eMedExpert Home > Medications Facts > Bupropion (Wellbutrin)

Bupropion was synthesized in 1966 by Burroughs Research' group of scientists seeking "an agent that would be active in antidepressant screening models, but differ chemically and pharmacologically from the tricyclics, and not be sympathomimetic, cholinolytic, nor an inhibitor of monoamine oxidase" (Soroko et al. 1977). The bupropion research endeavour led to the discovery of a molecule with a novel mechanism of action and a favorable side-effect profile that minimized the anticholinergic, sympathomimetic, and cardiac effects of many of the antidepressants that were currently in use. Bupropion was patented by Burroughs-Wellcome (later Glaxo-Wellcome, and, as of 2000, GlaxoSmithKline) in 1974.

There is evidence that bupropion's development was inspired by the structure of amphetamine, which had been used, with limited success, as an antidepressant in the 1930s. Bupropion is similar in structure to the stimulant cathinone (a monoamine alkaloid found in the shrub Catha edulis - Khat), and to phenethylamines in general. It is a chemical derivative of diethylpropion, an amphetamine-like substance used as an anorectic.

It was originally approved by the FDA in 1985 and marketed under the name Wellbutrin (IR formulation) as an antidepressant. However, a significant incidence of seizures at the originally recommended dosage (400-600 mg) caused the removal of the drug from the market in 1986. It was subsequently discovered that reducing the dose by about half greatly reduced the risk of seizures. Bupropion was re-introduced to the market in 1989 with the maximum dose of 450 mg/day.

Glaxo then developed a sustained-release (SR) version of Wellbutrin which releases bupropion hydrochloride at a slower rate. It was approved by the FDA in 1996. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the brand name Zyban.

Extended Release bupropion, Wellbutrin XL, is the most recent formulation of bupropion (approved in 2003) and is taken orally once a day2. Because of this altered mechanism of delivery and reduced dosing, incidence of seizures with bupropion is comparable to, and in some cases, lower than that of other antidepressants.

Bupropion was licensed as a pharmacotherapy for smoking cessation in the United Kingdom in 2000, and for the prevention of seasonal major depressive episodes in patients with seasonal affective disorder in the United States in 2006.

In some countries bupropion is approved only as a smoking cessation aid and not as a treatment of depression.

• Major depressive disorder
• Seasonal affective disorder (Extended-release formulation)
• Smoking cessation (Sustained-release formulation)

• weight loss 18, 19, 20
• attention-deficit hyperactivity disorder (ADHD) 16
• bipolar depression 7
• chronic fatigue syndrome 24
• pathological gambling (PG) 27
• methamphetamine dependence 15
• improvement in sexual functioning in women 21, 23
• augmentation of SSRIs and venlafaxine in partial and non-responders 8
• antidote for SSRI-induced sexual dysfunction 22
• dysthymic disorder (DD)
• neuropathic pain 17
• schizoaffective disorder 25

Switching to bupropion (Wellbutrin) from SSRI
Switching to bupropion, for depressed patients not responding to SSRIs, is a popular strategy among clinicians. The study assessed the efficacy of bupropion SR in the management of major depressive disorder resistant to a prospective trial of fluoxetine. Approximately 60% of patients with MDD resistant to a prospective trial of fluoxetine experienced a full or partial response to bupropion SR. Bupropion SR should be considered as a potential treatment for patients who remain depressed despite treatment with SSRIs. 10

Bupropion (Wellbutrin) for weight loss
Bupropion efficacy and tolerability was studied in overweight and obese adult women. In the study were included 50 overweight and obese women. All women were prescribed a 1600 kcal/d balanced diet. 25 women receiving bupropion achieved greater mean weight loss over the first 8 weeks: 4.9% +/- 3.4%, compared with 25 women in placebo group: 1.3% +/- 2.4%. For those who completed the 8 weeks, 12 of 18 of the bupropion subjects (67%) lost over 5% of baseline body weight compared with 2 of 13 in the placebo group (15%). In the continuation phase, 14 bupropion responders who completed 24 weeks achieved weight loss of 12.9% +/- 5.6% with fat accounting for 73.5% +/- 3.7% of the weight lost and no change in bone mineral density as assessed by DXA. Bupropion was generally well-tolerated in this sample 18.

