No Causal Relation Between Bupropion in Therapeutic Dose and Serotonin Toxicity

We would like to thank Murray and colleagues for sharing their analysis of data collected by the Toxicology Investigators Consortium (ToxIC) [1]. They described 266 single-agent bupropion intoxications, with 13 patients diagnosed with serotonin toxicity (ST), and conclude that bupropion overdose may be associated with ST. Due to this potential association, the authors suggest that physicians should avoid concomitant use of bupropion and serotonergic agents. We would like to discuss this interpretation and the role of bupropion in causing ST.

The most important question is if bupropion should be considered a serotonergic agent, as the use of a serotonergic agent is an essential requirement for ST [2]. ST is a clinical diagnosis, with the Hunter Criteria as the most reliable set of signs and symptoms [3, 4]. A limitation of the study was insufficient information to apply the Hunter Criteria, and consequently the diagnosis of ST was only based on the clinical observation [1]. This clinical observation can be difficult, with other toxidromes such as sympathicomimetic and neuroleptic malignant toxidromes that share similar features [3]. It is also possible that patients incorrectly diagnosed with ST were entered in the database by the toxicologists and fellows in training. In this respect, the relatively low number of 13 cases of ST can be explained by an incorrect diagnosis.

With respect to the pharmacological profile, current insights indicate that bupropion is an antidepressant with a mixed neuropharmacological profile, acting mainly as inhibitor of dopamine and norepinephrine reuptake [5]. Bupropion has no significant serotonergic activity [6]. We agree with the authors that there is a theoretical possibility that bupropion might cause ST by an unknown mechanism, such as indirect effects or effects of bupropion metabolites [7]. In this respect, databases have proven to be valuable in generating hypotheses and studying toxidromes, with registries from the Hunter Area Toxicology Service and the ToxIC as good examples [4, 8]. A challenge for such registries remains to maximize the quality of the data.

An interesting aspect is that the bupropion intoxications were primarily cases of self-harm and abuse, likely associated with high doses. A Canadian study showed an association between increased bupropion dose and risk of seizures [9]. As the risk profile of bupropion in the therapeutic range has proven to be acceptable without any proven risks for ST [5, 6], it is remarkable that Murray advises to avoid the combination of bupropion with serotonergic medication. With a number of prescriptions of bupropion of about 25 million prescriptions in the USA in 2017 [10], it can be expected that a substantial number of patients combine bupropion with serotonergic medication. Avoidance of this combination is likely to result in negative consequences for both health care professional and patient. Unnecessary alerts will cause alert fatigue for health care professionals [11] and, for the patient switching medication, can result in reduced trust in medication and less adherence [12].

In conclusion, bupropion should not be considered as a serotonergic drug, as there is insufficient evidence. Until evidence for a serotonergic pathway is available, bupropion in therapeutic dose can be used safely in combination with serotonergic drugs.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.