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{{drugbox || IUPAC_name = (±)-1-(3-chlorophenyl)-2--
1-propanone| image = Bupropion.png| image2 = Bupropion-3d-CPK.png| width = 135| CAS_number = 34841-39-9| ATC_prefix = N07| ATC_suffix = BA02| PubChem = 444| DrugBank = APRD00621| C = 13 | H = 18 | Cl = 1 | N = 1 | O = 1| molecular_weight = 239.74 g/mol| bioavailability = 5 to 20% in animals; no studies in humans| metabolism = Liver—important CYP2B6 and
CYP2D6 involvement| elimination_half-life = 20 hours| excretion = Kidney (87%), fecal (10%)| pregnancy_AU = B2| pregnancy_US = C| legal_US = Rx-only| legal_UK = POM| routes_of_administration = Oral-->
Bupropion (International Nonproprietary Name; previously known as
amfebutamone,The INN originally assigned in 1974 by the
World Health Organization was "amfebutamone". In 2000, the INN was reassigned as
bupropion. See brand names
Wellbutrin,
Zyban,
Budeprion and
Buproban) is an atypical
antidepressant that acts as a
norepinephrine reuptake inhibitor and
dopamine reuptake inhibitor, and nicotinic antagonist. Bupropion belongs to the chemical class of aminoketones and is similar in structure to the stimulant cathinone, to the anorectic diethylpropion, and to phenethylamines in general.
Initially researched and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. In 2006 it was the fourth-most prescribed antidepressant in the United States retail market, with more than 21 million prescriptions.After sertraline, escitalopram and
fluoxetine. The bupropion prescriptions were calculated as a total of prescriptions for Wellbutrin XR, Budeprion XR, Bupropion XR and Bupropion ER using data from the charts for generic and brand-name drugs.
Bupropion lowers seizure threshold and its potential to cause seizures was widely publicized. However, at the recommended dose the risk of seizures is comparable to the one observed for other antidepressants. In contrast to many psychiatric drugs, bupropion does not cause weight gain or
sexual dysfunction.
History
Bupropion was first synthesized by Burroughs Research in 1966, and patented by Burroughs–Wellcome (now
GlaxoSmithKline) in 1974. It was approved by the United States Food and Drug Administration (FDA) as an antidepressant on December 30
1985 and marketed under the name Wellbutrin.WELLBUTRIN Label and Approval History. U.S.
Food and Drug Administration Center for Drug Evaluation and Research. Retrieved on 2007-08-18. Data available for download on FDA website. However, a significant incidence of seizures at the originally recommended dosage (400–600 mg) caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a maximum recommended dose of 450 mg/day.
In 1996, the FDA approved a
sustained release formulation of bupropion called Wellbutrin SR, intended to be taken twice a day (as compared to three times a day for immediate-release Wellbutrin)." Bupropion Helps People With Schizophrenia Quit Smoking."
National Institute on Drug Abuse. Research Findings, Vol. 20, No. 5 (April 2006). Retrieved on August 19, 2007. In 2003 the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing. Wellbutrin SR and XL are available in the United States in
generic drug form. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.Staff Writer. " Seasonal affective disorder drug Wellbutrin XL wins approval."
CNN. June 14, 2006. Retrieved on
August 19,
2007.
Therapeutic uses
Depression
Placebo-controlled double-blind clinical studies have confirmed the efficacy of bupropion for
clinical depression. Comparative clinical studies demonstrated the equivalency of bupropion and sertraline (Zoloft), fluoxetine (Prozac),
paroxetine (Paxil) and
escitalopram (Lexapro) as antidepressants. A significantly higher
remission rate for bupropion treatment than for venlafaxine (Effexor) was observed in a recent study. Unlike all other antidepressants, except
mirtazapine (Remeron) and
maprotiline (Ludiomil), bupropion does not cause sexual dysfunction and the occurrence of sexual side effects is not different from placebo. For the review, see: For another review, see: Bupropion treatment is not associated with weight gain; on the contrary, at the end of every study comparing bupropion with placebo or other antidepressants the bupropion group had a lower average weight. For a short review, see: Bupropion is more effective than SSRIs at improving symptoms of
hypersomnia and
fatigue (medical) in depressed patients.
