What is a good adjunct medication for a patient already on a selective serotonin reuptake inhibitor (SSRI)?

Adjunct Medication for SSRI Therapy

For patients with inadequate response to SSRI monotherapy, aripiprazole (starting at 5 mg daily, titrating to 10-15 mg daily) is the evidence-based adjunctive medication of choice, with FDA approval for this indication and demonstrated superiority over placebo in reducing depressive symptoms. 1, 2

Primary Recommendation: Aripiprazole Augmentation

Aripiprazole is FDA-approved as adjunctive therapy to antidepressants for major depressive disorder, making it the first-line augmentation strategy when SSRIs alone prove insufficient. 1

Dosing Protocol

• Start at 5 mg daily and titrate to 10-15 mg daily based on response (mean effective dose 11 mg/day in clinical trials). 2
• Allow 6-8 weeks at optimized doses before determining treatment failure, though some improvement should be evident by 2-4 weeks. 3
• Response rates reach 32.4% and remission rates 25.4%, significantly superior to placebo (17.4% and 15.2% respectively). 2

Mechanism and Efficacy

• Aripiprazole acts as a partial agonist at dopamine D2/D3 and serotonin 5-HT1A receptors, with antagonism at 5-HT2A receptors, providing complementary mechanisms to SSRIs. 1
• 59% of treatment-resistant patients showed "much improved" or "very much improved" status when aripiprazole was added to SSRIs at 12 weeks. 4
• Early response can occur within 1-5 weeks, with sustained benefits throughout treatment. 4, 5

Safety Profile and Monitoring

• Akathisia is the most common adverse effect (25.9% vs 4.2% placebo), though most cases are mild-to-moderate and rarely lead to discontinuation (5/1090 patients across trials). 1, 2
• Weight gain risk is minimal over 6 weeks, distinguishing it from other antipsychotic augmentation strategies. 1
• Discontinuation rates due to adverse events remain low (3.7%), indicating good overall tolerability. 2
• Monitor for akathisia, particularly in the first 2-4 weeks after initiation or dose increases. 1

Alternative Augmentation Strategies

When Aripiprazole Is Not Suitable

If a second SSRI is preferred over antipsychotic augmentation:

• Sertraline is the recommended choice for SSRI switching or combination, starting at 50 mg daily and titrating to 50-200 mg daily using 1-2 week intervals. 3
• Avoid fluoxetine due to its long half-life requiring 3-4 week intervals between dose adjustments, which delays optimization. 3
• Avoid paroxetine due to higher rates of sexual dysfunction and weight gain. 3

For treatment-resistant cases after SSRI failure:

• Clomipramine augmentation demonstrated superiority to quetiapine augmentation in the only head-to-head trial, though it carries significant drug interaction risks including seizures, arrhythmias, and serotonin syndrome due to elevated blood levels of both medications. 6
• Tricyclic antidepressants (TCAs) show efficacy for global symptom relief (RR 0.67), though they require careful monitoring and are associated with higher withdrawal rates due to adverse effects (RR 2.11). 6

Condition-Specific Considerations

For OCD with inadequate SSRI response:

• Antipsychotic augmentation (risperidone or aripiprazole) has established efficacy, though effect sizes are modest with only one-third achieving clinically meaningful response. 6
• Clomipramine augmentation or switching represents an alternative strategy, with fluoxetine plus clomipramine demonstrating superiority to fluoxetine plus quetiapine. 6

For bipolar depression:

• The combination of olanzapine and fluoxetine is FDA-approved for this specific indication. 6
• SSRIs should only be used with concurrent mood stabilizers due to risk of mood destabilization or manic induction. 6

Critical Safety Warnings

Monitor for serotonin syndrome when combining medications, particularly in the first 24-48 hours after dose changes, watching for mental status changes, neuromuscular hyperactivity, and autonomic instability. 3

Avoid unnecessary polypharmacy—ensure each medication serves a distinct therapeutic purpose rather than adding agents indiscriminately. 6, 3

For patients on tamoxifen for breast cancer, use mild CYP2D6 inhibitors (sertraline, citalopram, escitalopram) rather than potent inhibitors (paroxetine, fluoxetine) to avoid reducing tamoxifen efficacy and increasing recurrence risk. 6