What are the adjunctive therapy options for patients with depression who have not responded to Selective Serotonin Reuptake Inhibitors (SSRIs)?

Adjunctive Therapy Options for SSRI-Resistant Depression

Primary Recommendation

After inadequate response to SSRIs within 6-8 weeks, clinicians should either switch to a non-SSRI antidepressant (bupropion, mirtazapine, or venlafaxine) or augment with an atypical antipsychotic, as both strategies provide similar symptomatic relief. 1

Treatment Algorithm for SSRI Non-Response

Step 1: Verify Adequate SSRI Trial

• Ensure at least 6-8 weeks at therapeutic dose before declaring treatment failure 1, 2
• Confirm maximum recommended or tolerated dose was achieved 2
• Assess adherence and monitor for worsening symptoms beginning 1-2 weeks after any medication change 1

Step 2: Choose Second-Step Strategy

Switching to Non-SSRI Antidepressants (Preferred after two SSRI failures):

• Bupropion sustained release provides modest advantage when switching to a different antidepressant class and has significantly lower rates of sexual adverse effects compared to SSRIs 2, 3
• Venlafaxine extended release is another evidence-based option based on STAR*D trial data 2
• Mirtazapine can be considered as an alternative non-SSRI option 1

Augmentation with Atypical Antipsychotics:

• All standard-dose atypical antipsychotics show significant efficacy over placebo (standardized mean differences ranging from -0.27 to -0.43) 3
• Aripiprazole demonstrates benefits in reducing depressive symptoms and improving quality of life, with response rates of 50% in treatment-resistant cases 3, 4
• Risperidone shows superior benefits for quality of life/functioning compared to other atypicals 3
• Quetiapine (mean 250-350 mg daily) is effective but has higher all-cause discontinuation rates 3

Critical Considerations for Atypical Antipsychotic Augmentation

When to Consider Antipsychotic Augmentation

• Reserve for true treatment-resistant depression (failure of adequate trials of multiple antidepressants) rather than simple inadequate response 5
• Consider specifically for patients with severe ruminations, melancholia, or major sleep disturbance that respond well to antipsychotics 5
• Use short-term only; there is no support for long-term use 5

Tolerability Profile

• All standard-dose atypical antipsychotics except risperidone have significantly more side-effect discontinuations than placebo (odds ratios 2.72 to 6.40) 3
• Monitor for akathisia, weight gain, metabolic disturbances, and sedation 3, 6
• Low-dose strategies (aripiprazole 2.5-10 mg/day) may improve tolerability while maintaining efficacy 6

Common Pitfalls to Avoid

• Inadequate trial duration: Most patients require 6-8 weeks at therapeutic dose; 38% do not achieve response and 54% do not achieve remission during this timeframe 1
• Premature polypharmacy: Verify adequate dosing and duration before adding agents 2
• Ignoring sexual dysfunction: Bupropion is particularly advantageous when sexual adverse effects contributed to previous SSRI failures 2, 3
• Long-term antipsychotic use without reassessment: Antipsychotics should be used short-term and discontinued if no benefit is observed 5

Monitoring Requirements

• Assess therapeutic response and adverse effects regularly, beginning 1-2 weeks after initiation or modification 1
• Monitor for suicidal ideation intensively during first 1-2 months, as risk for suicide attempts is greater during this period 1
• For antipsychotic augmentation, monitor weight, metabolic parameters, and extrapyramidal symptoms 3

Duration of Successful Treatment

• Continue treatment for 4-9 months after satisfactory response in first-episode depression 1
• For patients with two or more depressive episodes, longer duration (years to lifelong) may be beneficial 1