Another clinical study evaluated the efficacy and tolerability of bupropion sustained-release (bupropion SR) in reducing weight and depressive symptoms in obese adults. The bupropion SR group (n = 193) lost an average of 4.4 kg (4.6% of baseline weight) vs. 1.7 kg (1.8% of baseline weight) on placebo (n = 191). More patients in the bupropion SR group than in the placebo group (40% vs. 16% of intent-to-treat sample, 50% vs. 28% of completers, respectively) lost at least 5% of baseline weight. The percentage of patients reporting > or =50% decrease in depressive symptoms did not differ between groups, but depressive symptoms improved more with bupropion SR than with placebo. In the sample as a whole, improvement in depressive symptoms was related to weight loss of > or =5% regardless of treatment 19.

The results of the 48-week double-blind, placebo- controlled trial have shown, that bupropion SR 300 and 400 mg/d are well-tolerated by obese adults and are associated with a 24-week weight loss of 7.2% and 10.1% and sustained weight losses at 48 weeks 20.

Bupropion (Wellbutrin) for Attention-deficit hyperactivity disorder (ADHD)
This was a double-blind, placebo-controlled, randomized, parallel, 6-week trial comparing 21 patients receiving bupropion SR (up to 200 mg b.i.d.) to 19 patients receiving placebo. Bupropion treatment was associated with a significant change in ADHD symptoms at the week-6 endpoint (42% reduction), which exceeded the effects of placebo (24% reduction). In analyses using a cutoff of 30% or better reduction to denote response, 76% of the subjects receiving bupropion improved, compared to 37% of the subjects receiving placebo. Similarly, in analyses using Clinical Global Impression scale scores, 52% of the subjects receiving bupropion reported being "much improved" to "very improved," compared to 11% of the subjects receiving placebo. These results indicate a clinically and statistically significant effect of bupropion in improving ADHD in adults 16.

• Advantages:
• low rates of sexual side effects 12
• does not cause weight gain
• REM sleep enhancement (shortens REM latency and increases REM sleep) 4
• least chance of triggering mania 5
• lower risk of inducing switches to hypomania or mania in bipolar depression 7
• does not affect psychomotor performance 9
• similar effectiveness to SSRIs 12, 13
• less nausea, diarrhea, somnolence than with SSRIs 13
• increased libido, perhaps evidence of its dopaminergic properties
• Disadvantages:
• dose-related risk of seizures (with the dose 450 mg/day or less the risk is about 0.48%) 6
• potential for hepatotoxicity
• not suitable for persons with anorexia or bulimia
• high rate of activating side effects
• high potential for drug-drug interactions

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor.

The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated 26.

The mean elimination half-life of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.

Bupropion has at least three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. Hydroxybupropion's half-life is 20 hours, threohydrobupropion's half-life is 37 hours and erythrohydrobupropion's 33 hours.

So, it may take 5 to 8 days for bupropion to clear out the system.

Full antidepressant effect may not be evident until several weeks of treatment.

The efficacy of bupropion SR (Wellbutrin SR) in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial 1.

In animal studies and small studies with persons having experience with the use of amphetamines or cocaine, bupropion caused drug-seeking behaviour (animal experiments) and was recognized as an amphetamine-like drug by the humans. In a scale ranging from placebo on the lower side to benzedrine, it was given an intermediate score indicating moderate likelihood of abuse. In clinical practice, it has been shown that the dose required for significant abuse would cause seizures in most patients. Abuse has not become a significant problem in clinical usage, but the drug should be given with caution to patients with a history of drug or alcohol abuse or dependence.

• Bupropion (Wellbutrin) versus Other Medications

• 1. U.S. Food and Drug Administration. Wellbutrin SR U.S. Prescribing Information. Available at: PDF Format
• 2. FDA Center for Drug Evaluation and Research. Drug Details for Wellbutrin. Drugs FDA
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