[NOTE: This article has been posted prior to peer review for use in an active research program. This content will be updated with a peer reviewed version as soon as it is available.]
Hypersensitivity
Some patients may exhibit an allergic reaction to bupropion, including rash, hives, angioedema, and anaphylaxis.1,2 Manufacturers advise that patients with a known history of hypersensitivity to bupropion or any of their inactive ingredients should avoid the use of bupropion.
Hypersensitivity to bupropion is rare, so the exact incidence is difficult to estimate. A study was conducted using Taiwan's national health insurance dataset from 2000 to 2009 that included 65,988 patients with depressive disorders.3 Among these, 2,839 new users of bupropion were identified and matched with 11,356 non-bupropion users based on age and sex. Within four weeks of starting bupropion, the incidence of urticaria 16.56 per 1,000 patients compared to 9.16 per 1,000 controls (Relative Risk [RR] 1.81, 95% Confidence Interval [CI] [1.28-2.54], p=0.001).
Suicidal Ideation
Manufacturer prescribing information warns that large placebo-controlled trials of antidepressant drugs (n of about 77,000) including bupropion have found that treatment can increase the incidence of suicidal thoughts and behaviors in younger patients.1,2 The estimated incidence among those less than 18 years of age was 14 additional patients per 1,000 patients treated, and for those 18-24 years of age was 5 additional patients per 1,000 patients treated. Among those 25 years or older, use of antidepressant medication decreased the incidence of suicidal thoughts and behaviors. It is unknown whether this risk extends to long-term use as these trials were limited to four months in duration.
Manufacturers recommend that all patients treated with any antidepressant be monitored for worsening of clinical signs and symptoms, including suicidal thoughts and behaviors, especially in the first few months of drug therapy and at times of dose changes.1,2 They further advise that family members and caregivers should be alert to these signs and symptoms and consult the patient’s physician if they notice concerning changes.
Neuropsychiatric Adverse Events
Manufacturers warn that bupropion has been associated with neuropsychiatric adverse events, especially when used as a smoking cessation aid.1,2 However, studies have found that these effects are limited to those with pre-existing psychiatric conditions and that reported effects are relatively non-severe. A 2016 randomized controlled trial compared the incidence of neuropsychiatric events among both patients with psychiatric conditions (n=4,074) and those without (n=3,984) using either a nicotine patch, varenicline, or bupropion as a smoking cessation aid.4 Neuropsychiatric events reported included anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal behavior, and suicidal ideation. Rates of neuropsychiatric adverse events were lower among those taking medications compared to a nicotine patch and placebo in the non-psychiatric cohort (1.3% for varenicline, 2.2% for bupropion, 2.5% for nicotine patch, and 2.4% for placebo). In the psychiatric cohort, rates were higher among those taking medications (6.5% varenicline, 6.7% bupropion, 5.2% nicotine patch, 4.9% placebo). The rate of suicidal behavior or ideation was higher in placebo groups than in those treated with bupropion for both those with psychiatric conditions and those without.
Mania
Bupropion may precipitate mania in patients with bipolar disorder being treated for a depressive episode.1,2 Manufacture clinical trials found that mania or hypomania were reported in 0.1% of patients treated with SSRIs.
A study investigated the risk of switches in mood polarity into hypomania and mania during acute (10-week) and continuation trials (up to 1 year) of antidepressant therapy (bupropion, sertraline, or venlafaxine) in bipolar depressive patients (n=159).5 During acute treatment trials, 11.6% of patients experienced threshold switches to full-duration hypomania, and 9.3% experienced switches to mania. During continuation treatment, these rates increased to 21.8% for hypomania and 14.9% for mania.
Angle-Closure Glaucoma
In patients with anatomically narrow angles in their eyes may be susceptible to angle closure attack glaucoma when taking bupropion.1,2 Antidepressant drugs including bupropion can cause pupillary dilation, which can cause narrow angles to be closed off, blocking the proper drainage of fluid in the eyes and leading to increased pressures. Manufacturers advise against the use of bupropion in those with untreated anatomically narrow angles.
Angle-closure glaucoma in association with bupropion use has only been reported in case studies, so the exact incidence is difficult to estimate. In manufacturer clinical trials comprised of thousands of people, there were no reported cases.
Seizures
Bupropion has been linked to seizures in a dose-dependent relationship with limited risk as therapeutic doses and elevated risk at higher than recommended doses.1,2 In manufacturer drug trials, the incidence of seizures was 0.1% for those taking up to 300 mg per day and 0.4% for those taking 300-450 mg/day. However, this risk increased almost ten-fold to approximately 4% in doses of 450-600 mg/day. Therefore, manufacturers recommend that dosing not exceed 450 mg/day.
In a 2003 study examining the incidence of adverse events among 11,735 patients taking bupropion at therapeutic doses as a smoking cessation aid, the incidence of convulsion or seizure was 0.1%, which was comparable to the population-level expected incidence of epileptic seizure of 1:1,000.6 Of the eleven reported convulsion events reported, four were associated with a past history of seizure.
References
- Wellbutrin (bupropion hydrochloride) tablets [package insert]. Durham, NC: GlaxoSmithKline; 2024.
- Wellbutrin XL (bupropion hydrochloride extended-release) tablets [package insert]. Bridgewater, NJ: Bausch Health; 2024.
- Hu LY, Liu CJ, Lu T, et al. Delayed onset urticaria in depressive patients with bupropion prescription: a nationwide population-based study. PLoS One. 2013;8(11):e80064. doi:10.1371/journal.pone.0080064
- Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet (London, England). Jun 18 2016;387(10037):2507-20. doi:10.1016/s0140-6736(16)30272-0
- Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. Feb 2006;163(2):232-9. doi:10.1176/appi.ajp.163.2.232
- Boshier A, Wilton LV, Shakir SA. Evaluation of the safety of bupropion (Zyban) for smoking cessation from experience gained in general practice use in England in 2000. Eur J Clin Pharmacol. Dec 2003;59(10):767-73. doi:10.1007/s00228-003-0693-0
