Add-On Medication Options for SSRI-Resistant Depression
For patients with treatment-resistant depression who have failed an adequate SSRI trial (6-8 weeks at therapeutic doses), the most effective first-line augmentation strategies are aripiprazole or quetiapine, which offer relatively rapid onset of action and superior outcomes compared to switching to another SSRI alone. 1
Confirming Treatment Resistance
Before initiating augmentation therapy, confirm the patient has received an adequate trial:
- Duration: At least 6-8 weeks of continuous SSRI therapy 2
- Dosing: Therapeutic doses (e.g., sertraline 50-200 mg/day) 1
- Adherence: Verify medication compliance and rule out other factors contributing to poor response 3
First-Line Augmentation Strategies
Atypical Antipsychotics (Preferred Pharmacologic Option)
Aripiprazole and quetiapine are the most evidence-based augmentation agents, with FDA approval for treatment-resistant depression 4, 5:
- Efficacy: Approximately one-third of SSRI-resistant patients achieve clinically meaningful response 6
- Approved agents: Aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination 4
- Onset: Relatively rapid compared to other strategies 1
Critical monitoring requirements:
- Weight gain and metabolic parameters (glucose, lipids) must be monitored regularly 1, 6
- Risk of akathisia and tardive dyskinesia 4
- Ongoing risk-benefit assessment is essential given the moderate effect size 6
Cognitive Behavioral Therapy (CBT) Augmentation
Adding CBT to SSRI therapy produces effect sizes larger than antipsychotic augmentation and may provide more sustainable long-term outcomes 1, 6:
- Superior to risperidone augmentation in head-to-head comparison 6
- Should be prioritized when available and patient is willing 1
Alternative Augmentation Options
Other Antidepressants
Combining antidepressants with different mechanisms is an effective strategy 7, 5:
- Bupropion + SSRI: Well-studied combination 7, 5
- Mirtazapine + venlafaxine: Evidence-supported combination 7
- Tricyclic antidepressants: Can be added to SSRIs 5
Additional Augmentation Agents
When first-line options fail or are not tolerated 5:
- Lithium: Established augmentation agent 5
- Liothyronine (T3): Effective thyroid hormone augmentation 5
- Lamotrigine: Demonstrated efficacy 5
- Buspirone: Alternative option 6
Switching Strategies
If augmentation is unsuccessful or not tolerated, switching to a non-SSRI antidepressant is superior to switching to another SSRI 1, 8:
- Remission rates: 28% with non-SSRI switch vs. 23.5% with SSRI switch 8
- Preferred alternatives: Venlafaxine, duloxetine (SNRIs), bupropion, or mirtazapine 1, 8
- The advantage is modest (NNT = 22) but statistically significant 8
Treatment Duration
Once satisfactory response is achieved with augmentation:
- First episode: Continue for 4-9 months 2, 1
- Recurrent depression (≥2 episodes): Longer duration (years to lifelong) may be beneficial 2, 1
Common Pitfalls to Avoid
- Premature switching: Ensure adequate trial duration (6-8 weeks) before declaring treatment failure 2
- Inadequate dosing: Verify therapeutic doses were achieved 1
- Neglecting metabolic monitoring: Atypical antipsychotics require ongoing surveillance for weight gain and metabolic dysregulation 1, 6
- Ignoring CBT: When available, CBT augmentation may be preferable to medication augmentation alone 1, 6
budget:budget_used