In a patient with major depressive disorder who has not shown clinical improvement after an adequate trial of a selective serotonin reuptake inhibitor, what is the next step in management?

Management of SSRI Non-Response in Major Depressive Disorder

If a patient with major depressive disorder has not responded adequately to an SSRI after 6-8 weeks at therapeutic dose, clinicians should modify treatment by either switching to a different antidepressant class (particularly bupropion, venlafaxine, or mirtazapine) or augmenting with another agent. 1, 2

First: Confirm Adequate Treatment Trial

Before declaring treatment failure, verify the following critical elements:

• Duration: At least 6-8 weeks of treatment at therapeutic dose 1, 2
• Dosing: Maximum recommended or tolerated dose was achieved 2
• Adherence: Confirm medication compliance through patient history and, ideally, pharmacy records 1
• Diagnosis: Exclude bipolar disorder, active substance use disorder, or personality disorders that may complicate treatment 1

Common pitfall: Many apparent "treatment failures" are actually inadequate trials due to insufficient duration or subtherapeutic dosing. 2

Switching Strategies After SSRI Failure

Switch to Non-SSRI Antidepressant (Preferred After Single SSRI Failure)

The American College of Physicians recommends switching to a non-SSRI antidepressant, as this provides a modest but statistically significant advantage over switching to another SSRI. 2

Specific medication options based on STAR*D trial evidence:

• Bupropion sustained-release: Particularly advantageous when sexual dysfunction contributed to SSRI failure, as it has lower rates of sexual adverse effects 2
• Venlafaxine extended-release: Showed modest benefit over SSRIs in pooled analyses (NNT=13) 2, 3
• Mirtazapine: Another evidence-based option for switching 2

Switch to Another SSRI (Alternative Strategy)

• Moderate-quality evidence shows no significant difference in response rates when switching between SSRIs (bupropion vs. sertraline vs. venlafaxine) 1
• However, switching to another SSRI may still be reasonable, with response rates of 12-86% reported in open studies 3
• Preliminary evidence suggests approximately 50% of patients may respond to a second SSRI after first SSRI failure 4

Augmentation Strategies

Augmentation with Another Antidepressant

• Bupropion augmentation: Low-quality evidence shows no difference in response/remission compared to buspirone augmentation, but bupropion decreases depression severity more 1
• Augmentation with bupropion has lower discontinuation rates due to adverse events compared to buspirone 1

Augmentation with Aripiprazole

• Aripiprazole is FDA-approved as adjunctive therapy for treatment-resistant depression 5
• Specific indication: Consider particularly in patients ≥65 years old, where augmentation with aripiprazole was more effective than switching to bupropion 6
• Also more effective in patients with severe mixed hypomanic symptoms 6

Cognitive Therapy as Alternative

• Low-quality evidence shows no difference between switching to cognitive therapy versus switching to another antidepressant 1
• This represents a viable non-pharmacologic option when appropriate 1

Assessment Timeline

Begin monitoring within 1-2 weeks of any treatment modification and reassess therapeutic response regularly. 1

• If no adequate response after 6-8 weeks of the new strategy, consider this a second treatment failure 1
• After two SSRI failures with different mechanisms of action, the patient meets criteria for treatment-resistant depression (TRD) 1

Critical Considerations for Treatment-Resistant Depression

After two failed antidepressant trials (each ≥4 weeks at adequate dose with different mechanisms of action), the patient has TRD: 1

• Both failures should be within the current episode and within the past two years 1
• Document treatment failures with medical records, not just patient recall 1
• Consider more intensive interventions such as vagus nerve stimulation for severe TRD 5

Prognostic Factors

Patients more likely to achieve remission with next-step treatment: 6

• Employed status
• Less severe and chronic depression
• Lower anxiety levels
• Absence of complicated grief symptoms
• No childhood adversity
• Better baseline quality of life

The number of previous antidepressant failures negatively correlates with treatment outcome—earlier intervention changes improve success rates. 3