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The Patient
You have a patient who suffers from schizophrenia. Positive symptoms have been well controlled with an antipsychotic for several months. He requests alleviation of his nicotine habit. You consider bupropion, but, knowing the mechanism of action of bupropion, you are concerned that positive symptoms may be exacerbated.
The Question
What is the risk of exacerbating positive psychotic symptoms in patients with schizophrenia stabilized on an antipsychotic?
The Analysis
PubMed (www.pubmed. gov) was used to search Medline for the following key words: bupropion, Wellbutrin, or Zyban. This search was then combined with one for psychosis, psychotic, schizophrenia, or schizoaffective.

Related Results

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The Evidence
Bupropion is an inhibitor of norepinephrine and dopamine reuptake (J. Clin. Psychopharmacol. 23[3]:233-39, 2003). Since drugs that increase dopaminergic activity often cause or exacerbate psychosis, it stands to reason that bupropion may be problematic for at-risk patients.
An early case report by Dr. Robert N. Golden and his colleagues of four patients described the development of acute psychosis in patients treated with bupropion (Am. J. Psychiatry 142[12]:1459-62, 1985). Three of the patients had previously experienced psychotic symptoms. The authors speculate that the mechanism of action responsible for that development might involve perturbations of dopamine systems and suggested that caution be exercised when using this medication with patients vulnerable to psychosis.
In Dr. Golden’s follow-up study, 11 patients were treated for depression with 300-500 mg/day bupropion. Of the four nonresponders, three became psychotic. Those three patients had elevated homovanillic acid levels consistent with those seen in schizophrenia (Arch. Gen. Psychiatry 45[2]:139-43, 1988).
More recent case reports have reported similar findings in nonschizophrenic/schizoaffective disordered patients. For example, in one case report, a 29-year-old man with no previous psychiatric history experienced positive psychotic symptoms after treatment with 300 mg/day bupropion (prescribed for nicotine addiction). Substance abuse was ruled out as causative (Pharmacopsychiatry 35[6]:247-48, 2002).
In another report, a 79-year-old man with no history of psychiatric disorders or substance abuse was treated with 300 mg/day bupropion for depression. Within 1 week, he also began experiencing positive psychotic symptoms. He ultimately did well with 25 mg t.i.d. bupropion, suggesting that such toxicity might be dose related (Am.J. Psychiatry 156[12]:2017-18, 1999).
In an open study, 20 patients diagnosed with schizoaffective disorder, depressed type were randomly assigned to receive treatment with bupropion or bupropion plus haloperidol (Haldol). Most of the patients received 750 mg/day bupropion (a far higher dosage than that currently used). The authors found that of the nine patients treated with bupropion monotherapy, three experienced exacerbation of psychotic symptoms. The authors concluded that treating schizoaffective disordered patients with bupropion alone carries significant risk of exacerbating psychosis (J. Clin. Psychiatry 44[7]:253-55, 1983).
In a more recent open study, eight patients with a mean age of 29 years who had been diagnosed with schizophrenia were examined for the effects of bupropion and supportive group therapy on cigarette consumption. Bupropion was prescribed at a dosage of 300 mg/day. Clinical assessments included the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS).
Between baseline and study completion at week 14, no significant changes were seen in BPRS scores. Bupropion treatment was associated with an 18% drop in the SANS score, but the difference was not significant. But a significant decrease was seen in the SANS alogia factor score (Am. J. Psychiatry 158[4]:635-7, 2001).
Finally, Dr. Tony P. George and his colleagues performed a randomized, double-blind, placebo-controlled study on 32 patients diagnosed with schizophrenia or schizoaffective disorder. Inclusion criteria included stability of psychotic and affective symptomatology. Subjects received either placebo or 300 mg/day bupropion combined with either typical or atypical antipsychotics. Subjects had been treated with an antipsychotic for at least 6 months before study entry. Positive and negative symptoms were rated with the Positive and Negative Syndrome Scale. The authors concluded, in part, that “there were no effects of bupropion versus placebo on positive symptoms of schizophrenia … but there was a reduction in negative symptoms by bupropion during the trial” (Biol. Psychiatry 52[1]:53-61, 2002).
The Conclusion
Available evidence suggests that bupropion does pose a risk in a dose-related manner of creating or exacerbating psychosis in a fashion consistent with inferences from its mechanism of action. At particular risk are those who suffer with a primary psychotic disorder. Evidence also suggests that vulnerable patients may have this risk of exacerbating psychosis reduced if they are first stabilized on antipsychotics. But given the small sample sizes in the studies cited above, the side effects may have been underestimated.