What additional treatment can be added to mirtazapine for a 24‑year‑old with severe major depressive disorder, suicidal ideation, failure to thrive, and irritability?

Augmentation Strategy for Severe Depression with Suicidal Ideation on Mirtazapine

Add bupropion SR 150–400 mg daily to the existing mirtazapine regimen, as this combination provides complementary mechanisms (norepinephrine-dopamine reuptake inhibition plus enhanced noradrenergic/serotonergic neurotransmission) and has demonstrated efficacy in treatment-resistant depression with significantly lower discontinuation rates than buspirone augmentation. 1

Immediate Safety Considerations

• Assess suicidal ideation at every contact during the first 1–2 months, as suicide risk is greatest during initial treatment periods and after medication changes 1
• Monitor specifically for behavioral activation (agitation, impulsiveness, disinhibited behavior) within the first 24–48 hours after starting bupropion, particularly given the patient's irritability 2
• Do not prescribe bupropion if the patient has a seizure disorder, eating disorder, or is currently highly agitated, as these are absolute contraindications 2

Primary Augmentation Strategy: Bupropion SR

Rationale

• The STAR*D trial demonstrated that bupropion augmentation achieved similar remission rates to buspirone (approximately 30%) but with significantly lower discontinuation due to adverse events (12.5% vs. 20.6%, p<0.001) 1
• Bupropion's activating properties specifically target low motivation and energy deficits that often persist despite mirtazapine therapy 2
• The combination provides synergistic mechanisms: mirtazapine enhances noradrenergic and serotonergic neurotransmission via alpha-2 blockade, while bupropion inhibits norepinephrine-dopamine reuptake 3, 2

Dosing Protocol

• Start bupropion SR at 150 mg once daily (given in the morning to minimize insomnia risk) 2
• Increase by 150 mg every 3–7 days as tolerated, targeting a total daily dose of 300–400 mg given in divided doses 2
• Administer the second dose before 3 p.m. to reduce insomnia risk 2
• Allow 6–8 weeks at the optimized dose before declaring treatment failure 1

Alternative Augmentation: Cognitive-Behavioral Therapy

• Add individual CBT immediately while optimizing medication, as combination therapy demonstrates superior efficacy compared to medication alone for depression 1
• CBT provides synergistic benefit and can be initiated without waiting for medication optimization 1
• This is particularly important given the patient's suicidal ideation and failure to thrive, as CBT addresses both neurobiological and psychological components 2

If Bupropion Is Contraindicated

• Aripiprazole augmentation is the next evidence-based option when bupropion cannot be used due to seizure disorders or eating disorders 2
• One trial showed higher remission rates with aripiprazole augmentation (55.4%) compared to bupropion (34.0%, p=0.031), though this was a high risk-of-bias study 1

Switching Strategy (If Augmentation Fails)

• Switch to venlafaxine 150–225 mg daily or duloxetine 40–120 mg daily if augmentation does not produce adequate response after 8 weeks 1, 2
• SNRIs demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression 1, 2
• The American College of Physicians found no significant difference between switching versus augmenting strategies overall, with approximately 25% of patients achieving remission after a switch 1

Monitoring Protocol

• Evaluate treatment response every 2–4 weeks using standardized depression rating scales (PHQ-9 or HAM-D) to objectively track symptoms 1, 2
• Contact the patient within 1 week of initiating bupropion to evaluate adherence, tolerability, and early adverse events 2
• Reassess depressive symptom response 6–8 weeks after reaching the target bupropion dose before declaring treatment failure 1

Common Pitfalls to Avoid

• Do not switch medications before allowing adequate trial duration (6–8 weeks at therapeutic dose), as this delays recovery and misses opportunities for response 1
• Do not combine mirtazapine with other serotonergic agents (SSRIs, MAOIs) due to serotonin syndrome risk 2
• Do not exceed recommended bupropion doses or administer late in the day, as this increases seizure risk and insomnia 2
• Do not continue ineffective treatment beyond 8 weeks, as guideline-recommended reassessment occurs at 6–8 weeks 1, 2

Duration of Continuation Therapy

• Continue treatment for 4–9 months after achieving satisfactory response for a first episode of major depressive disorder 1
• For patients with recurrent depression (≥2 episodes), consider maintenance therapy for years to lifelong to prevent relapse 1, 2

Mirtazapine-Specific Considerations

• Mirtazapine has demonstrated rapid onset of action compared to SSRIs, with superiority at weeks 1–4 in some trials 4, 5
• Common side effects include somnolence, weight gain, and increased appetite, which may actually benefit patients with failure to thrive 3, 6
• Mirtazapine's anxiolytic and sleep-improving effects make it particularly suitable for patients with anxiety/agitation symptoms 3, 4
• The drug has minimal drug-drug interactions via CYP450 enzymes, making it safe for combination therapy 3, 4