What is the next step for a patient with depression who does not respond to two different Selective Serotonin Reuptake Inhibitors (SSRIs) according to the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines?

Treatment After Two Failed SSRIs in Major Depression

After failure of two SSRIs, switch to a non-SSRI antidepressant (venlafaxine, bupropion, or mirtazapine) rather than trying a third SSRI. 1

Evidence-Based Rationale

The most recent guideline evidence from the American College of Physicians (2023) indicates that for second-step therapies after initial SSRI failure, different switching and augmentation strategies provide similar symptomatic relief, though the certainty of evidence is low. 1 However, when examining the specific question of switching strategies, meta-analytic evidence demonstrates a modest but statistically significant advantage for switching to a different class.

Switching to Non-SSRI Antidepressants

Patients switched to non-SSRI antidepressants (bupropion, mirtazapine, or venlafaxine) achieve higher remission rates than those switched to a second SSRI:

• Remission rate with non-SSRIs: 28% 2
• Remission rate with second SSRI: 23.5% 2
• Risk ratio for remission: 1.29 (p = 0.007) 2
• Number needed to treat = 22 to obtain one additional remitter 2

Specific Medication Options After Two SSRI Failures

The STAR*D trial, the largest real-world study of treatment-resistant depression, provides critical guidance: 3

• Bupropion sustained release 1, 3
• Venlafaxine extended release 1, 2, 3
• Sertraline (if switching within SSRI class) 1, 3

All three options showed comparable outcomes in head-to-head comparison, with approximately 21% achieving remission and 9% achieving response without remission. 3

Expected Outcomes and Trial Duration

Critical timing considerations:

• Only 21% of patients remit with a second-step switch to another monoaminergic antidepressant 3
• 58% experience no meaningful clinical benefit 3
• Half of responses and two-thirds of remissions occur after 6 weeks of treatment 3
• One-third of responses occur after ≥9 weeks of treatment 3
• A 12-week trial duration is necessary to capture maximum responders 3

Early Triage Indicator

Patients with ≥20% reduction in depressive symptoms by week 2 are 6 times more likely to ultimately respond or remit than those without this early improvement. 3 This provides a useful clinical marker for deciding whether to continue the current medication or consider alternative strategies.

Alternative Strategies: Augmentation vs. Switching

While the question specifically asks about next steps after two SSRI failures, the evidence shows that both augmentation and switching strategies provide similar symptomatic relief in treatment-resistant depression. 1

Common Pitfalls to Avoid

• Inadequate trial duration: Many clinicians switch too early; ensure at least 6-8 weeks at therapeutic dose before declaring treatment failure 1
• Inadequate dosing: Verify maximum recommended or tolerated dose was achieved 1
• Trying a third SSRI: The evidence favors switching to a different mechanism of action after two SSRI failures 2
• Premature discontinuation: Continue monitoring through 12 weeks to capture late responders 3

Adverse Effect Considerations

Bupropion has lower rates of sexual adverse effects compared to SSRIs (fluoxetine, sertraline, paroxetine), making it particularly advantageous when sexual dysfunction contributed to previous SSRI failures. 1

Dropout rates due to side effects vary considerably (5%-39%) across different agents, requiring individualized assessment of tolerability profiles. 4

Treatment Resistance and Prognosis

The number of previous antidepressant failures negatively correlates with treatment outcome. 4 After two SSRI failures, patients are entering a more treatment-resistant phase where response rates decline significantly, emphasizing the importance of optimizing each treatment trial before switching.