What is the role of adding a dopamine blocker, such as aripiprazole (Abilify), to a serotonin-norepinephrine reuptake inhibitor (SNRI) in adult patients, aged 18-65, with treatment-resistant major depressive disorder or anxiety disorder?

Aripiprazole Augmentation of SNRIs in Treatment-Resistant Depression

For adults aged 18-65 with treatment-resistant major depressive disorder or anxiety disorder who have failed an adequate SNRI trial, aripiprazole augmentation is the evidence-based first-line strategy, with 44-59% achieving clinically meaningful improvement compared to 29% with placebo. 1, 2

Primary Recommendation: Aripiprazole as First-Line Augmentation

Aripiprazole should be added to the existing SNRI at a target dose of 10-15 mg daily for treatment-resistant depression. 1, 2

Evidence Supporting Aripiprazole

• The American College of Physicians and other guideline societies recommend aripiprazole as the first-line augmentation strategy for patients with partial response to SNRIs, with approximately one-third to one-half of patients showing clinically meaningful response 1, 2

• In a high-quality randomized controlled trial of older adults (age >60), aripiprazole augmentation achieved 44% remission rates versus 29% with placebo (NNT = 6.6), with significant improvement beginning as early as week 1 2

• Response rates of 52-70% have been demonstrated when aripiprazole is used to augment antidepressants in treatment-resistant depression 1

• A trial comparing augmentation strategies found higher remission rates for aripiprazole than bupropion (55.4% vs 34.0%), with no difference in discontinuation due to adverse events 3

Practical Implementation

• Dosing: Start aripiprazole at 5 mg daily, titrate to target dose of 10 mg daily, with maximum of 15 mg daily if needed 2

• Timeline: Assess response at 1-2 weeks, as significant improvement can begin early; continue for full 12-week trial before declaring treatment failure 1, 4, 2

• Duration: Maintain effective augmentation for 12-24 months after achieving remission due to high relapse rates after discontinuation 1

Critical Pre-Augmentation Requirements

Before adding aripiprazole, confirm the patient has completed an adequate SNRI trial of 8-12 weeks at maximum tolerated dose with verified medication adherence. 1

• The American Psychiatric Association requires confirmation of adequate antidepressant trial duration and adherence before labeling as treatment-resistant 1

• Consider switching to a different antidepressant class rather than augmenting, as STAR*D data showed similar efficacy between switch strategies (to bupropion SR, escitalopram, duloxetine, sertraline, or venlafaxine) and augmentation approaches 3

Alternative Augmentation Options (When Aripiprazole is Not Suitable)

Bupropion Augmentation

• STAR*D data showed similar efficacy between bupropion SR and aripiprazole augmentation of SSRIs/SNRIs 3
• Bupropion has lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%) 3
• However, bupropion has no evidence base for anxiety disorders and should be avoided in patients with prominent anxiety symptoms 1

Cognitive Behavioral Therapy (CBT)

• CBT augmentation produces larger effect sizes than pharmacological augmentation alone and should be implemented if not already in place 1
• STAR*D showed similar efficacy between medication augmentation and CBT augmentation 3

Monitoring and Safety Considerations

Common Adverse Effects

• Akathisia is the most common adverse effect, occurring in 26% of patients on aripiprazole versus 12% on placebo 2
• Parkinsonism occurs in 17% versus 2% with placebo, requiring clinical monitoring for extrapyramidal symptoms 2
• Aripiprazole has the most favorable metabolic profile among antipsychotics, though ongoing monitoring of weight, glucose, and lipids remains essential 1, 5

What to Monitor

• Assess for akathisia and extrapyramidal symptoms at each visit, particularly in first 4 weeks 2
• Monitor metabolic parameters (weight, fasting glucose, lipid panel) at baseline, 3 months, and annually 1
• Treatment-emergent suicidal ideation does not differ from placebo but should be monitored in all patients 2

Common Pitfalls to Avoid

• Do not use buspirone augmentation as it has higher discontinuation rates (20.6%) and no evidence for anxiety disorders 3, 1

• Do not prematurely declare treatment resistance without confirming 8-12 weeks at adequate SNRI dose with verified adherence 1

• Do not overlook CBT as it produces larger effect sizes than pharmacological augmentation alone when available 1

• Do not use bupropion in patients with prominent anxiety symptoms as it lacks evidence for anxiety disorders despite efficacy in depression 1