According to several surveys, the augmentation of a prescribed SSRI with bupropion is the preferred strategy among clinicians when the patient does not respond to the SSRI. Although no placebo-controlled studies of bupropion augmentation have been conducted, open-label trials and case reports generally support this strategy. For the most recent review, see: For example, the combination of bupropion and
citalopram (Celexa) was observed to be more effective than switching to another antidepressant. The addition of bupropion to an SSRI (primarily fluoxetine or sertraline) resulted in a significant improvement in 70–80% of patients who had an incomplete response to the first-line antidepressant. Bupropion improved ratings of "energy", which had decreased under the influence of the SSRI; also noted were improvements of mood and motivation, and some improvement of cognitive and sexual functions. Sleep quality and anxiety ratings in most cases were unchanged. In the STAR*D study, the patients who did not respond to citalopram (Celexa) were randomly assigned to augmentation by bupropion or
buspirone (Buspar). Approximately 30% of subjects in both groups achieved a remission. However, bupropion augmentation gave better results based on the patients' self-ratings and was much better tolerated. The authors observed that "these findings reveal a consistently more favorable outcome with sustained-release bupropion than with buspirone augmentation of citalopram." The same study indicated a possibility of higher remission rate when the non-responders to citalopram received bupropion augmentation rather than were switched to bupropion (30% vs. 20%).
Smoking cessation
Bupropion reduces the severity of nicotine cravings and withdrawal symptoms. After a seven-week treatment, 27% of subjects who received bupropion reported that an urge to smoke was a problem, versus 56% of those who received placebo. In the same study, 21% of the bupropion group reported mood swings, versus 32% of the placebo group. The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. The efficacy of bupropion is similar to that of nicotine replacement therapy. Bupropion approximately doubles the chance of quitting smoking successfully after three months. One year after the treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group. The combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison,
varenicline (Chantix) showed superior efficacy: after one year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline. Bupropion slows the weight gain that often occurs in the first weeks after quitting smoking (after seven weeks, the placebo group had an average 2.7 kg increase in weight, versus 1.5 kg for the bupropion group). With time, however, this effect becomes negligible (after 26 weeks, both groups recorded an average 4.8 kg weight gain).
Sexual dysfunction
A large body of evidence exists in favor of treating pharmacologically induced sexual dysfunction with bupropion, though it is not an FDA-approved indication. According to a survey, bupropion is the drug of choice among psychiatrists for the treatment of SSRI-induced sexual dysfunction. 36 percent of responding psychiatrists preferred switching patients with sexual dysfunction to bupropion; however, 43 percent favored the augmentation of the current medication with bupropion. There are studies demonstrating the efficacy of both approaches; improvement of the desire and orgasm components of sexual function were the most often noted. For the augmentation approach, the addition of at least 200 mg/day of bupropion to the SSRI regimen may be necessary to achieve an improvement since the addition of 150 mg/day of bupropion did not produce a statistically significant difference from placebo.
Several studies have indicated that bupropion also relieves sexual dysfunction in people who do not have depression. In a mixed-gender double-blind study, 63% of subjects on a 12-week course of bupropion rated their condition as improved or much improved, versus 3% of subjects on placebo. Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire, resulting in significant improvement of arousal, orgasm and overall satisfaction. Bupropion also showed promise as a treatment for sexual dysfunction caused by
chemotherapy for breast cancer and for orgasmic dysfunction. As with the treatment of SSRI-induced sexual disorder, a higher dose of bupropion (300 mg) may be necessary: a randomized study employing a lower dose (150 mg) failed to find a significant difference between bupropion, sexual therapy or combined treatment. Bupropion does not affect any measures of sexual functioning in healthy men.
Obesity
A recent
meta-analysis of
anti-obesity drugs pooled the results of three double-blind, placebo-controlled trials of bupropion. It confirmed the efficacy of bupropion given at 400 mg per day for treating obesity. Over a period of 6 to 12 months, weight loss in the bupropion group (4.4 kg) was significantly greater than in the placebo group (1.7 kg). The same review found the differences in weight loss between bupropion and other established weight-loss medications, such as sibutramine,
orlistat and diethylpropion, to be statistically insignificant.
