Managing Anxiety in Patients Taking Wellbutrin (Bupropion)
Bupropion does not worsen anxiety in most patients and can be safely continued or initiated even in those with comorbid anxiety disorders, though adding an SSRI is recommended for optimal anxiety management. 1, 2
Evidence Against the Clinical Myth
The longstanding belief that bupropion exacerbates anxiety is not supported by recent evidence:
A large naturalistic study (N=8,457) found no difference in anxiety outcomes between patients prescribed SSRIs versus bupropion over 12 weeks of treatment. Using propensity matching to control for baseline differences, both groups improved comparably with no significant interactions between medication type and anxiety severity over time. 1
Baseline anxiety levels do not predict differential response to bupropion versus sertraline. A pooled analysis of two randomized controlled trials (n=692) demonstrated that pretreatment anxiety symptoms were not associated with different antidepressant responses between bupropion SR and sertraline, nor did anxiety levels differentiate responders between the two medications. 2
Historical placebo-controlled trials actually showed bupropion reduced anxiety symptoms in depressed patients. Studies from the 1980s demonstrated that bupropion (300-600 mg/day) was significantly more effective than placebo in treating both depression and accompanying anxiety, with the 300 mg/day dose showing particular benefit for anxiety reduction. 3, 4
FDA Safety Monitoring Requirements
The FDA label mandates specific monitoring for neuropsychiatric symptoms:
Instruct patients and families to monitor for emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, worsening depression, and suicidal ideation, especially during early treatment and dose adjustments. These symptoms should be reported immediately if severe, abrupt in onset, or not part of presenting symptoms. 5
Families and caregivers must observe for symptom emergence on a day-to-day basis since changes may be abrupt. Such symptoms may indicate increased risk for suicidal thinking and require very close monitoring and possible medication changes. 5
When to Add an SSRI for Anxiety Management
If anxiety is a primary concern or persists despite bupropion treatment, add an SSRI rather than discontinuing bupropion. 6, 7
First-Line SSRI Options:
Sertraline is the preferred first choice because it is well-tolerated with minimal effect on metabolism of other medications compared to other SSRIs, and has demonstrated comparable anxiolytic efficacy to bupropion in head-to-head trials for depression with anxiety. Start at 50 mg daily, target 100-200 mg daily. 6, 7
Escitalopram is an excellent alternative because it has the least effect on CYP450 isoenzymes, minimizing drug interactions with bupropion. Start at 10 mg daily, maximum 20 mg daily (not 40 mg as previously recommended due to QTc concerns). 7
Avoid paroxetine as first-line due to higher anticholinergic effects and greater risk of discontinuation syndrome, though it can be used if other SSRIs fail. 7
Evidence Supporting Combination Therapy:
Head-to-head trials showed no difference in efficacy among SSRIs (fluoxetine, paroxetine, sertraline) and bupropion for treating depression with accompanying anxiety symptoms. Six fair-quality trials demonstrated similar antidepressive efficacy across these agents in patients with major depressive disorder and anxiety. 6
A pilot controlled trial demonstrated bupropion XL (150-300 mg/day) had comparable anxiolytic efficacy to escitalopram (10-20 mg/day) in patients with generalized anxiety disorder. Both treatments were well-tolerated over 12 weeks, suggesting bupropion may have direct anxiolytic properties. 8
Monitoring Parameters When Continuing Bupropion
Monitor blood pressure and heart rate periodically, especially in the first 12 weeks, as bupropion can cause elevations in both parameters. 9
Assess for neuropsychiatric adverse effects including agitation, restlessness, and behavioral changes within 1-2 weeks of initiation. 9
Allow 6-8 weeks at an adequate dose before determining treatment response for both depression and anxiety symptoms. 9
Critical Contraindications to Verify
Before continuing or initiating bupropion in anxious patients, confirm absence of:
Seizure disorders or any condition predisposing to seizures (bupropion lowers seizure threshold with risk approximately 0.1% at 300 mg/day). 9, 5
Uncontrolled hypertension (bupropion can elevate blood pressure and heart rate). 9
Current or recent MAOI use (within 14 days). 9
Eating disorders (bulimia or anorexia nervosa have increased seizure risk). 9
Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs (increases seizure risk). 5
Dosing Considerations
Standard therapeutic dosing for depression is bupropion SR 150 mg twice daily (300 mg total daily) or bupropion XL 300 mg once daily. 9
Maximum dose should not exceed 450 mg/day to maintain seizure risk at 0.1%. 9
For patients on multiple psychotropic medications, start with 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated, with the second dose given before 3 PM to minimize insomnia risk. 9
Common Pitfalls to Avoid
Do not discontinue bupropion solely based on the clinical myth that it worsens anxiety—the evidence does not support this concern in most patients. 1, 2
Do not add benzodiazepines for chronic anxiety management—they are not first-line per anxiety treatment guidelines and carry dependence risk with chronic use. 7
Do not use buspirone as monotherapy augmentation—it has less robust evidence compared to SSRIs and takes 2-4 weeks to become effective. 7
Monitor for serotonin syndrome when combining SSRIs and bupropion, though risk is low with this combination. 7