What are the best combination strategies for an adult patient with depression who has not responded to initial psychotropic medication treatment, assuming no significant comorbidities or contraindications?

Best Combination Strategies for Treatment-Resistant Depression

Initial Verification Before Augmentation

Before initiating any combination strategy, confirm the patient has received an adequate trial: minimum 6-8 weeks at therapeutic doses (e.g., sertraline 50-200 mg/day). 1

First-Line Augmentation Strategies

Add either an atypical antipsychotic (aripiprazole 2-15 mg daily or quetiapine 150-300 mg daily) or Cognitive Behavioral Therapy (CBT) to the existing antidepressant—both strategies show comparable efficacy for symptom reduction. 1, 2

Atypical Antipsychotic Augmentation

• Aripiprazole (2-15 mg daily) or quetiapine (150-300 mg daily) provide relatively rapid onset of action and superior symptom reduction compared to switching antidepressants alone. 1, 2
• Monitor closely for metabolic adverse effects including weight gain, lipid abnormalities, and glucose dysregulation. 1
• Moderate-quality evidence shows higher dropout rates with atypical antipsychotics compared to other strategies, primarily due to adverse effects. 2

CBT Augmentation

• Adding CBT to ongoing antidepressant therapy produces similar short-term benefits to medication augmentation but may provide more sustainable long-term outcomes. 1, 3
• Moderate-quality evidence demonstrates improvement of -4.07 points on the Beck Depression Inventory when CBT is added to usual care with antidepressants. 3
• CBT augmentation shows benefits extending to medium-term (12 months: -3.40 points on BDI) and long-term (46 months: -1.90 points on BDI). 3
• CBT added to antidepressants increases remission rates (RR 1.92) and response rates (RR 1.80) over the short term. 3

Second-Line Augmentation: Bupropion

If first-line augmentation fails or is not tolerated, add bupropion (150-300 mg daily) to the existing SSRI. 2

• Moderate-quality evidence shows bupropion augmentation decreases depression severity more than buspirone augmentation. 4, 2
• Bupropion has lower discontinuation rates due to adverse events compared to buspirone (moderate-quality evidence). 4, 2
• Bupropion can be used either as augmentation or as a switch agent, with no significant difference in response rates when switching between second-generation antidepressants. 2

Switching Strategies (Alternative to Augmentation)

If augmentation is unsuccessful or not tolerated, switch to a different antidepressant class: venlafaxine (75-225 mg daily) for patients with prominent anxiety, or mirtazapine (15-45 mg at bedtime) for patients with anxiety plus insomnia. 2

• Moderate-quality evidence shows no significant difference in response or remission when switching between different second-generation antidepressants (bupropion vs. sertraline vs. venlafaxine). 4
• Low-quality evidence shows no difference between switching to another antidepressant versus switching to cognitive therapy. 4, 2

Novel Pharmacological Options for Highly Refractory Cases

Reserve ketamine or intranasal esketamine for patients who have failed multiple (≥3) adequate pharmacologic trials. 2

• Esketamine (intranasal) with twice-weekly dosing improves depressive symptoms and remission rates up to 28 days when added to ongoing antidepressant treatment. 2
• Ketamine shows improvement in depressive symptoms for up to 7 days when added to ongoing antidepressant therapy. 2

Treatment Duration and Maintenance

Continue the augmentation strategy for at least 4-9 months after achieving satisfactory response. 1

• For patients with recurrent depression (≥2 episodes), longer treatment duration is beneficial. 1
• High-quality evidence shows no difference in dropout rates (acceptability) between augmentation strategies and usual care alone over the short term (RR 0.85). 3

Critical Monitoring Points

• Verify each previous antidepressant was tried at therapeutic doses for minimum 4 weeks at a licensed dosage before declaring treatment failure. 2
• Investigate adherence, missed diagnosis of psychotic depression, bipolar disorder, or comorbid anxiety as reasons for treatment failure before proceeding with augmentation. 5
• Economic analysis from UK NHS perspective reveals that adjunctive CBT is cost-effective over nearly four years. 3

Common Pitfalls to Avoid

• Do not prematurely declare treatment failure—ensure adequate dose and duration (6-8 weeks minimum) before augmenting. 1
• Do not overlook non-pharmacologic options—CBT augmentation provides comparable efficacy to medication augmentation with potentially more durable effects. 1, 3
• Do not ignore metabolic monitoring—atypical antipsychotics require vigilant monitoring for weight gain, lipid changes, and glucose abnormalities. 1