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Bupropion (Wellbutrin)

wellbutrinpillsWellbutrin is available by prescription in the United States.

Addictive Potential: Low

Emergency Room Visits Yearly: Unknown

Mandatory Minumum Sentence: Not Scheduled, Does Not Apply; Legal by Prescription

Mechanism of Action: Increases the Neurotransmitter Dopamine and Norepinephrine


Bupropion (INN; also amfebutamone, brand names Wellbutrin and Zyban) is an antidepressant of the aminoketone class, chemically unrelated to tricyclics or selective serotonin reuptake inhibitors (SSRIs). It is similar in structure to the stimulant cathinone, anorectic diethylpropion and to phenethylamines in general.

Bupropion is both a dopamine reuptake inhibitor and a norepinephrine reuptake inhibitor. It is used as a smoking cessation aid under the brand name Zyban, and as an antidepressant under the brand name Wellbutrin, Wellbutrin SR and Wellbutrin XL.

Side Effects and Adverse Reactions:

The common adverse effects associated with 12-hour sustained-release bupropion (with the greatest difference from placebo) are dry mouth, nausea, insomnia, tremor, excessive sweating and tinnitus. Those that most often resulted in interruption of the treatment in the same trial were rash (2.4%) and nausea (0.8%).

Seizure is the most controversial side effect of bupropion, and was responsible for its initial withdrawal from the market. The risk of seizure is highly dose-dependent: 0.1% at 100–300 mg of bupropion, 0.4% at 300–450 mg, and 2% at 600 mg. For comparison, the incidence of the first unprovoked seizure in the general population is 0.07–0.09%. The risk of seizure for other antidepressants is as follows: 0.1–0.6% for imipramine, depending on dosage; 0–0.06% for amitriptyline, depending on dosage; 0.5% for clomipramine; 0.4% for maprotiline; and 0.2% for fluoxetine and fluvoxamine. Experiments on mice indicate that increased susceptibility to seizure is a general side effect of chronically using antidepressants that inhibit norepinephrine transporter, such as imipramine, desipramine and reboxetine. Clinical depression itself was reported to increase the occurrence of seizures two-to-sevenfold compared with the general population; in this light, the above statistics could indicate that low to moderate doses of antidepressants, including bupropion, may actually have an anti-convulsive action.

The prescribing information notes that hypertension, sometimes severe, was observed in some patients, both with and without pre-existing hypertension. The frequency of this adverse effect was under 1% and not significantly higher than that found with placebo. In a group of cardiac patients with depression, high doses of bupropion (400–500 mg/day) caused a rise in supine blood pressure but had no effect on pulse rate. No statistically significant changes in blood pressure or heart rate occurred in patients with or without heart conditions at a lower dose of 300 mg/day. In a study of bupropion for ADHD, a rise of systolic blood pressure by 6 mm Hg and of heart rate by 7 beats per minute (both statistically significant) were observed. A study of smokers hospitalized for heart disease found a 1.5-fold increase (close to being statistically significant) in subsequent cardiovascular events in the bupropion group, compared with the placebo group, but found no difference in blood pressure. Although the cardiovascular side effects of bupropion appear to be mild, it cannot be recommended for patients with heart disease, since the safety comparison with SSRIs (such as sertraline and fluoxetine, which may have a preventative effect after a myocardial infarction) is not in its favor.

In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion’s approval by the MHRA as part of the Yellow Card Scheme, which monitored side effects. Approximately 540,000 people were treated with bupropion for smoking cessation during that period. The MHRA received 60 reports of “suspected [emphasis MHRA’s] adverse reactions to Zyban which had a fatal outcome”. The agency concluded that “in the majority of cases the individual’s underlying condition may provide an alternative explanation.” This is consistent with a large, 9,300-patient safety study that showed that the mortality of smokers taking bupropion is not higher than the natural mortality of smokers of the same age.

Other isolated adverse affects have been reported. Three cases of liver toxicity have been described in the literature, a very low incidence given the widespread use of the drug. A single case of clitoral priapism (clitorism) has been reported in the literature.

Suicidality and other psychiatric side effects

The FDA requires all antidepressants, including bupropion, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.

Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, bupropion and nine other antidepressants were not statistically different from placebo. Only fluoxetine caused a significant decrease in suicidal ideation.

Suicidal behavior is less likely when bupropion is prescribed for smoking cessation. According to a 2007 Cochrane Database review, there have been four suicides per one million prescriptions and one case of suicidal ideation per ten thousand prescriptions of bupropion for smoking cessation in the UK. The review concludes, “Although some suicides and deaths while taking bupropion have been reported, thus far there is insufficient evidence to suggest they were caused by bupropion.”

Two years later, the FDA issued a health advisory, which warned that the prescription of bupropion and varenicline for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some patients have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide. This advisory was based on the postmarket review of anti-smoking products, which identified 153 reports of the suicidal adverse events for varenicline over the first year it was marketed and 75 reports for bupropion over ten years. No clear association with suicidality was identified for nicotine patch products.

There is evidence of several neuropsychiatric symptoms associated with bupropion in patients with depression, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms are reduced or eliminated by decreasing the dose or ceasing treatment. The prescribing information notes that “it is generally believed (though not established in controlled trials)” that, should an episode of depression actually be the first presentation of bipolar disorder, treating it with antidepressants, including bupropion, may precipitate a manic episode. More recent data indicate that the addition of newer antidepressants, including bupropion, to a mood stabilizer does not cause the switch to mania more often than the addition of placebo. Moreover, when added to a mood stabilizer, bupropion and sertraline had a twice lower switch risk than venlafaxine.

According to several case reports, stopping bupropion abruptly may result in discontinuation syndrome expressed as dystonia, irritability, anxiety, mania, headache, aches and pains.


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