Bupropion's Effect on Anxiety
Bupropion does not worsen anxiety in most patients and demonstrates comparable anxiolytic efficacy to SSRIs when treating depression with comorbid anxiety symptoms. 1
Evidence from Clinical Trials
The most robust evidence comes from a 2008 meta-analysis of 2,890 patients across 10 randomized controlled trials, which found no significant difference in anxiety reduction between bupropion and SSRIs when treating major depressive disorder with anxiety symptoms. 1 Both medication classes produced comparable improvements on the Hamilton Anxiety Scale (HAM-A: -8.8 vs. -9.1, p=0.177) and the Hamilton Depression Rating Scale Anxiety-Somatization factor (HDRS-AS: -3.8 vs. -3.9, p=0.130). 1
A 2023 naturalistic study of 8,457 patients using propensity matching found no significant differences in anxiety outcomes between SSRI and bupropion groups over 12 weeks of treatment, with both groups improving comparably over time. 2 This directly contradicts the longstanding clinical belief that bupropion exacerbates anxiety. 2
Anxiolytic Effects in Depression
Bupropion demonstrates significant anxiolytic effects when treating depression with comorbid anxiety. 3 A 1983 placebo-controlled trial showed bupropion was significantly more effective than placebo (P < 0.01) in reducing both depression and accompanying anxiety symptoms on the Hamilton Anxiety Scale. 3
The presence of comorbid anxiety does not appear to significantly affect bupropion's comparative efficacy based on STAR*D trial analyses. 4
Mechanism and Clinical Profile
Bupropion's catecholaminergic effects (norepinephrine and dopamine reuptake inhibition) produce particularly robust effects on anhedonia and positive affect rather than anxiety symptoms. 5 This mechanism differs from SSRIs but does not translate to increased anxiety in clinical practice. 5
Important Caveats and Monitoring
While bupropion is generally not anxiogenic, its stimulating properties can provoke anxiety in some patients, particularly at higher doses. 6 Common side effects that may be misinterpreted as anxiety include agitation (occurring at rates requiring discontinuation in 1.8% at 400 mg/day), insomnia, and tremor. 7
Start at lower doses (150 mg once daily for 3 days, then 150 mg twice daily) and monitor for anxiogenic symptoms during titration. 4 The second dose should be administered before 3 PM to minimize insomnia risk, which can secondarily worsen anxiety. 4
Residual Anxiety After Remission
There is no difference in residual anxiety between bupropion and SSRI-treated patients who achieve remission from depression (69.2% vs. 74.7% with HDRS-AS >0, p=0.081). 1 The severity of residual anxiety symptoms is also comparable between groups (HAM-A: 3.30 vs. 3.31, p=0.552). 1
Clinical Decision-Making
For patients with depression and mild to moderate anxiety, bupropion shows comparable efficacy to SSRIs. 6 However, for severe depression with prominent anxious distress, SSRIs may be preferable as first-line agents. 6
Bupropion offers distinct advantages including significantly lower rates of sexual dysfunction and minimal weight gain compared to SSRIs, making it an appropriate choice even in anxious patients when these side effects are concerns. 4
Contraindications Related to Anxiety Disorders
Bupropion is not FDA-approved for primary anxiety disorders and should be avoided in patients with eating disorders (bulimia/anorexia nervosa) due to increased seizure risk. 8, 7 The maximum dose should not exceed 450 mg/day to maintain seizure risk at 0.1%. 4