Attention-deficit hyperactivity disorder
Although attention-deficit hyperactivity disorder (ADHD) is not an approved indication, bupropion was found to be effective for adult ADHD. There have been many positive case studies and other uncontrolled clinical studies of bupropion for ADHD in minors.For the review,see: However, in the largest to date double-blind study, which was conducted by GlaxoSmithKline, the results were inconclusive. Aggression and hyperactivity as rated by the children's teachers were significantly improved in comparison to placebo; in contrast, parents and clinicians could not distinguish between the effects of bupropion and placebo. The 2007 guideline on the ADHD treatment from American Academy of Child and Adolescent Psychiatry notes that the evidence for bupropion is "far weaker" than for the FDA-approved treatments. Its effect may also be "considerably less than of the approved agents... Thus it may be prudent for the clinician to recommend a trial of behavior therapy at this point, before moving to these second-line agents." Similarly, the 2006 guideline from the Texas Department of State Health Services recommends considering bupropion or a
tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and
atomoxetine (Strattera).
A study of prophylactic bupropion for the prevention of smoking among teenagers with ADHD yielded unexpected results. The teenagers taking bupropion were twice more likely (close to statistical significance) to begin smoking than the teenagers in the placebo group. At the same time, the sub-group of patients taking stimulants in addition to bupropion or placebo had a five times lower risk of smoking initiation.
Other uses
Bupropion is used for the prevention of
seasonal affective disorder, and has been approved by the FDA for the latter indication. There is considerable disagreement regarding whether the addition of an antidepressant, including bupropion, to a
mood stabilizer in patients with bipolar depression is useful.For the review indicating that antidepressants are not better than placebo, see: For the review in favor of the antidepressant use, see: For the guidelines recommending the use of bupropion with a mood stabilizer, see:
No properly controlled double-blind studies of bupropion for Parkinson's disease have been conducted. A small 1984 study funded by bupropion's manufacturer found that addition of bupropion to
carbidopa or
levodopa improved Parkinson's symptoms in ten out of twenty patients; however, the side effects, particularly nausea and vomiting, were frequent. The American Psychiatric Association notes that, "there is no evidence favoring any particular antidepressant medicationfrom the standpoint of therapeutic efficacy in patients with Parkinson’s disease complicatedby major depressive disorder."
Contraindications
GlaxoSmithKline advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the
seizure threshold, such as alcohol or
benzodiazepine discontinuation,
anorexia nervosa, bulimia, or active
brain tumors. It should be avoided in individuals who are also taking
MAO inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications. The prescribing information approved by the FDA recommends that caution should be exercised when treating patients with liver damage, severe
kidney disease, and severe
hypertension, as well as in pediatric patients, adolescents and young adults due to the increased risk of suicidal ideation.
According to a
retrospective case series published in 1993, bupropion treatment may exacerbate tics in children with comorbidity
Attention-deficit hyperactivity disorder and Tourette syndrome. No further research of this side effect has been conducted.
Risk of suicide
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 even less likely when bupropion is prescribed for smoking cessation. According to a Cochrane Library 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."
Adverse effects
The common
adverse drug reactions associated with 12-hour sustained-release bupropion (with the greatest difference from placebo) are
dry mouth, nausea, insomnia,
tremor,
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%). The development of mild to moderate skin
rashes is associated with sensitivity to dye components within the pill coating. This can often be alleviated simply by prescribing a differently colored pill.
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-seven-fold 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.
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.
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
Medicines and Healthcare products Regulatory Agency 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 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. Free full text
Other isolated adverse affects have been reported. Three cases of liver toxicity have been described in the literature,For the most recent report, see: a very low incidence given the widespread use of the drug. A single case of clitoral priapism (clitorism) has been reported in the literature.
Overdose
Overdose of bupropion results in significant clinical effects in over one-third of cases. The most common symptoms include
sinus tachycardia,
hypertension, drowsiness, lethargy, agitation, nausea and vomiting, and in particular
delirium and
seizures. Less commonly additional symptoms include auditory and visual hallucinations, coma, and Electrocardiogram changes such as conduction disturbance or cardiac arrhythmia.
