evidence but requires baseline and ongoing monitoring of thyroid function, renal function, and serum levels. 4, 7

• Buspirone 30-60 mg daily in divided doses showed equivalent efficacy to bupropion in STAR*D but higher discontinuation rates due to adverse events. 2

Critical Nuances and Divergent Evidence

The 2023 ACP guideline emphasizes that switching antidepressants and augmentation strategies show similar overall efficacy (moderate-certainty evidence), suggesting either approach is reasonable. 2 However, this conclusion is based on aggregate data across multiple agents, whereas individual augmentation agents differ substantially in their evidence base and tolerability profiles. 2, 5

The OCD guidelines 2 are not applicable here—they address SSRI-resistant OCD, not major depressive disorder, and recommend antipsychotic augmentation specifically for obsessive-compulsive symptoms, not depressive symptoms. These should be disregarded for this question.

Omega-3 fatty acids show benefit only as adjunctive therapy (not monotherapy) with small-to-moderate effect sizes, and the evidence favors EPA-predominant formulations (≥1000 mg EPA daily). 2 However, this represents a complementary strategy rather than a primary augmentation medication.

Common Pitfalls to Avoid

• Do not add a second antidepressant from the same class (e.g., adding another SSRI to an SSRI)—switching between SSRIs does not produce significant differences in response rates. 4

• Do not use olanzapine-fluoxetine combination as first-line augmentation despite FDA approval—metabolic side effects (weight gain, diabetes risk) limit its use compared with aripiprazole. 5, 6

• Do not pursue augmentation without first confirming adequate dose and duration (minimum 4-6 weeks at maximum FDA-approved dose) and documented adherence to the current antidepressant. 4, 5

• Do not overlook cognitive-behavioral therapy as an augmentation strategy—adding CBT to ongoing pharmacotherapy produces outcomes superior to medication alone in treatment-resistant depression. 2, 4

Risk-Benefit Considerations

Atypical antipsychotics carry a smaller effect size than initial antidepressant therapy, with only one-third of SSRI-resistant patients showing clinically meaningful response to antipsychotic augmentation. 2 This necessitates ongoing monitoring of the risk-benefit ratio, particularly for weight gain, metabolic dysregulation, akathisia, and tardive dyskinesia risk. 2, 5

Bupropion augmentation avoids metabolic and extrapyramidal risks but is contraindicated in seizure disorders and eating disorders due to dose-dependent seizure risk. 3, 6

The choice between aripiprazole and bupropion should weigh:

• Aripiprazole: Higher remission rates in head-to-head comparison with bupropion (55.4% vs 34.0%, P=0.031) in one trial, though this was rated high risk of bias. 2
• Bupropion: Lower sexual dysfunction rates and no metabolic monitoring requirements, making it preferable when metabolic syndrome or sexual side effects are primary concerns. 4, 3