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===Smoking cessation===
===Smoking cessation===
Bupropion reduces the severity of [[nicotine]] cravings and [[withdrawal]] symptoms. After a seven-week treatment, 27% of subjects who received bupropion reported an urge to smoke, 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.<ref name = "Tonnesen2003">{{cite journal | author = Tonnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel P I, Hider A, Sweet R, Townsend J| title = A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation | journal = J Intern Med| volume = 254|issue = 2|pages = 184–192| year = 2003 |id=PMID 12859700}}</ref> 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 roughly 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.<ref>{{cite journal | author = Wu P, Wilson K, Dimoulas P, Mills E J | title = Effectiveness of smoking cessation therapies: a systematic review and meta-analysis | journal = BMC Public Health| volume = 6|pages = 300–315 | year = 2006}}</ref> The combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison, the newer [[varenicline]] (Chantix) showed superior efficacy: after one year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline.<ref>{{cite journal | author = Jorenby D E, Hays J T, Rigotti N A, Azoulay S, Watsky E J, Williams K E, Billing C B, Gong J, Reeves K R| title = Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial | journal = JAMA| volume = 296|issue = 1|pages = 56–63| year = 2006 |id=PMID 16820547}}</ref> 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).<ref name = "Tonnesen2003"/>
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.<ref name = "Tonnesen2003">{{cite journal | author = Tonnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel P I, Hider A, Sweet R, Townsend J| title = A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation | journal = J Intern Med| volume = 254|issue = 2|pages = 184–192| year = 2003 |id=PMID 12859700}}</ref> 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.<ref>{{cite journal | author = Wu P, Wilson K, Dimoulas P, Mills E J | title = Effectiveness of smoking cessation therapies: a systematic review and meta-analysis | journal = BMC Public Health| volume = 6|pages = 300–315 | year = 2006}}</ref> 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.<ref>{{cite journal | author = Jorenby D E, Hays J T, Rigotti N A, Azoulay S, Watsky E J, Williams K E, Billing C B, Gong J, Reeves K R| title = Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial | journal = JAMA| volume = 296|issue = 1|pages = 56–63| year = 2006 |id=PMID 16820547}}</ref> 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).<ref name = "Tonnesen2003"/>


