Bupropion-induced psychosis: folklore or a fact? A systematic review of the literature

Abstract

Objective

Bupropion is a substituted phenyl-ethylamine that is extensively utilized for the treatment of major depressive disorder and for smoking cessation. It is a reuptake inhibitor of dopamine and norepinephrine, and it also has some nicotinic antagonism. There are concerns that it may increase the risk of psychosis due to its dopaminergic effects. Our objective is to review the literature and analyze the risk of bupropion precipitating a psychotic illness in the general population as well as in the populations with a history of psychotic symptoms.

Methods

A Medline database search limited to human and English-language studies was conducted using the keywords “bupropion” and “psychosis.” A total of 23 articles were selected based on the relevance of the articles and their references. The data from these articles were collated.

Results

Collated data show that there is some evidence to suggest that bupropion may cause or worsen psychosis in selected subpopulations. Higher doses of bupropion appear more likely to be associated with the outcome severity. Preexisting psychotic symptoms, substance abuse and drug interactions also seem to increase the risk. Concurrent use of antipsychotics at adequate doses appears to be protective.

Conclusions

The literature is incomplete and in some cases contradictory. In selected cases, bupropion appears to be associated with the induction of psychotic symptoms in addition to the precipitation or worsening of an existing psychotic syndrome. Further research including controlled studies is required to clarify the risk of bupropion precipitating a psychotic illness in vulnerable populations.

Introduction

Bupropion is a substituted phenyl-ethylamine antidepressant that was approved in 1989 by the Food and Drug Administration (FDA) in the United States for treatment of depression, with a recommended maximum daily dose of 450 mg. In 1997, it was also FDA approved for the indication of smoking cessation under the name Zyban, and in 2006, bupropion extended release was FDA approved for prophylaxis of seasonal depression. The original immediate-release formulation of bupropion was dosed three times daily. In an effort to improve tolerability and safety, a sustained-release (SR) formulation of bupropion, dosed twice daily, was subsequently introduced, and a once-daily extended-release formulation became available in 2003 [1]. Bupropion is a reuptake inhibitor of dopamine (DA) and norepinephrine (NE). It also acts as an antagonist at nicotinic acetylcholine receptors (nAchR), but it has no clinically significant effect on serotonin transporters [2], [3], [4], [5]. It is reported to be more potent at the DA transporter as compared to the NE transporter, thereby increasing DA activity to a greater extent particularly in nucleus accumbens and in prefrontal cortex [4]. Bupropion undergoes extensive first-pass hepatic metabolism to multiple active metabolites that contribute to its psychotropic effects [4], [5], [6]. Bupropion is a substrate for cytochrome P450 (CYP) 2B6, and it is an inhibitor of CYP 2D6 [6]. Genetic polymorphisms and age-related variability in activity of CYP2B6 may have an impact on blood levels of bupropion and its metabolites in different people [5], [7]. Inhibition of bupropion metabolism could also occur with drugs such as paroxetine, sertraline, fluoxetine, diazepam, clonazepam, ritonavir, efavirenz and others that may inhibit CYP2B6 by competitive or noncompetitive enzyme inhibition activity [6], [8].

Bupropion has been found to have an efficacy comparable to the serotonin reuptake inhibitors (SSRIs) in major depression. In addition, it has been reported to augment the antidepressant effects of SSRIs in major depression and to have a beneficial effect in attention-deficit/hyperactivity disorder and seasonal affective disorder [4], [5]. One significant advantage of bupropion is a reduced risk of sexual side effects when compared to SSRIs [4]. In addition, Post et al. found that it presented less risk of precipitating a manic switch in comparison to serotonin–norepinephrine reuptake inhibitors such as venlafaxine and that the risk might be comparable to SSRIs when used as an antidepressant in patients with bipolar disorder especially the rapid cycling type [9].

Due to its dopaminergic action, bupropion has a potential of precipitating psychosis in selected at-risk populations [10], [11], [12]. Excess DA is implicated in the pathogenesis of psychosis [13], [14], [15]. The potency of typical antipsychotics is directly correlated with their affinity for dopamine 2 receptors. It is also suggested that, at least in animal models, various types of injuries including stimulant exposure cause a preponderance of high-affinity states among DA receptors [13] that may be linked to the onset of psychotic symptoms. These observations support the view that even if the DA hypothesis does not fully explain the etiology of psychosis and schizophrenia, DA does play a significant role in the pathogenesis of psychosis. Therefore, as bupropion is a DA reuptake inhibitor and is related chemically to ethylamine stimulants, there is a question regarding the risk of bupropion precipitating psychosis de novo or initiating a recurrent psychotic episode in persons with a preexisting psychotic disorder.