Introduction

Bupropion hydrochloride is a popular psychotropic drug that inhibits norepinephrine and dopamine reuptake with minimal effect on serotonin. It is prescribed to millions of patients worldwide for the treatment of major depressive disorders and bipolar depression. In 1997, bupropion was approved by the U.S. Food and Drug Administration (FDA) for use as a smoking cessation aid[1,2].

The U.S. prescribing information for bupropion discloses serious allergic reactions as potential side effects, including urticaria, angioedema, erythema multiforme, Stevens-Johnson syndrome, and even anaphylactic shock. However, these allergic reactions have been rarely reported with bupropion[3]. Two large-scale studies were designed to examine the safety of bupropion as a treatment for smoking cessation in England and France, respectively[4,5]; however, assessment of allergic reactions was not emphasized in these studies. In addition, adverse effects of bupropion in depressive patients, which had been highly associated with urticaria[6], is rarely mentioned in the literature.

To date, only case reports have described bupropion-induced allergic reactions, and it is important to note that clinical features of delayed onset urticaria seems to be present in most of these patients[7-10]. Some studies have postulated that delayed onset urticaria may be overlooked and underreported[9,11] because patients who take bupropion may receive treatment for bupropion-induced delayed onset urticaria by other physicians or hospitals[9,11].

To address these inadequacies in the literature and to assess the pattern of bupropion-induced urticaria, we designed a nationwide population-based study to investigate the actual incidence and timing of new onset urticaria in patients with depression who receive bupropion prescriptions.

Patients and Methods

Results

Incidence of Urticaria

Figure 1 shows the cumulative incidences of urticaria occurrence across all participants. The urticaria risk within 4 weeks was significantly higher for patients in the bupropion cohort (cumulative incidence, 16.56‰) than for patients in the comparison cohort (9.16‰) (risk ratio, 1.81; 95% CI 1.28–2.54, p = 0.001) (Table 2). We also stratified patients by age and gender and found that bupropion use was associated with higher urticaria risk in patients under 40 years of age (risk ratio, 2.25; 95% CI 1.41–3.60, p < 0.001), but not in patients over 40 years of age. The use of bupropion was associated with a higher risk of urticaria occurrence in both males and females.

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Figure 1. The cumulative incidences of urticaria in depressive patients with and without bupropion prescription.

Follow-up(days) =0 indicates the initiation of antidepressants use.

https://doi.org/10.1371/journal.pone.0080064.g001

	Bupropion cohort	Matched cohort	Risk ratio	p value
	n (‰)	n (‰)	(95% CI)
Total	47(16.56)	104(9.16)	1.81 (1.28–2.54)	0.001
Age
20–39	27(21.16)	48(9.40)	2.25(1.41–3.60)	< 0.001
40–59	15(14.29)	39(9.29)	1.54(0.85–2.78)	0.151
≥ 60	5(9.75)	17(8.28)	1.18(0.44–3.17)	0.748
Sex
Male	16(14.15)	33(7.29)	1.94 (1.07–3.51)	0.026
Female	31(18.15)	71(10.39)	1.75 (1.15–2.65)	0.008

Table 2. Incidence of urticaria occurrence in depressive patients within the first 4 weeks of taking the antidepressants.

CI: confidence interval

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Discussion

To the best of our knowledge, the present study is possibly the largest study to analyze urticaria risk in patients with depression after starting a bupropion prescription. There are several important findings from the nationwide study. First, the unexpected high risk for urticaria occurrence was observed in patients with depression who received bupropion, especially in patients under 40 years of age. Second, the risk of urticaria occurrence in bupropion cohort were significantly higher in Day 15–28 than Day 1–14 and the delayed onset trend was not observed in other antidepressants users in our study. Finally, a history of urticaria may be an important predictor of urticaria development after taking bupropion. The findings may arouse public interest regarding safety issues in bupropion use.

In order to examine the safety of bupropion use, two large-scale studies were previously conducted to quantify the incidence of events reported for patients who were prescribed bupropion and to identify any previously unrecognized adverse drug reactions in England and France[4,5]. In the study conducted in England, data were derived from questionnaires sent to general practitioners at least 6 months following the first prescription. However, the study achieved a response rate of only 48.1% in the patients prescribed bupropion, and therefore a recall and selection bias could not be avoided. In the French study, the safety profile of bupropion use was monitored through a spontaneous report system; thus, the results may be underestimated. The design of those previous studies may explain why the incidence of bupropion-induced urticaria was much lower than that found in our study. Although those studies provide insight into the association between bupropion administered for smoking cessation and urticaria, the association between bupropion administered for depression and unitcaria is rarely mentioned in the literature, and importantly depression has been shown to be strongly associated with urticaria[6]. In addition, our study relied on a claim-based dataset, and therefore the data related to the medical charge, such as antidepressant use, were precise. A diagnosis of urticaria would not be omitted even if the patients had received treatment at different hospitals or times.

