What are the treatment options for patients who do not respond to traditional antidepressants, specifically atypical antidepressants like bupropion (Wellbutrin), mirtazapine (Remeron), and trazodone (Oleptro)?

Atypical Antidepressants for Treatment-Resistant Depression

Primary Recommendation

When patients fail to respond to traditional antidepressants (SSRIs/SNRIs), switch to bupropion, mirtazapine, or trazodone as monotherapy alternatives, with selection based on specific symptom profiles and side effect considerations rather than superior efficacy. 1

Evidence for Treatment-Resistant Depression

Efficacy of Switching Strategies

• The landmark STAR*D trial demonstrated that switching to bupropion SR, sertraline, or venlafaxine XR after initial treatment failure resulted in approximately 25% of patients achieving remission, with no significant difference among the three agents. 1

• Second-generation antidepressants show no clinically meaningful differences in efficacy for acute-phase major depressive disorder, though approximately 38% of patients fail to achieve treatment response and 54% fail to achieve remission after 6-8 weeks. 1

Specific Atypical Antidepressants

Bupropion (Wellbutrin)

• Mechanism: Inhibits norepinephrine and dopamine reuptake with no appreciable serotonin activity—the only antidepressant in the U.S. with this profile. 2

• Dosing: Start 37.5 mg every morning, increase by 37.5 mg every 3 days to maximum 150 mg twice daily (immediate-release: 450 mg/day max; sustained-release: 400 mg/day max). 1

• Advantages:

  • Lower rates of sexual dysfunction compared to SSRIs 1
  • Activating properties useful for patients with apathy or low energy 1
  • Produces similar remission rates to SSRIs with median time to relapse of 44 weeks 2
  • 49% response rate in TCA nonresponders in standardized trials 3

• Key Cautions:

  • Most serious risk is seizures—requires gradual titration 2
  • Avoid in agitated patients and those with seizure disorders 1
  • Give second dose before 3 PM to minimize insomnia 1
  • Dose reduction required in renal and hepatic disease 1

Mirtazapine (Remeron)

• Mechanism: Blocks alpha-2 presynaptic adrenoceptors, enhancing norepinephrine and serotonin release; antagonizes 5-HT2, 5-HT3, and H1 receptors. 4, 2

• Dosing: Start 7.5-15 mg at bedtime, titrate to maximum 30-45 mg at bedtime. 1

• Advantages:

  • Fastest onset of action among second-generation antidepressants—statistically significant improvement within 1-2 weeks compared to SSRIs 1, 2
  • After 4 weeks, response rates become similar to other agents 1
  • Promotes sleep and appetite—beneficial for patients with insomnia and weight loss 1, 2
  • Well tolerated with lower rates of gastrointestinal and sexual side effects compared to SSRIs 5

• Key Cautions:

  • Agranulocytosis risk: 2 out of 2,796 patients in premarketing trials developed agranulocytosis; discontinue immediately if sore throat, fever, or infection with low WBC occurs 4
  • Most common side effects: sedation, increased appetite, weight gain (49% of pediatric patients gained ≥7% body weight in 8 weeks) 4, 2
  • Serotonin syndrome risk when combined with other serotonergic agents 4
  • QTc prolongation reported in postmarketing surveillance 4
  • Dose reduction considerations in renal/hepatic impairment 1

Trazodone (Oleptro)

• Mechanism: 5-HT2A and 5-HT2C receptor antagonist with selective serotonin reuptake inhibition. 2

• Dosing: Start 25-50 mg/day, maximum 200-400 mg/day in divided doses (outpatient); hospitalized patients may receive up to 600 mg/day with monitoring. 1

• Advantages:

  • One-third of inpatients and one-half of outpatients respond by end of first week 2
  • Little to no anticholinergic activity compared to tricyclics 1
  • Useful for depression with comorbid insomnia 1

• Key Cautions:

  • Most common adverse effect is drowsiness 2
  • Use with caution in patients with premature ventricular contractions 1
  • Dose reduction required in hepatic disease 1
  • Evidence for efficacy when used alone is relatively weak 1

Treatment Algorithm for Non-Responders

Step 1: Assess Adequate Trial (6-8 Weeks)

• Verify adequate dosage, duration, and adherence before declaring treatment failure 1
• Monitor patient status within 1-2 weeks of initiation and regularly thereafter 1

Step 2: Select Atypical Antidepressant Based on Clinical Profile

For patients with:

• Apathy, low energy, or sexual dysfunction from SSRIs → Bupropion 1
• Insomnia, anxiety, or weight loss → Mirtazapine 1, 2
• Insomnia as primary concern with depression → Trazodone 1

Step 3: Consider Comorbidities

• Depression with comorbid insomnia: Sedating antidepressants (trazodone, mirtazapine) may be considered, though evidence for trazodone alone is weak 1
• Depression with anxiety: No significant differences among second-generation antidepressants 1
• Depression with pain: Limited evidence shows duloxetine and paroxetine have similar efficacy 1

Critical Monitoring Requirements

Mirtazapine-Specific Monitoring

• Monitor for signs of infection (sore throat, fever, stomatitis) with WBC count if infection suspected—discontinue immediately if agranulocytosis develops 4
• Monitor weight and appetite regularly 4
• Watch for serotonin syndrome symptoms if combined with other serotonergic drugs 4

All Atypical Antidepressants

• Monitor for suicidal thoughts/behaviors, especially in patients <24 years old, during initial months and at dose changes 4
• Assess therapeutic response and adverse effects regularly beginning 1-2 weeks after initiation 1

Duration of Treatment

• Continue treatment 4-9 months after satisfactory response for first episode of major depressive disorder 1
• For patients with ≥2 episodes, longer duration (potentially indefinite) may be beneficial 1
• Antidepressant continuation reduces relapse risk based on meta-analysis of 31 trials 1

Common Pitfalls to Avoid

• Do not use low-dose sedating antidepressants (including trazodone, mirtazapine) as adequate monotherapy for major depression with comorbid insomnia—they require full antidepressant dosing 1
• Avoid paroxetine and fluoxetine in older adults due to anticholinergic effects and agitation risk, respectively 1
• Do not combine mirtazapine with MAOIs or initiate within 14 days of MAOI discontinuation due to serotonin syndrome risk 4
• Recognize that sedation with mirtazapine is paradoxically more common at subtherapeutic doses (<15 mg) 5