What is the safest next pharmacologic step for a patient whose anxiety worsened on bupropion (Wellbutrin) and who is experiencing marked nausea on sertraline?

Switching to Mirtazapine for Anxiety Worsened by Bupropion and Nausea from Sertraline

Switch to mirtazapine 15 mg at bedtime, which addresses both the anxiety exacerbation and nausea intolerance while offering faster onset of antidepressant action than SSRIs.

Rationale for Mirtazapine Selection

Mirtazapine is the optimal choice because it has a significantly faster onset of action than sertraline, paroxetine, or fluoxetine, and causes less nausea than venlafaxine or SSRIs. 1 The evidence shows mirtazapine had statistically significantly faster onset of action than citalopram, fluoxetine, paroxetine, or sertraline, though after 4 weeks most response rates were similar. 1

Key Advantages Over Other Options

• Lower gastrointestinal side effects: Sertraline has a higher rate of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, or venlafaxine 1
• Reduced nausea risk: Nausea and vomiting were the most common reasons for discontinuation in efficacy studies with SSRIs, whereas mirtazapine has lower rates of these adverse effects 1
• Anxiolytic properties: Unlike bupropion's activating profile, mirtazapine provides sedation and anxiolytic effects beneficial for anxious depression 1

Why Not Continue Bupropion

The clinical concern about bupropion worsening anxiety has mixed evidence. Recent large-scale naturalistic data (N=8,457) using propensity matching showed no significant differences in anxiety outcomes between SSRI and bupropion groups across 12 weeks of treatment. 2 Additionally, pooled data from controlled trials demonstrated that bupropion SR and sertraline had comparable anxiolytic effects with equally rapid onset (median 4 weeks to clinically significant anxiolytic effect). 3

However, baseline anxiety levels do not predict differential response between bupropion and sertraline, 4 and the patient's subjective experience of worsened anxiety on bupropion warrants medication change regardless of population-level data. 1

Why Not Other SSRIs

Switching from sertraline to another SSRI (fluoxetine, paroxetine, citalopram, escitalopram) is not recommended because:

• Cross-intolerance of nausea: All SSRIs share similar gastrointestinal adverse effect profiles, with venlafaxine having even higher incidence of nausea and vomiting than other SSRIs 1
• Paroxetine concerns: Paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline, and has been associated with increased risk of suicidal thinking compared to other SSRIs 1
• No efficacy advantage: Available evidence does not support clinically significant differences in efficacy among SSRIs, SNRIs, or other second-generation antidepressants for acute-phase major depressive disorder 1

Mirtazapine Dosing Protocol

Start mirtazapine 15 mg at bedtime. 1 This low starting dose minimizes initial sedation while providing therapeutic benefit. The sedating properties are advantageous for patients with anxiety and can be taken at night to avoid daytime somnolence. 1

• Assess response within 1-2 weeks of initiation, monitoring for therapeutic response and adverse effects 1
• If inadequate response after 6-8 weeks at 15 mg, increase to 30 mg at bedtime 1
• Maximum dose is typically 45 mg daily if needed 1

Critical Monitoring Parameters

Monitor within 1-2 weeks of starting mirtazapine for:

• Suicidal ideation and behavioral changes, especially if patient is under 24 years old (risk for suicide attempts is greatest during first 1-2 months of treatment) 1
• Weight gain, as mirtazapine results in higher weight gain than sertraline, trazodone, or venlafaxine 1
• Somnolence and sedation 1

Assess adequacy of response at 6-8 weeks. If no adequate response occurs by 6-8 weeks at therapeutic doses, modify the treatment approach. 1 Remember that 38% of patients do not achieve treatment response during 6-12 weeks of treatment with second-generation antidepressants, and 54% do not achieve remission. 1

Important Caveats

Discontinue sertraline gradually to avoid discontinuation syndrome, which is characterized by dizziness, nausea, sensory disturbances, and anxiety—symptoms that could be misattributed to the underlying condition. 1 Sertraline has been associated with discontinuation syndrome, though less so than paroxetine. 1

Weight gain consideration: Mirtazapine and paroxetine result in higher weight gain than sertraline, trazodone, or venlafaxine. 1 Counsel the patient about this potential adverse effect and monitor weight regularly.

Avoid combining with other serotonergic agents during the transition period to minimize risk of serotonin syndrome, though this is rare. 5 Allow appropriate washout when switching medications, particularly if considering any MAOI in the future (contraindicated within 14 days). 1