How many Selective Serotonin Reuptake Inhibitor (SSRI) trials are recommended before switching to a different antidepressant?

How Many SSRI Trials Before Switching?

After failure of one adequate SSRI trial (at maximum tolerated dose for 8-12 weeks), you should consider switching to a different antidepressant or augmentation strategy. 1

Defining an Adequate SSRI Trial

Before considering a switch, ensure the initial SSRI trial meets these criteria:

• Duration: Minimum 8-12 weeks at therapeutic dose 1, 2
• Dosing: Maximum tolerated or recommended dose achieved 1
• Response threshold: Less than 25% improvement in depressive symptoms defines treatment resistance 1
• Adherence: Documented compliance with the medication regimen (ideally confirmed through pharmacy records or clinical documentation) 1

The Evidence for Switching After One Failed SSRI

The landmark STAR*D trial provides the clearest guidance: after citalopram failure, switching to a second antidepressant (bupropion SR, sertraline, or venlafaxine ER) resulted in only 21% remission and 9% response without remission, with 58% showing no meaningful benefit. 3 This means that while switching is reasonable after one failed SSRI, expectations should be modest—only about 1 in 5 patients will achieve remission with a second antidepressant. 3

Within-Class vs. Between-Class Switching

There is no compelling evidence that switching between antidepressant classes is superior to switching within the SSRI class. 1, 4, 5

• Moderate-quality evidence from STAR*D showed no difference in response when switching from citalopram to bupropion vs. sertraline vs. venlafaxine 1
• A meta-analysis found only a modest and clinically equivocal benefit for switching to venlafaxine over another SSRI (number needed to treat = 13) 4
• For mild-to-moderate depression, switching within the SSRI class is reasonable; for severe depression or melancholia, consider switching out-of-class 6

Critical Timing Considerations

Most patients who will respond to a second antidepressant do so within 6 weeks, but one-third of responses occur after 9 weeks of treatment. 3 This means:

• Assess response at 2 weeks: patients with at least 20% symptom reduction are 6 times more likely to ultimately respond or remit 3
• If minimal improvement by 6 weeks, consider changing strategy rather than waiting longer 3
• A 12-week trial duration is necessary to capture the maximum number of responders 3

Alternative to Switching: Augmentation

Adding cognitive behavioral therapy (CBT) to the existing antidepressant may be more effective than switching medications alone. 1

• Low-quality evidence showed no difference between switching to another antidepressant vs. switching to CBT alone 1
• Augmenting with CBT plus medication switch resulted in 54.8% response vs. 40.5% for medication switch alone in adolescents (P = .009) 7
• Augmenting citalopram with bupropion showed similar efficacy to augmenting with buspirone or CBT 1

Common Pitfalls to Avoid

• Don't switch prematurely: Ensure the first SSRI received an adequate 8-12 week trial at maximum tolerated dose 1
• Don't assume between-class switching is superior: Evidence does not support this common clinical assumption 4, 5
• Don't continue ineffective treatment indefinitely: If there's less than 20% improvement by week 2, the likelihood of eventual response is low 3
• Don't forget to document adherence: Many apparent "treatment failures" are actually non-adherence 1

Special Consideration: Treatment-Resistant Depression Definition

For clinical trial purposes and regulatory definitions, treatment-resistant depression (TRD) requires a minimum of two failed treatments with less than 25% improvement, while partial response depression (PRD) can be defined after a single treatment with 25-50% improvement. 1 However, both treatment failures should occur within the current episode, and for long episodes, only failures within the last two years should be considered. 1