===Sexual dysfunction===
===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. In that survey, 36 percent of responding psychiatrists said they preferred switching patients with sexual dysfunction to bupropion; however, 43 percent said they favored the augmentation of bupropion with the current medication.<ref>{{cite journal | author =Dording CM, Mischoulon D, Petersen TJ, Kornbluh R, Gordon J, Nierenberg AA, Rosenbaum JE, Fava M.| title = The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists| journal = Ann Clin Psychiatry| volume = 14|issue=3| pages = 143–7 | year = 2002|id=PMID 12585563}}</ref> There are studies demonstrating the efficacy of both approaches, showing improvements in sexual desire and ability to reach orgasm most often noted. For the augmentation approach, the addition of at least 200&nbsp;mg/day of bupropion to the SSRI is necessary to achieve a statistically significant improvement. The addition of 150&nbsp;mg/day of bupropion to the SSRI regimen did not produce a statistically significant difference from placebo.<ref>{{cite journal | author = Walker PW, Cole JO, Gardner EA, Hughes AR, Johnston JA, Batey SR, Lineberry CG| title = Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion| journal = J Clin Psychiatry| volume = 54 |issue=12| pages = 459–65 | year = 1993|id=PMID 8276736}}</ref><ref>{{cite journal | author = Dobkin RD, Menza M, Marin H, Allen LA, Rousso R, Leiblum SR| title = Bupropion improves sexual functioning in depressed minority women: an open-label switch study| journal = J Clin Psychiatry| volume = 26|issue=1| pages = 21–6 | year = 2006|id=PMID 16415700}}</ref><ref>{{cite journal | author = Masand PS, Ashton AK, Gupta S, Frank B| title = Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study| journal = Am J Psychiatry | volume = 158|issue=5| pages = 805–807 | year = 2001|id=PMID 11329407}}</ref><ref>{{cite journal | author =DeBattista C, Solvason B, Poirier J, Kendrick E, Loraas E|title = A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction| journal = J Clin Psychiatry | volume = 66|issue=7| pages = 844–8 | year = 2005}}</ref><ref>{{cite journal | author = Ashton AK, Rosen RC| title = Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction.| journal = J Clin Psychiatry| volume = 59|issue=3| pages = 112–5 | year = 1998|id=PMID 9541153}}</ref><ref>{{cite journal | author =Clayton AH, Warnock JK, Kornstein SG, Pinkerton R, Sheldon-Keller A, McGarvey EL| title = A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction| journal = J Clin Psychiatry | volume = 65|issue=1| pages = 62–7 | year = 2004|id=PMID 14744170}}</ref>
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 .<ref>{{cite journal | author =Dording CM, Mischoulon D, Petersen TJ, Kornbluh R, Gordon J, Nierenberg AA, Rosenbaum JE, Fava M.| title = The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists| journal = Ann Clin Psychiatry| volume = 14|issue=3| pages = 143–7 | year = 2002|id=PMID 12585563}}</ref> There are studies demonstrating the efficacy of both approaches; improvement of desire and orgasm components of the sexual function being the most often noted. For the augmentation approach, the addition of at least 200&nbsp;mg/day of bupropion to the SSRI regimen may be necessary to achieve an improvement since the addition of 150&nbsp;mg/day of bupropion did not produce a statistically significant difference from placebo.<ref>{{cite journal | author = Walker PW, Cole JO, Gardner EA, Hughes AR, Johnston JA, Batey SR, Lineberry CG| title = Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion| journal = J Clin Psychiatry| volume = 54 |issue=12| pages = 459–65 | year = 1993|id=PMID 8276736}}</ref><ref>{{cite journal | author = Dobkin RD, Menza M, Marin H, Allen LA, Rousso R, Leiblum SR| title = Bupropion improves sexual functioning in depressed minority women: an open-label switch study| journal = J Clin Psychiatry| volume = 26|issue=1| pages = 21–6 | year = 2006|id=PMID 16415700}}</ref><ref>{{cite journal | author = Masand PS, Ashton AK, Gupta S, Frank B| title = Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study| journal = Am J Psychiatry | volume = 158|issue=5| pages = 805–807 | year = 2001|id=PMID 11329407}}</ref><ref>{{cite journal | author =DeBattista C, Solvason B, Poirier J, Kendrick E, Loraas E|title = A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction| journal = J Clin Psychiatry | volume = 66|issue=7| pages = 844–8 | year = 2005}}</ref><ref>{{cite journal | author = Ashton AK, Rosen RC| title = Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction.| journal = J Clin Psychiatry| volume = 59|issue=3| pages = 112–5 | year = 1998|id=PMID 9541153}}</ref><ref>{{cite journal | author =Clayton AH, Warnock JK, Kornstein SG, Pinkerton R, Sheldon-Keller A, McGarvey EL| title = A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction| journal = J Clin Psychiatry | volume = 65|issue=1| pages = 62–7 | year = 2004|id=PMID 14744170}}</ref