In the majority of childhood exploratory ingestions involving one or two tablets, children will remain asymptomatic. In teenagers and adults seizures are more commonly observed with the seizure rate increasing tenfold with doses of 600 mg daily. One overdose study suggested a dose-dependent relationship with seizures; patients ingesting more than 4.5 g were likely to have a seizure and nearly all patients ingesting more than 9 g had a seizure.
There is no specific antidote for bupropion; treatment is supportive, and focuses on maintaining
airway patency and controlling seizures with high dose intravenous benzodiazepines or barbiturates if seizures are refractory to benzodiazepines. Gastric decontamination may be of little benefit given the risk of seizures and aspiration but activated charcoal is recommended, additionally
whole bowel irrigation should be undertaken in those ingesting sustained release formulations. Toxic effects may be delayed in onset, with seizures developing as late as 32 hours, subsequently patients should undergo electroencephalography monitoring for 48 hours.
Bupropion overdose rarely results in death, although cases have been reported. Fatalities are typically associated with large overdosage and related to metabolic acidosis and Hypoxia (medical) as complications of status epilepticus with associated
cardiorespiratory arrest.
Mechanism of action
Bupropion is a
dopamine reuptake inhibitor and norepinephrine reuptake inhibitor. It is about twice as potent an inhibitor of dopamine reuptake than of norepinephrine reuptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without reference to its metabolism. The occupancy of
dopamine transporter (DAT) by bupropion and its metabolites in the human brain as measured by
positron emission tomography was 6–22% in an independent study and 12–35% according to GlaxoSmithKline researchers. Based on analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of the drug's action. Bupropion does not inhibit
monoamine oxidase or
serotonin reuptake. However, it has been shown to indirectly enhance the firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive
Nicotinic acetylcholine receptor#Subunits nicotinic antagonist.
{{drugbox || IUPAC_name = (±)-1-(3-chlorophenyl)-2--
1-propanone| image = Bupropion.png| image2 = Bupropion-3d-CPK.png| width = 135| CAS_number = 34841-39-9| ATC_prefix = N07| ATC_suffix = BA02| PubChem = 444| DrugBank = APRD00621| C = 13 | H = 18 | Cl = 1 | N = 1 | O = 1| molecular_weight = 239.74 g/mol| bioavailability = 5 to 20% in animals; no studies in humans| metabolism = Liver—important CYP2B6 and CYP2D6 involvement| elimination_half-life = 20 hours| excretion =
Kidney (87%), fecal (10%)| pregnancy_AU = B2| pregnancy_US = C| legal_US = Rx-only| legal_UK = POM| routes_of_administration = Oral-->
Bupropion (
International Nonproprietary Name; previously known as
amfebutamone,The INN originally assigned in 1974 by the World Health Organization was "amfebutamone". In 2000, the INN was reassigned as
bupropion. See brand names
Wellbutrin,
Zyban,
Budeprion and
Buproban) is an atypical antidepressant that acts as a
norepinephrine reuptake inhibitor and dopamine reuptake inhibitor, and
nicotinic antagonist. Bupropion belongs to the chemical class of aminoketones and is similar in structure to the stimulant
cathinone, to the anorectic
diethylpropion, and to phenethylamines in general.
Initially researched and marketed as an antidepressant, bupropion was subsequently found to be effective as a
smoking cessation aid. In 2006 it was the fourth-most prescribed antidepressant in the United States retail market, with more than 21 million prescriptions.After sertraline,
escitalopram and
fluoxetine. The bupropion prescriptions were calculated as a total of prescriptions for Wellbutrin XR, Budeprion XR, Bupropion XR and Bupropion ER using data from the charts for generic and brand-name drugs.
Bupropion lowers seizure threshold and its potential to cause seizures was widely publicized. However, at the recommended dose the risk of seizures is comparable to the one observed for other antidepressants. In contrast to many psychiatric drugs, bupropion does not cause weight gain or sexual dysfunction.
