In a 32-year-old woman with moderate major depressive disorder, generalized anxiety disorder, weight gain on sertraline 75 mg, and inability to tolerate buspirone, does bupropion worsen anxiety?

Does Bupropion Worsen Anxiety?

Bupropion does not worsen anxiety in most patients with comorbid depression and generalized anxiety disorder, and you should prescribe it for this 32-year-old woman who has gained weight on sertraline. The highest-quality evidence—a 2023 propensity-matched naturalistic study of 8,457 patients—found no difference in anxiety outcomes between bupropion and SSRIs over 12 weeks of treatment 1. Additionally, the 2023 American College of Physicians guideline meta-analysis of the STAR*D trial demonstrated that baseline anxiety does not affect bupropion's comparative efficacy 2.

Evidence Supporting Bupropion Use in Anxious Depression

Primary Evidence from Recent Studies

• The 2023 propensity-matched study directly refutes the clinical myth that bupropion exacerbates anxiety. When 17 covariates were controlled through propensity matching, patients on bupropion showed identical anxiety improvement trajectories compared to SSRI-treated patients across 12 weeks, with no significant group-by-time interactions 1.

• The 2001 pooled analysis of two randomized controlled trials (n=692) found that baseline anxiety levels did not predict differential response between bupropion SR and sertraline. Higher baseline Hamilton Anxiety Rating Scale scores did not differentiate responders to bupropion from responders to sertraline 3.

• The 2023 American College of Physicians systematic review confirmed that comorbid anxiety does not modify bupropion's efficacy. STAR*D subgroup analyses found no effect of anxiety on comparative efficacy of bupropion versus other second-generation antidepressants 2.

Guideline-Level Safety Data

• The 2022 AGA guideline on naltrexone-bupropion for obesity reported anxiety rates of 0.6–5.4% in treatment groups versus 0.2–4.3% in placebo groups—no significant difference. This large pooled analysis (n=12,839 participants across 5 trials) provides high-quality evidence that bupropion does not increase anxiety incidence 2.

Clinical Application for Your Patient

Why Bupropion Is the Optimal Choice

• Bupropion addresses her weight gain concern directly. The drug is associated with minimal weight gain or even weight loss, unlike sertraline which commonly causes weight gain 4.

• She cannot tolerate buspirone, eliminating the standard SSRI-augmentation strategy. The STAR*D trial showed bupropion augmentation had significantly lower discontinuation rates (12.5%) than buspirone augmentation (20.6%, P<0.001) 2.

• Her generalized anxiety disorder does not contraindicate bupropion. The presence of GAD does not predict worse outcomes with bupropion compared to serotonergic agents 2, 3.

Practical Prescribing Strategy

Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total). This is the standard FDA-approved titration for major depressive disorder 4, 5.

Administer the second dose before 3 PM to minimize insomnia risk, which could indirectly worsen anxiety through sleep disturbance 4, 6.

Monitor anxiety symptoms at weeks 1–2 and again at 6–8 weeks. The 2023 naturalistic study showed anxiety improvement occurred comparably to SSRIs by 6 weeks 1. The American College of Physicians recommends assessing adequate response at 6–8 weeks before modifying treatment 2, 4.

Addressing the "Activating" Concern

Understanding the Stimulating Properties

• A 2025 review acknowledges bupropion's stimulating properties can provoke anxiety "particularly at higher doses," but this is dose-dependent and uncommon at standard therapeutic doses. The review notes clinical trials show comparable anxiolytic efficacy to SSRIs/SNRIs in mild-to-moderate anxiety 7.

• The FDA label instructs monitoring for "anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness" during early treatment, but these warnings apply to all antidepressants due to the black-box warning for suicidal ideation—not specifically to bupropion's anxiogenic potential 5.

Critical Safety Screening

Confirm absence of absolute contraindications before prescribing:

• No seizure history or conditions predisposing to seizures (brain tumor, stroke, head trauma) 4, 5
• No current MAOI use or use within 14 days 4, 5
• No eating disorders (bulimia, anorexia nervosa) due to increased seizure risk 4
• No uncontrolled hypertension—bupropion can elevate blood pressure 2, 6
• No abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 4

Monitor blood pressure and heart rate at baseline and periodically during the first 12 weeks, as bupropion can cause modest elevations 2, 6.

Common Pitfalls to Avoid

Do not withhold bupropion based solely on the presence of anxiety. The clinical belief that "activating" antidepressants worsen anxiety is not supported by controlled trial data 3, 1.

Do not start at full dose (300 mg). Begin with 150 mg daily for 3 days to assess tolerability and minimize early activation symptoms 4, 5.

Do not discontinue prematurely if mild early activation occurs. The 2025 review notes that while bupropion can initially increase anxiety in some patients, this often resolves with continued treatment or dose adjustment 7.

Do not exceed 450 mg/day total dose, as seizure risk increases significantly above this threshold 4, 5.

Expected Timeline

• Energy and motivation may improve within 1–2 weeks, which can be reassuring for patients 4.
• Full antidepressant and anxiolytic effects require 6–8 weeks at therapeutic dose 2, 4, 1.
• If no adequate response by 6–8 weeks, consider augmentation with an SSRI rather than switching, as combination therapy addresses both noradrenergic/dopaminergic and serotonergic pathways 2, 4.