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.<ref>{{cite journal | author =Crenshaw TL, Goldberg JP, Stern WC| title = Pharmacologic modification of psychosexual dysfunction| journal = J Sex Marital Ther| volume = 13|issue=4| pages = 239–52 | year = 1987|id=PMID 3121861}}</ref> Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire,<ref>{{cite journal | author = Segraves RT, Croft H, Kavoussi R, Ascher JA, Batey SR, Foster VJ, Bolden-Watson C, Metz A| title = Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women| journal = J Sex Marital Ther| volume = 27|issue=3| pages = 303–16 | year = 2001|id=PMID 11354935}}</ref><ref>{{cite journal | author = Segraves RT, Clayton A, Croft H, Wolf A, Warnock J.| title =Bupropion sustained release for the treatment of hypoactive sexual desire disorder in premenopausal women| journal = J Clin Psychopharmacol| volume = 24|issue=3| pages = 339–42 | year = 2004|id=PMID 15118489}}</ref> 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<ref>{{cite journal | author =Mathias C, Cardeal Mendes CM, Ponde de Sena E, Dias de Moraes E, Bastos C, Braghiroli MI, Nunez G, Athanazio R, Alban L, Moore HC, del Giglio A| title = An open-label, fixed-dose study of bupropion effect on sexual function scores in women treated for breast cancer| journal = Ann Oncol| volume = 17|issue=12| pages = 1792–6 | year = 20060|id=PMID 16980597}}</ref> and for orgasmic dysfunction.<ref>{{cite journal | author =Modell JG, May RS, Katholi CR| title =Effect of bupropion-SR on orgasmic dysfunction in nondepressed subjects: a pilot study| journal = J Sex Marital Ther| volume = 26|issue=3| pages = 231-40 | year = 2000|id=PMID 10929571}}</ref> As with the treatment of SSRI-induced sexual disorder, a higher dose of bupropion (300&nbsp;mg) may be necessary: a randomized study employing a lower dose (150&nbsp;mg) failed to find a significant difference between bupropion, sexual therapy or combined treatment.<ref>{{cite journal | author = Cabello F| title = Effectiveness of the Treatment of Female Hypoactive Sexual Desire Disorder | journal = J Sex Research| month = Feb| year = 2006| accessdate = 2007-04-05 | url = http://www.findarticles.com/p/articles/mi_m2372/is_1_43/ai_n16102437}}</ref> Bupropion does not affect any measures of sexual functioning in healthy men.<ref>{{cite journal | author =Labbate LA, Brodrick PS, Nelson RP, Lydiard RB, Arana GW| title =Effects of bupropion sustained-release on sexual functioning and nocturnal erections in healthy men| journal = J Clin Psychopharmacol| volume = 22|issue=1| pages = 99–103 | year = 2001|id=PMID 11199957}}</ref>
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.<ref>{{cite journal | author =Crenshaw TL, Goldberg JP, Stern WC| title = Pharmacologic modification of psychosexual dysfunction| journal = J Sex Marital Ther| volume = 13|issue=4| pages = 239–52 | year = 1987|id=PMID 3121861}}</ref> Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire,<ref>{{cite journal | author = Segraves RT, Croft H, Kavoussi R, Ascher JA, Batey SR, Foster VJ, Bolden-Watson C, Metz A| title = Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women| journal = J Sex Marital Ther| volume = 27|issue=3| pages = 303–16 | year = 2001|id=PMID 11354935}}</ref><ref>{{cite journal | author = Segraves RT, Clayton A, Croft H, Wolf A, Warnock J.| title =Bupropion sustained release for the treatment of hypoactive sexual desire disorder in premenopausal women| journal = J Clin Psychopharmacol| volume = 24|issue=3| pages = 339–42 | year = 2004|id=PMID 15118489}}</ref> 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<ref>{{cite journal | author =Mathias C, Cardeal Mendes CM, Ponde de Sena E, Dias de Moraes E, Bastos C, Braghiroli MI, Nunez G, Athanazio R, Alban L, Moore HC, del Giglio A| title = An open-label, fixed-dose study of bupropion effect on sexual function scores in women treated for breast cancer| journal = Ann Oncol| volume = 17|issue=12| pages = 1792–6 | year = 20060|id=PMID 16980597}}</ref> and for orgasmic dysfunction.<ref>{{cite journal | author =Modell JG, May RS, Katholi CR| title =Effect of bupropion-SR on orgasmic dysfunction in nondepressed subjects: a pilot study| journal = J Sex Marital Ther| volume = 26|issue=3| pages = 231-40 | year = 2000|id=PMID 10929571}}</ref> As with the treatment of SSRI-induced sexual disorder, a higher dose of bupropion (300&nbsp;mg) may be necessary: a randomized study employing a lower dose (150&nbsp;mg) failed to find a significant difference between bupropion, sexual therapy or combined treatment.<ref>{{cite journal | author = Cabello F| title = Effectiveness of the Treatment of Female Hypoactive Sexual Desire Disorder | journal = J Sex Research| month = Feb| year = 2006| accessdate = 2007-04-05 | url = http://www.findarticles.com/p/articles/mi_m2372/is_1_43/ai_n16102437}}</ref> Bupropion does not affect any measures of sexual functioning in healthy men.<ref>{{cite journal | author =Labbate LA, Brodrick PS, Nelson RP, Lydiard RB, Arana GW| title =Effects of bupropion sustained-release on sexual functioning and nocturnal erections in healthy men| journal = J Clin Psychopharmacol| volume = 22|issue=1| pages = 99–103 | year = 2001|id=PMID 11199957}}</ref>
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==Contraindications==
==Contraindications==
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 tumor]]s. It should be avoided in individuals that are also taking [[MAO inhibitor]]s. When switching from an MAOI to bupropion, it is important to include a washout period of about two weeks between the medications.<font size="-1"><ref name="WellbutrinPI"/></font> 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.<font size="-1"><ref name="WellbutrinPI"/></font>
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 tumor]]s. It should be avoided in individuals that are also taking [[MAO inhibitor]]s. When switching from a MAOI to bupropion, it is important to include a washout period of about two weeks between the medications.<font size="-1"><ref name="WellbutrinPI"/></font> 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.<font size="-1"><ref name="WellbutrinPI"/></font>