Several smaller reports have shown that nearly all of the antidepressants seemed to be associated with an onset of urticaria, including fluoxetine[15], paroxetine[16], sertraline[17], escitalopram[17], venlafaxine[18], bupropion[5,7,9,10,19-25], mirtazapine[18], and tricyclic antidepressants[26]. However, very few attempts have been made to compare the occurrence of urticaria among the various antidepressants. In our study, the results showed that bupropion use was associated with the highest risk of urticaria development and the delayed onset phenomenon of urticaria occurrence was only shown in the bupropion users compared with all other antidepressant prescriptions in Taiwan assessed.

In addition to bupropion-induced urticaria[21-23], many smaller studies have described a relationship between bupropion use and allergic reactions, including angioedema[20], erythema multiform[24], Stevens-Johnson syndrome[27], and serum sickness-like reactions[7-11,25]. Moreover, most of the studies noticed delayed onset characteristics of these allergic reactions. Although some researchers had presumed that the bupropion-induced urticaria may be underestimated[9,11], unanswered reasons still remain. According to our results, we hypothesized that the reason of underestimation may be related to the delayed onset phenomenon of bupropion-induced urticaria. In addition, bupropion-induced urticaria seldom develops alone and is sometimes accompanied with other more serious allergic reactions, including angioedema[19,20], arthralgia[8], serum sickness-like reaction[7,9-11], or symptoms of anaphylaxis, which may indicate a medical emergency. Therefore, if medical personnel do not recognize the adverse drug reaction, then patients could be put at risk for more severe drug hazards.

The mechanisms of urticaria are thought to be associated with histamine and other mediators being released from mast cells and basophils. The higher occurrence of bupropion-induced urticaria in younger patients could be explained by immunosenescence, which is an age-related decline in immune functions. It has been reported that mast cell development declines through the aging process[28], and the number of dermal mast cells decreases with age in human subjects[29]. However, the mechanism of bupropion-induced urticaria is currently unknown. We hypothesize that the adverse drug reaction may be linked to the structure of bupropion, which is chemically similar to amfepramone. Amfepramone is considered a selective norepinephrine releasing agent, and norepinephrine may play an important role in adrenergic urticaria, which is considered to be a form of neurogenic reaction that is mainly triggered by stress. Moreover, in recent years, bupropion has been suggested to have effects as an anti-inflammatory agent by down-regulating tumor necrosis factor synthesis, which may slow the course of some inflammatory processes[30,31]. Therefore, we hypothesized that the anti-inflammation effect may delay the allergic reaction and lead to delayed onset urticaria.

While urticaria may be confused with a variety of other dermatologic diseases that are similar in appearance and are also pruritic, it is possible that other urticaria-like skin reactions may have been misclassified under the code based on claims data. In order to make the diagnosis more specific, subgroup of the urtiacria diagnosed by dermatologic specialists in our study group were further analyzed and the higher risk for overall urticaria occurrence and delayed onset trend were similar to the results of the urtiacria patients diagnosed by general practitioners in the bupropion cohort.

Several limitations inherent in using claims databases also need to be taken into consideration. First, because patients’ identifications were blocked for protection of privacy, we have no way to assess for actual intake of prescribed antidepressants. However, such a limitation usually leads toward an under-estimation of risk. Besides, although no evidence has shown that the difference of drug compliance between bupropion and other antidepressants, it is reasonable to assume that the higher risk of delayed onset urticaria in the bupropion cohort may be associated with the influence of drug compliance. Second, drugs which may cause were not adjusted for. Although urticaria is really often caused by the many drugs including antibiotics and anticonvulsants use in our clinical experience. However, these drugs were not selected for adjustment in this study because the antibiotics and anticonvulsants were less common co-medications used by our study subjects (patients with depressive disorders). Besides, the frequency of antibiotics and anticonvulsants co-prescriptions with antidepressants is relatively low during a short follow-up period (4 weeks) in our study. Third, a number of other potential confounding factors that might affect urticaria risk were not available in the reimbursement data used in this study, such as psychosocial stresses, foods, family history of urticaria, recent travel history, exposure to environmental stimulants and smoking[32]. {Stockli, 2007 #51}Among these non-observable confounders, for the reason that the use of bupropion may be helpful to depressive patients who smoke[33], therefore, smoking may be an important non-observable confounder in our study. Finally, further investigations are needed to explore such associations in different populations and ethnic groups.

In conclusion, our study has found that patients with depressive disorders who received bupropion were at an unusually higher risk for delayed onset urticaria. Based upon our data, we suggest that more attention should be focused on the bupropion-induced urticaria in patients with depressive disorders and urge caution over the delayed onset phenomenon, especially in patients under 40 years of age and with past history of urticaria, in order to avoid more severe drug allergies as a result of prescribing the same drugs. Although more research is needed, this article serves to broaden physicians’ knowledge base when prescribing bupropion.

Supporting Information

Acknowledgments

We thank Huei-Sing Chang and Cheng-Fang Hong for technical support.