What is the next step in managing an adult patient who has not responded to an adequate ≥6‑week trial of a selective serotonin reuptake inhibitor (SSRI)?

Treatment After SSRI Failure in Depression

Switch to a non-SSRI antidepressant such as bupropion, venlafaxine, or mirtazapine after confirming an adequate trial of at least 6-8 weeks at therapeutic dose. 1

First: Confirm the SSRI Trial Was Adequate

Before making any treatment changes, verify that the patient received:

• Minimum 6-8 weeks at therapeutic dose – this is the threshold to declare true SSRI failure 1
• Adequate dosing – the maximum recommended or tolerated dose must have been achieved, not just the starting dose 1
• Verified adherence – use patient interview and pharmacy refill data to confirm the patient actually took the medication 1

Common pitfall: Many apparent "treatment failures" are actually inadequate trials due to insufficient dose or duration. 1 Do not proceed to next-step treatments until you have documented a proper trial.

Second: Switch to a Different Antidepressant Class

Switching to a non-SSRI antidepressant provides a modest but statistically significant advantage over switching to another SSRI. 1

Recommended Non-SSRI Options:

• Bupropion (sustained or extended release) – particularly advantageous if sexual dysfunction contributed to SSRI discontinuation, as it has lower rates of sexual adverse effects 1
• Venlafaxine (extended release) – an SNRI that targets both serotonergic and noradrenergic systems 1
• Mirtazapine – offers a different mechanism with noradrenergic and specific serotonergic activity 1

Evidence quality: Moderate-quality evidence supports switching to a non-SSRI over switching to another SSRI. 1 The STAR*D trial provides critical guidance for these specific medication choices. 1

Alternative: Switch to Another SSRI

If a non-SSRI is contraindicated or not tolerated, switching to a different SSRI is acceptable, though meta-analyses show no significant difference in response rates when switching between SSRIs versus other antidepressants. 1

Third: Consider Augmentation Instead of Switching

If the patient had partial response (25-50% symptom reduction) rather than complete non-response, augmentation may be preferable:

Augmentation with Bupropion:

• Greater reduction in depression severity compared to buspirone augmentation 1
• Lower discontinuation rates due to adverse events than buspirone 1, 2
• Evidence quality is low, but bupropion shows practical advantages 1

Augmentation with Cognitive Behavioral Therapy:

• Equivalent outcomes to medication switches – no difference in response or remission when switching to CBT versus switching to another antidepressant 1, 2
• Can be combined with medication adjustments for additive benefit 2

Critical Safety Considerations

Never abruptly discontinue the SSRI – taper gradually to avoid SSRI withdrawal syndrome and psychiatric decompensation. 2 When switching between antidepressants (excluding MAOIs), several strategies exist:

• Direct switch – stop the first medication and start the second immediately
• Cross-taper – gradually reduce the first while introducing the second
• Conservative approach – complete taper of the first before starting the second

No single switching strategy has proven superiority over another for non-MAOI switches. 3 Choose based on the specific medications involved and the patient's clinical stability.

MAOI exception: A sufficient washout period (typically 2 weeks for most antidepressants, 5 weeks for fluoxetine) is mandatory when switching to or from an MAOI. 3

Timeline for Assessing the New Treatment

• Initiate monitoring within 1-2 weeks of the medication change 1
• Reassess at 6-8 weeks – if no adequate response by this point, consider it a second treatment failure 1
• Document all trials in the medical record rather than relying on patient recall 1

When Two Adequate Trials Have Failed

After two failed antidepressant trials (each ≥4-6 weeks at adequate dose with different mechanisms of action), the patient meets criteria for treatment-resistant depression (TRD). 1, 2 At this stage:

• Consider specialized treatments beyond standard antidepressant switches 2
• Refer to psychiatry if not already involved
• Evaluate for neuromodulation options (TMS, ECT) or augmentation with atypical antipsychotics 4

Prognostic Factors

Employment status and lower baseline anxiety levels are associated with higher likelihood of remission after the next treatment step. 1 These factors can help set realistic expectations with patients.