===Risk of suicide===
===Risk of suicide===
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Hydroxybupropion (but not bupropion) is itself an inhibitor of [[CYP2D6]], as well as a substrate of that enzyme. A significant increase in the concentration of some drugs metabolized by CYP2D6 (venlafaxine, [[desipramine]] and [[dextromethorphan]], but not fluoxetine or paroxetine) has been observed when they are taken with bupropion.<ref name="pmid16368442"/><ref name="pmid11926715">{{cite journal |author=Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB |title=Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects |journal=J Clin Psychiatry |volume=63 |issue=3 |pages=181–6 |year=2002 |pmid=11926715 |doi=}}</ref>
Hydroxybupropion (but not bupropion) is itself an inhibitor of [[CYP2D6]], as well as a substrate of that enzyme. A significant increase in the concentration of some drugs metabolized by CYP2D6 (venlafaxine, [[desipramine]] and [[dextromethorphan]], but not fluoxetine or paroxetine) has been observed when they are taken with bupropion.<ref name="pmid16368442"/><ref name="pmid11926715">{{cite journal |author=Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB |title=Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects |journal=J Clin Psychiatry |volume=63 |issue=3 |pages=181–6 |year=2002 |pmid=11926715 |doi=}}</ref>


Bupropion lowers the seizure threshold, so extreme care should be taken when prescribing bupropion with other medications that also lower it, such as antipsychotics, [[theophylline]], [[steroid]]s, and some [[tricyclic antidepressant]]s.<ref name="WellbutrinPI"/> Its combination with [[nicotine replacement therapy|nicotine replacement therapies]] can elevate blood pressure; since this combination is no more effective than either a nicotine patch or bupropion alone, it is not recommended.
Bupropion lowers the seizure threshold; accordingly, extreme care should be taken when prescribing bupropion with other medications that also lower it, such as antipsychotics, [[theophylline]], [[steroid]]s, and some [[tricyclic antidepressant]]s.<ref name="WellbutrinPI"/> Its combination with [[nicotine replacement therapy|nicotine replacement therapies]] can elevate blood pressure; since this combination is no more effective than either a nicotine patch or bupropion alone, it is not recommended.


The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold.<ref name="WellbutrinPI"/> A small study conducted by GSK indicated that bupropion (100&nbsp;mg) may counteract the subjective effects of small doses of alcohol (16–32&nbsp;mL, slightly less than 1–2 standard US drinks). The volunteers reported feeling more sober and clear-headed and less sedated. Bupropion also reduced the detrimental effect of alcohol on auditory vigilance. The combination of bupropion (100&nbsp;mg) and two drinks of alcohol increased heart rate by six beats per minute, a statistically significant increase.<ref>{{cite web |url=http://ctr.gsk.co.uk/Summary/bupropion/I_031.pdf |title=P02-31UK I Examination of Bupropion and Ethanol, Alone and in Combination, on Human Performance Tests, Subjective Rating Scales, EEG and Autonomic Responses |accessdate=2007-06-04 |author= |authorlink= |coauthors= |date= |format=PDF |work=GlaxoSmithKline Clinical Trial Register. Bupropion Studies |publisher= |pages= |language= |archiveurl= |archivedate= |quote=}}</ref>
The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold.<ref name="WellbutrinPI"/> A small study conducted by GSK indicated that bupropion (100&nbsp;mg) may counteract the subjective effects of small doses of alcohol (16–32&nbsp;mL, slightly less than 1–2 standard US drinks). The volunteers reported feeling more sober and clear-headed and less sedated. Bupropion also reduced the detrimental effect of alcohol on auditory vigilance. The combination of bupropion (100&nbsp;mg) and two drinks of alcohol increased heart rate by six beats per minute, a statistically significant increase.<ref>{{cite web |url=http://ctr.gsk.co.uk/Summary/bupropion/I_031.pdf |title=P02-31UK I Examination of Bupropion and Ethanol, Alone and in Combination, on Human Performance Tests, Subjective Rating Scales, EEG and Autonomic Responses |accessdate=2007-06-04 |author= |authorlink= |coauthors= |date= |format=PDF |work=GlaxoSmithKline Clinical Trial Register. Bupropion Studies |publisher= |pages= |language= |archiveurl= |archivedate= |quote=}}</ref>