History
Bupropion was first synthesized by Burroughs Research in 1966, and patented by Burroughs–Wellcome (now GlaxoSmithKline) in 1974. It was approved by the United States Food and Drug Administration (FDA) as an antidepressant on
December 30 1985 and marketed under the name Wellbutrin.WELLBUTRIN Label and Approval History. U.S.
Food and Drug Administration Center for Drug Evaluation and Research. Retrieved on
2007-08-18. Data available for download on FDA website. However, a significant incidence of
seizures at the originally recommended dosage (400–600 mg) caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a maximum recommended dose of 450 mg/day.
In 1996, the FDA approved a sustained release formulation of bupropion called Wellbutrin SR, intended to be taken twice a day (as compared to three times a day for immediate-release Wellbutrin)." Bupropion Helps People With Schizophrenia Quit Smoking."
National Institute on Drug Abuse. Research Findings, Vol. 20, No. 5 (April 2006). Retrieved on August 19,
2007. In 2003 the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing. Wellbutrin SR and XL are available in the United States in
generic drug form. In 1997, bupropion was approved by the FDA for use as a
smoking cessation aid under the name Zyban. In 2006, Wellbutrin XL was similarly approved as a treatment for
seasonal affective disorder.Staff Writer. " Seasonal affective disorder drug Wellbutrin XL wins approval."
CNN. June 14,
2006. Retrieved on August 19,
2007.
Therapeutic uses
Depression
Placebo-controlled double-blind clinical studies have confirmed the efficacy of bupropion for clinical depression. Comparative clinical studies demonstrated the equivalency of bupropion and sertraline (Zoloft), fluoxetine (Prozac),
paroxetine (Paxil) and escitalopram (Lexapro) as antidepressants. A significantly higher
remission rate for bupropion treatment than for
venlafaxine (Effexor) was observed in a recent study. Unlike all other antidepressants, except mirtazapine (Remeron) and maprotiline (Ludiomil), bupropion does not cause sexual dysfunction and the occurrence of sexual side effects is not different from placebo. For the review, see: For another review, see: Bupropion treatment is not associated with weight gain; on the contrary, at the end of every study comparing bupropion with placebo or other antidepressants the bupropion group had a lower average weight. For a short review, see: Bupropion is more effective than
SSRIs at improving symptoms of hypersomnia and fatigue (medical) in depressed patients.
According to several surveys, the
augmentation of a prescribed SSRI with bupropion is the preferred strategy among clinicians when the patient does not respond to the SSRI. Although no placebo-controlled studies of bupropion augmentation have been conducted, open-label trials and case reports generally support this strategy. For the most recent review, see: For example, the combination of bupropion and citalopram (Celexa) was observed to be more effective than switching to another antidepressant. The addition of bupropion to an SSRI (primarily fluoxetine or sertraline) resulted in a significant improvement in 70–80% of patients who had an incomplete response to the first-line antidepressant. Bupropion improved ratings of "energy", which had decreased under the influence of the SSRI; also noted were improvements of mood and motivation, and some improvement of cognitive and sexual functions. Sleep quality and anxiety ratings in most cases were unchanged. In the STAR*D study, the patients who did not respond to citalopram (Celexa) were randomly assigned to augmentation by bupropion or
buspirone (Buspar). Approximately 30% of subjects in both groups achieved a remission. However, bupropion augmentation gave better results based on the patients' self-ratings and was much better tolerated. The authors observed that "these findings reveal a consistently more favorable outcome with sustained-release bupropion than with buspirone augmentation of citalopram." The same study indicated a possibility of higher remission rate when the non-responders to citalopram received bupropion augmentation rather than were switched to bupropion (30% vs. 20%).
Smoking cessation
Bupropion reduces the severity of nicotine cravings and withdrawal symptoms. After a seven-week treatment, 27% of subjects who received bupropion reported that an urge to smoke was a problem, versus 56% of those who received placebo. In the same study, 21% of the bupropion group reported mood swings, versus 32% of the placebo group. The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. The efficacy of bupropion is similar to that of nicotine replacement therapy. Bupropion approximately doubles the chance of quitting smoking successfully after three months. One year after the treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group. The combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison, varenicline (Chantix) showed superior efficacy: after one year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline. Bupropion slows the weight gain that often occurs in the first weeks after quitting smoking (after seven weeks, the placebo group had an average 2.7 kg increase in weight, versus 1.5 kg for the bupropion group). With time, however, this effect becomes negligible (after 26 weeks, both groups recorded an average 4.8 kg weight gain).
