What are the next treatment options for a patient with depression who has not responded to Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and Selective Serotonin Reuptake Inhibitors (SSRIs)?

Treatment Options for SSRI/SNRI-Resistant Depression

Switch to bupropion, mirtazapine, or another second-generation antidepressant from a different class, as approximately 25% of patients achieve remission with this strategy. 1

Evidence for Switching Strategies

The landmark STAR*D trial provides the strongest evidence for treatment-resistant depression management 1:

• One in four patients (25%) became symptom-free after switching from a failed SSRI/SNRI to an alternative second-generation antidepressant 1
• Sustained-release bupropion, sertraline, and extended-release venlafaxine showed no significant differences in efficacy when used as switch agents 1
• Since the patient has already tried both SSRIs and SNRIs, switching to bupropion (a norepinephrine-dopamine reuptake inhibitor) represents a mechanistically distinct option 1

Specific Switching Options

First-Line Switch Strategy

• Bupropion sustained-release 300 mg daily is a reasonable choice given its different mechanism of action (dopamine/norepinephrine reuptake inhibition) 1, 2
• Mirtazapine 15-30 mg daily offers faster onset of action than SSRIs (though response rates equalize after 4 weeks) and works through alpha-2 antagonism 1
• Both options have demonstrated 60-70% response rates in SSRI-resistant patients 2

Alternative Considerations

• Duloxetine (an SNRI) may still be considered if the prior SNRI trial was inadequate, though this represents less mechanistic diversity 2
• Tricyclic antidepressants remain an option but are used less commonly due to higher toxicity in overdose 1

Augmentation vs. Switching

While combination therapy is widely used in practice, the evidence does not strongly support adding mirtazapine to existing SSRI/SNRI therapy 3:

• A large RCT found only a -1.83 point difference on BDI-II scores (not clinically meaningful) when mirtazapine was added to ongoing SSRI/SNRI treatment 3
• More participants withdrew due to adverse effects with combination therapy (46 vs. 9) 3
• Switching rather than augmenting is the better-supported strategy based on current evidence 1, 3

Critical Implementation Details

Switching Technique

Multiple switching strategies exist with no proven superiority of one over another 4:

• Direct switch: Stop first antidepressant and immediately start new one (acceptable for most switches between SSRIs, SNRIs, and other second-generation agents) 4
• Crossover approach: Gradually taper first while titrating second 4
• Washout period is mandatory only when switching to/from MAOIs (14-day minimum) 5, 4

Dosing and Duration

• Titrate to maximum recommended or tolerated dose 1
• Allow at least 6-8 weeks at therapeutic dose before declaring treatment failure 1
• For bupropion: 300 mg daily extended-release 2
• For mirtazapine: Start 15 mg, increase to 30 mg after 2 weeks 5, 3

Monitoring Requirements

Assess response within 1-2 weeks of initiation and regularly thereafter 1:

• Monitor for suicidal ideation, especially in patients under age 25 5
• Watch for serotonin syndrome if any serotonergic agents are combined 5
• For mirtazapine specifically: monitor for agranulocytosis (fever, sore throat, infection) 5

Important Caveats

• 38% of patients do not respond to any single second-generation antidepressant, and 54% do not achieve remission 1
• If switching fails, consider referral for psychotherapy (CBT), augmentation with atypical antipsychotics, or other specialized interventions 1
• Avoid premature switching: Ensure adequate dose and duration (6-8 weeks) of current medication before declaring failure 1
• Selection should account for adverse effect profiles: bupropion has lower sexual dysfunction rates than SSRIs; mirtazapine causes more sedation and weight gain 1