In a 40-year-old male patient currently taking bupropion (Wellbutrin) 450 mg daily and trazodone 100 mg at bedtime, should the trazodone dose be increased for anxiety control?

Should Trazodone Be Increased for Anxiety Control in This Patient?

No, do not increase trazodone for anxiety control in this patient. Trazodone is not recommended as a treatment for anxiety disorders, and the American Academy of Sleep Medicine explicitly advises against using trazodone for insomnia due to lack of clinically significant efficacy 1. Instead, address the anxiety through optimization of the existing bupropion regimen or addition of an evidence-based anxiolytic agent.

Why Trazodone Should Not Be Increased for Anxiety

Lack of Evidence for Anxiety Treatment

• The 2017 American Academy of Sleep Medicine guidelines recommend against using trazodone for sleep onset or sleep maintenance insomnia based on weak evidence, with a single 50 mg trial showing no clinically significant improvements in sleep latency (reduced by only 10.2 minutes), total sleep time (increased by only 21.8 minutes), or wake after sleep onset (reduced by only 7.7 minutes) 1.
• Trazodone is FDA-approved only for major depressive disorder, not for anxiety disorders or insomnia, despite widespread off-label use 2, 3.
• While trazodone has been used off-label for generalized anxiety disorder and panic disorder, large randomized controlled trials evaluating its efficacy for anxiety are lacking 3.

Current Dosing Context

• The patient is already taking trazodone 100 mg at bedtime, which is within the typical range for off-label sleep use (25-100 mg) 1.
• Increasing trazodone beyond 100 mg for anxiety would move into antidepressant dosing territory (150-300 mg daily), which requires divided dosing and carries increased side effect burden including sedation, dizziness, and orthostatic hypotension 4, 2.

Optimize Bupropion Instead

Current Bupropion Dosing Assessment

• The patient is taking bupropion 450 mg daily, which is the maximum FDA-approved dose for the XL formulation 5.
• This dose should not be exceeded due to seizure risk (approximately 0.1% at 300 mg/day, rising significantly above 450 mg/day) 5, 6.

Bupropion and Anxiety: The Evidence

• Recent 2025 data indicate that bupropion may reduce anxiety symptoms in depressed patients, showing comparable efficacy to SSRIs and SNRIs for mild to moderate anxiety 7.
• However, bupropion's stimulating properties can provoke anxiety, particularly at higher doses 7.
• Clinical trials from the STAR*D study show that comorbid anxiety does not significantly affect bupropion's comparative efficacy for depression 5.

Critical Safety Consideration

• At 450 mg daily, the patient is already at maximum dosing—monitor closely for anxiety exacerbation, agitation, or activation symptoms that may indicate bupropion is contributing to rather than alleviating anxiety 5, 6.

Recommended Treatment Algorithm

Step 1: Assess Whether Bupropion Is Contributing to Anxiety

• If anxiety worsened after starting or increasing bupropion, consider reducing the dose to 300 mg daily (the standard therapeutic dose for depression) 5, 6.
• Monitor for improvement in anxiety symptoms over 1-2 weeks after dose reduction 6.

Step 2: Add Evidence-Based Anxiolytic Treatment

If anxiety persists despite optimized bupropion dosing:

• First-line option: Add an SSRI (e.g., escitalopram 10-20 mg daily) or SNRI, which have robust evidence for both depression and anxiety disorders 6.

  • The combination of bupropion plus SSRI is safe and well-studied, with no contraindications between these drug classes 6.
  • This addresses anxiety through complementary mechanisms: SSRIs via serotonin, bupropion via norepinephrine/dopamine 6.

• Alternative option: Add buspirone 15-30 mg daily in divided doses, though evidence shows bupropion augmentation of SSRIs is superior to buspirone augmentation 6.

• Consider low-dose mirtazapine 7.5-15 mg at bedtime if insomnia is a prominent feature, as it provides both anxiolytic and sedating effects 1.

Step 3: Maintain Trazodone at Current Dose for Sleep

• Continue trazodone 100 mg at bedtime for sleep maintenance if it is providing benefit 1.
• The 2008 American Academy of Sleep Medicine guidelines note that trazodone 100 mg nightly is safe when combined with escitalopram and bupropion 1.

Critical Safety Monitoring

Seizure Risk Factors to Screen For

• History of seizures, brain metastases, eating disorders (bulimia/anorexia), alcohol withdrawal, abrupt benzodiazepine discontinuation, or head trauma 5, 6.
• The seizure risk at 450 mg bupropion is approximately 0.4%, compared to 0.1% at 300 mg 5.

Cardiovascular Monitoring

• Monitor blood pressure and heart rate, especially in the first 12 weeks, as bupropion can cause elevations 5, 6.
• Uncontrolled hypertension is a contraindication to bupropion use 5, 6.

Neuropsychiatric Monitoring

• Assess for worsening depression, suicidal ideation, increased agitation, or behavioral changes, particularly in the first 1-2 weeks after any medication change 5, 6.
• The risk for suicide attempts is greatest during the first 1-2 months of antidepressant treatment 5.

Common Pitfalls to Avoid

• Do not increase trazodone above 100 mg for anxiety without recognizing you are moving into antidepressant dosing, which requires 150-300 mg daily in divided doses and lacks evidence for anxiety 4, 2.
• Do not exceed bupropion 450 mg daily—the patient is already at maximum dosing 5, 6.
• Do not add an MAOI or initiate within 14 days of MAOI discontinuation due to hypertensive crisis risk 6.
• Do not add tramadol, meperidine, or other serotonergic opioids if you add an SSRI, due to serotonin syndrome risk 6.
• Do not assume early activation or anxiety in the first 2-4 weeks represents treatment failure—allow 6-8 weeks at therapeutic doses before modifying the regimen 5, 6.