Sexual dysfunction
A large body of evidence exists in favor of treating pharmacologically induced sexual dysfunction with bupropion, though it is not an FDA-approved indication. According to a survey, bupropion is the drug of choice among psychiatrists for the treatment of SSRI-induced sexual dysfunction. 36 percent of responding psychiatrists preferred switching patients with sexual dysfunction to bupropion; however, 43 percent favored the augmentation of the current medication with bupropion. There are studies demonstrating the efficacy of both approaches; improvement of the desire and orgasm components of sexual function were the most often noted. For the augmentation approach, the addition of at least 200 mg/day of bupropion to the SSRI regimen may be necessary to achieve an improvement since the addition of 150 mg/day of bupropion did not produce a statistically significant difference from placebo.
Several studies have indicated that bupropion also relieves sexual dysfunction in people who do not have depression. In a mixed-gender double-blind study, 63% of subjects on a 12-week course of bupropion rated their condition as improved or much improved, versus 3% of subjects on placebo. Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire, resulting in significant improvement of arousal, orgasm and overall satisfaction. Bupropion also showed promise as a treatment for sexual dysfunction caused by chemotherapy for breast cancer and for orgasmic dysfunction. As with the treatment of SSRI-induced sexual disorder, a higher dose of bupropion (300 mg) may be necessary: a randomized study employing a lower dose (150 mg) failed to find a significant difference between bupropion, sexual therapy or combined treatment. Bupropion does not affect any measures of sexual functioning in healthy men.
Obesity
A recent meta-analysis of anti-obesity drugs pooled the results of three double-blind, placebo-controlled trials of bupropion. It confirmed the efficacy of bupropion given at 400 mg per day for treating obesity. Over a period of 6 to 12 months, weight loss in the bupropion group (4.4 kg) was significantly greater than in the placebo group (1.7 kg). The same review found the differences in weight loss between bupropion and other established weight-loss medications, such as
sibutramine,
orlistat and diethylpropion, to be statistically insignificant.
Attention-deficit hyperactivity disorder
Although
attention-deficit hyperactivity disorder (ADHD) is not an approved indication, bupropion was found to be effective for adult ADHD. There have been many positive case studies and other uncontrolled clinical studies of bupropion for ADHD in minors.For the review,see: However, in the largest to date double-blind study, which was conducted by GlaxoSmithKline, the results were inconclusive. Aggression and hyperactivity as rated by the children's teachers were significantly improved in comparison to placebo; in contrast, parents and clinicians could not distinguish between the effects of bupropion and placebo. The 2007 guideline on the ADHD treatment from American Academy of Child and Adolescent Psychiatry notes that the evidence for bupropion is "far weaker" than for the FDA-approved treatments. Its effect may also be "considerably less than of the approved agents... Thus it may be prudent for the clinician to recommend a trial of behavior therapy at this point, before moving to these second-line agents." Similarly, the 2006 guideline from the Texas Department of State Health Services recommends considering bupropion or a
tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and
atomoxetine (Strattera).
A study of prophylactic bupropion for the prevention of smoking among teenagers with ADHD yielded unexpected results. The teenagers taking bupropion were twice more likely (close to statistical significance) to begin smoking than the teenagers in the placebo group. At the same time, the sub-group of patients taking stimulants in addition to bupropion or placebo had a five times lower risk of smoking initiation.
