What is the best treatment approach for a patient with depression, generalized anxiety disorder, prediabetes, hyperlipidemia, and insomnia who previously responded to Wellbutrin (bupropion) but was switched to mirtazapine due to insomnia and now seeks an alternative?

Optimal Antidepressant Strategy for Treatment-Resistant Depression with Comorbid Anxiety and Insomnia

Direct Recommendation

Restart bupropion (Wellbutrin) sustained-release at 150 mg daily, titrating to 300 mg daily after one week, and add an SSRI (preferably sertraline 50-200 mg daily) to address both depression and generalized anxiety disorder. 1 For persistent insomnia, use low-dose trazodone 25-100 mg at bedtime as needed rather than relying on the antidepressant alone for sleep. 1

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Clinical Reasoning

Why Return to Bupropion

• The patient explicitly states bupropion "worked better" for his depression, which represents a documented prior treatment response—the single most important predictor of future response. 1

• The STAR*D trial (the highest-quality evidence for treatment-resistant depression) demonstrated that switching to bupropion SR, sertraline, or venlafaxine XR after initial treatment failure resulted in 25% achieving symptom-free status, with no significant differences among these three agents. 1

• Bupropion has distinct advantages for this patient's comorbidity profile: it causes significantly less sexual dysfunction than SSRIs 1, has no weight gain (critical given prediabetes) 2, 3, and does not worsen metabolic parameters 4, 2

Why Mirtazapine Failed and Should Not Be Restarted

• Mirtazapine was chosen primarily for insomnia, not depression efficacy, which represents treating a symptom rather than the underlying disorder. 1

• While mirtazapine has faster onset of action (1-2 weeks) compared to SSRIs 1, this advantage is irrelevant when the patient reports it "has not helped" after adequate trial duration.

• Mirtazapine causes significant weight gain and increased appetite 1, 4, 5, which is particularly problematic in a patient with prediabetes and hyperlipidemia.

• The American Heart Association guidelines note mirtazapine's safety in cardiovascular disease but acknowledge its efficacy in treating depression has not been adequately assessed in patients with comorbidities. 1

Addressing Generalized Anxiety Disorder

• Bupropion alone showed similar antidepressive efficacy to SSRIs in patients with comorbid depression and anxiety 1, but SSRIs remain first-line for generalized anxiety disorder.

• Adding an SSRI to bupropion provides complementary mechanisms: bupropion enhances dopamine and norepinephrine without serotonergic effects 4, 2, while SSRIs address the serotonergic component critical for anxiety management 1

• Sertraline is preferred among SSRIs because it has been extensively studied in patients with cardiovascular risk factors (relevant given hyperlipidemia), has lower QTc prolongation risk than citalopram/escitalopram 1, and demonstrated efficacy for both depression and anxiety 1

Managing Insomnia Appropriately

• Insomnia should not drive primary antidepressant selection—this is a common clinical pitfall that leads to suboptimal depression treatment. 1

• Cognitive behavioral therapy for insomnia is first-line treatment 1, but when pharmacotherapy is needed, trazodone 25-100 mg at bedtime or low-dose mirtazapine (15 mg) can be added specifically for sleep 1 rather than using a sedating antidepressant as monotherapy.

• The insomnia guideline explicitly states that sedating low-dose antidepressants (trazodone, mirtazapine) may be considered for insomnia, but evidence for efficacy when used alone is relatively weak. 1

• Benzodiazepines should be avoided given the patient's age and potential cognitive effects 1, and zolpidem requires caution due to next-morning impairment risk 1

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Specific Treatment Algorithm

Step 1: Restart Bupropion (Week 1-2)

• Start bupropion SR 150 mg once daily in the morning 6
• After 4-7 days, increase to 300 mg once daily 6
• Maximum dose is 300 mg daily for extended-release formulation to minimize seizure risk (0.1% at recommended doses) 6
• Monitor for insomnia, agitation, headache, dry mouth 6, 7

Step 2: Add SSRI for Anxiety (Week 2-3)

• Initiate sertraline 50 mg daily, can increase to 100-200 mg daily based on response 1
• Alternative: escitalopram 10-20 mg daily if sertraline not tolerated 1
• Monitor for serotonin syndrome when combining with bupropion, though risk is low given bupropion's minimal serotonergic activity 4, 2

Step 3: Address Insomnia Separately (As Needed)

• If insomnia persists after 2 weeks of antidepressant optimization, add trazodone 25-50 mg at bedtime, can increase to 100 mg 1
• Alternative: mirtazapine 7.5-15 mg at bedtime (lower doses are more sedating) 1, 5
• Avoid using the antidepressant dose of mirtazapine (30-45 mg) as this patient already failed this approach 1, 4, 5

Step 4: Monitoring Schedule

• Assess within 1-2 weeks of initiation for suicidality, agitation, and adverse effects 1, 6
• Evaluate therapeutic response at 6-8 weeks; if inadequate, modify treatment 1
• Monitor blood pressure (bupropion can cause mild increases), blood glucose (given prediabetes), and lipid panel 1, 6

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Critical Caveats

Seizure Risk with Bupropion

• Absolute contraindications: seizure disorder, eating disorders (anorexia/bulimia), abrupt alcohol/benzodiazepine discontinuation 6
• Relative contraindications requiring caution: diabetes treated with insulin/oral agents, head injury history, CNS tumor 6
• Never exceed 300 mg daily of extended-release formulation—seizure risk increases nearly tenfold at 450-600 mg daily 6

Drug Interactions

• Bupropion is metabolized by CYP2B6 and inhibits CYP2D6 4, 2
• Allow 14 days between discontinuing MAOIs and starting bupropion 6
• Monitor for increased side effects if patient takes other medications metabolized by CYP2D6 4, 2

Metabolic Considerations

• Bupropion does not worsen glycemic control or lipid profiles, making it ideal for patients with prediabetes and hyperlipidemia 4, 2, 3
• SSRIs are metabolically neutral 1
• Avoid mirtazapine long-term in this patient due to weight gain and transient cholesterol elevations 4, 5

When This Strategy Fails

• If no response after 6-8 weeks of optimized combination therapy, consider switching to venlafaxine XR (which showed superiority in some treatment-resistant depression studies) 1 or augmentation with buspirone for anxiety 1
• Do not continue ineffective treatment beyond 8 weeks—this is a strong recommendation from the American College of Physicians 1