Can Wellbutrin (bupropion) cause anxiety?

Can Wellbutrin Cause Anxiety?

Bupropion (Wellbutrin) can cause anxiety as a side effect, but high-quality evidence demonstrates that it does not increase anxiety more than placebo or SSRIs in most patients, and baseline anxiety does not predict worse outcomes with bupropion treatment.

Evidence on Anxiety as a Side Effect

• The FDA drug label for bupropion explicitly instructs patients and families to monitor for "emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness)" especially early in treatment and during dose adjustments. 1

• In pooled trials of naltrexone-bupropion for obesity (n ≈ 12,800), anxiety occurred in 0.6%–5.4% of bupropion-treated patients versus 0.2%–4.3% in placebo groups, with no statistically significant difference between groups. 2

• Common neurological side effects of bupropion include insomnia, headache, dizziness, and tremor, which may be misinterpreted as anxiety symptoms. 3

Clinical Trial Evidence: Anxiety Does Not Worsen

• A 2023 naturalistic study (N = 8,457) using propensity matching found no significant difference in anxiety outcomes between SSRI and bupropion groups across 12 weeks of treatment—both groups improved comparably over time on Generalized Anxiety Disorder Scale-7 scores. 4

• A 2005 analysis of 797 depressed outpatients treated with bupropion SR 300 mg/day found that baseline anxiety levels did not predict likelihood of antidepressant response (67% overall response rate), and higher baseline anxiety was actually associated with slightly earlier onset of response. 5

• The STAR*D trial meta-analysis confirmed that comorbid anxiety does not diminish bupropion's comparative efficacy versus other second-generation antidepressants in major depressive disorder. 2

Mechanism and Dose-Related Effects

• Bupropion's norepinephrine and dopamine reuptake inhibition produces activating properties that can manifest as increased energy, restlessness, or agitation—particularly at higher doses or in patients already prone to anxiety. 6

• A 2004 randomized trial showed that bupropion SR elicited greater declines than placebo on all depression measures except those assessing anxiety, suggesting its catecholaminergic effects target anhedonia/positive affect more robustly than anxious symptoms. 7

• An older 1983 study found that bupropion 300 mg/day reduced anxiety symptoms in hospitalized depressed patients, but the 450 mg/day dose did not, suggesting dose-dependent anxiogenic potential at higher levels. 8

Clinical Decision Algorithm

When to use bupropion despite anxiety concerns:

• Patients with depression and comorbid mild-to-moderate anxiety can safely receive bupropion, as clinical trials show comparable anxiolytic efficacy to SSRIs/SNRIs. 6
• Baseline anxiety does not predict treatment failure—proceed with standard dosing if no absolute contraindications exist. 5

When to avoid or use caution:

• Patients who are already highly agitated should avoid bupropion, as its activating effects may worsen agitation. 2
• Start at lower doses (150 mg once daily for 3 days, then 150 mg twice daily) and monitor closely during the first 1–2 weeks for emergent anxiety, agitation, or behavioral activation. 2, 1
• Administer the second daily dose before 3 PM to minimize insomnia, which can exacerbate anxiety symptoms. 2

Monitoring parameters:

• Assess for anxiety, agitation, panic attacks, insomnia, irritability, and akathisia within 1–2 weeks of initiation and after any dose adjustment. 1
• If anxiety worsens significantly, reduce the dose or switch to an SSRI (e.g., escitalopram, sertraline) rather than discontinuing all treatment. 2

Common Pitfalls to Avoid

• Do not assume bupropion is contraindicated in all anxious patients—propensity-matched data show no difference in anxiety outcomes versus SSRIs. 4
• Do not exceed 450 mg/day total dose, as higher doses increase both seizure risk and anxiogenic potential. 2, 8
• Do not mistake early behavioral activation for treatment failure—this often resolves with dose adjustment and typically emerges within the first month. 2
• Do not combine with other highly stimulating agents (e.g., high-dose stimulants) without close monitoring, as this amplifies anxiety risk. 2