Other uses
Bupropion is used for the prevention of seasonal affective disorder, and has been approved by the FDA for the latter indication. There is considerable disagreement regarding whether the addition of an antidepressant, including bupropion, to a mood stabilizer in patients with bipolar depression is useful.For the review indicating that antidepressants are not better than placebo, see: For the review in favor of the antidepressant use, see: For the guidelines recommending the use of bupropion with a mood stabilizer, see:
No properly controlled double-blind studies of bupropion for
Parkinson's disease have been conducted. A small 1984 study funded by bupropion's manufacturer found that addition of bupropion to carbidopa or levodopa improved Parkinson's symptoms in ten out of twenty patients; however, the side effects, particularly nausea and vomiting, were frequent. The American Psychiatric Association notes that, "there is no evidence favoring any particular antidepressant medicationfrom the standpoint of therapeutic efficacy in patients with Parkinson’s disease complicatedby major depressive disorder."
Contraindications
GlaxoSmithKline advises that bupropion should not be prescribed to individuals with
epilepsy or other conditions that lower the seizure threshold, such as alcohol or benzodiazepine discontinuation,
anorexia nervosa,
bulimia, or active
brain tumors. It should be avoided in individuals who are also taking MAO inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications. The prescribing information approved by the FDA recommends that caution should be exercised when treating patients with liver damage, severe
kidney disease, and severe hypertension, as well as in pediatric patients, adolescents and young adults due to the increased risk of suicidal ideation.
According to a
retrospective case series published in 1993, bupropion treatment may exacerbate
tics in children with comorbidity Attention-deficit hyperactivity disorder and
Tourette syndrome. No further research of this side effect has been conducted.
Risk of suicide
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 even less likely when bupropion is prescribed for smoking cessation. According to a Cochrane Library 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."
Adverse effects
The common adverse drug reactions associated with 12-hour sustained-release bupropion (with the greatest difference from placebo) are dry mouth, nausea,
insomnia, tremor, 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%). The development of mild to moderate skin
rashes is associated with sensitivity to dye components within the pill coating. This can often be alleviated simply by prescribing a differently colored pill.
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-seven-fold 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.
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.
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
Medicines and Healthcare products Regulatory Agency 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 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. Free full text
Other isolated adverse affects have been reported. Three cases of liver toxicity have been described in the literature,For the most recent report, see: a very low incidence given the widespread use of the drug. A single case of clitoral
priapism (clitorism) has been reported in the literature.
Overdose
Overdose of bupropion results in significant clinical effects in over one-third of cases. The most common symptoms include sinus tachycardia, hypertension, drowsiness, lethargy, agitation, nausea and vomiting, and in particular delirium and
seizures. Less commonly additional symptoms include auditory and visual
hallucinations,
coma, and
Electrocardiogram changes such as conduction disturbance or cardiac arrhythmia.
In the majority of childhood exploratory ingestions involving one or two tablets, children will remain asymptomatic. In teenagers and adults seizures are more commonly observed with the seizure rate increasing tenfold with doses of 600 mg daily. One overdose study suggested a dose-dependent relationship with seizures; patients ingesting more than 4.5 g were likely to have a seizure and nearly all patients ingesting more than 9 g had a seizure.
There is no specific antidote for bupropion; treatment is supportive, and focuses on maintaining
airway patency and controlling seizures with high dose intravenous
benzodiazepines or
barbiturates if seizures are refractory to benzodiazepines. Gastric decontamination may be of little benefit given the risk of seizures and aspiration but activated charcoal is recommended, additionally
whole bowel irrigation should be undertaken in those ingesting sustained release formulations. Toxic effects may be delayed in onset, with seizures developing as late as 32 hours, subsequently patients should undergo electroencephalography monitoring for 48 hours.
Bupropion overdose rarely results in death, although cases have been reported. Fatalities are typically associated with large overdosage and related to
metabolic acidosis and Hypoxia (medical) as complications of status epilepticus with associated cardiorespiratory arrest.
Mechanism of action
Bupropion is a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor. It is about twice as potent an inhibitor of dopamine reuptake than of norepinephrine reuptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without reference to its metabolism. The occupancy of
dopamine transporter (DAT) by bupropion and its metabolites in the human brain as measured by
positron emission tomography was 6–22% in an independent study and 12–35% according to GlaxoSmithKline researchers. Based on analogy with
serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of the drug's action. Bupropion does not inhibit monoamine oxidase or serotonin reuptake. However, it has been shown to indirectly enhance the firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive Nicotinic acetylcholine receptor#Subunits nicotinic antagonist.
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