Revision as of 20:23, 19 August 2007

Bupropion
Clinical data
Pregnancy
category
  • AU: B2
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5 to 20% in animals; no studies in humans
MetabolismHepatic—important CYP2B6 and 2D6 involvement
Elimination half-life20 hours
ExcretionRenal (87%), fecal (10%)
Identifiers
  • (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-
    1-propanone
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO
Molar mass239.74 g/mol g·mol−1

Bupropion (INN; also amfebutamone,[2] brand names Wellbutrin, Zyban, Budeprion and Buproban) is an atypical antidepressant that acts as a norepinephrine reuptake inhibitor, a dopamine reuptake inhibitor, and a nicotinic antagonist.[3][4] Bupropion belongs to the chemical class of aminoketones and is similar in structure to the stimulant cathinone, 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.[5]

Bupropion lowers seizure threshold and its potential to cause seizures was widely publicized. However, at the recommended dose the seizures frequency is not increased in comparison to other antidepressants. Bupropion is not considered dependence-forming, nor is there evidence of increased suicidal behaviour occurring with its use.


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.[6] However, a significant incidence of seizures at the originally recommended dosage (400–600 mg) caused the withdrawal of the drug in 1986. The risk of seizure increases from 0.1% at 100–300 mg/day to 0.3–0.4% at 450 mg/day,[7] and to 2% at 600 mg/day. Reflecting this finding, bupropion was re-introduced to the market in 1989 with a maximum recommended dose of 450 mg/day.

Wellbutrin XL

In 1996, the FDA approved a sustained-release formulation of bupropion called Wellbutrin SR, intended to be taken twice a day (as opposed to three times a day for instant-release Wellbutrin). In 2003 the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosage. Wellbutrin SR and XL are available in the United States in generic form. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. In late 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.

Therapeutic uses

Depression

Placebo-controlled studies have confirmed the efficacy of bupropion for clinical depression.[8] Comparative clinical studies demonstrated the equivalency of bupropion and sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil)[9] and escitalopram (Lexapro)[10] as antidepressants. A significantly higher remission rate for bupropion treatment than for venlafaxine (Effexor) was observed in a recent study.[11] 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.[12][13] 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.[14] Bupropion is more effective than SSRIs at improving symptoms of hypersomnia and fatigue in depressed patients.[15]

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.[16] For example, the combination of bupropion and citalopram 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.[17][18] 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.[18]

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.[19] 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.[20] 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.[21] 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).[19]

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 .[22] There are studies demonstrating the efficacy of both approaches; improvement of desire and orgasm components of the sexual function being 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.[23][24][25][26][27]Cite error: A <ref> tag is missing the closing </ref> (see the help page). Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire,[28][29] 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[30] and for orgasmic dysfunction.[31] 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.[32] Bupropion does not affect any measures of sexual functioning in healthy men.[33]

Obesity

A recent meta-analysis of anti-obesity medications 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, 10 lb) was significantly greater than in the placebo group (1.7 kg, 4 lb). 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.[34]

Other uses

Bupropion is also effective for adult attention-deficit hyperactivity disorder[35] and for the prevention of seasonal affective disorder,[36] and has been approved by the FDA for the latter indication.[37] A controversy exists on whether adding an antidepressant, including bupropion, to a mood stabilizer in patients with bipolar depressions is useful.[38][39][40]

Contraindications

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 that are also taking MAO inhibitors. When switching from a MAOI to bupropion, it is important to include a washout period of about two weeks between the medications.[41] 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.[41]

Risk of suicide

The FDA requires all antidepressants, including bupropion, to carry a black box warning that states, "Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders…The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%." Further warnings in the prescribing information say, "It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults…Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases."[41]

The FDA found that the risk of suicidal thoughts and behavior strongly depends on age. In addition to increasing this risk in children and adolescents, antidepressants may increase it as much as 1.5 times in those aged 18–24 (a finding that was close to statistical significance). However, they decrease the incidence of suicidal thoughts and behavior in those aged 31–64 by 23% (statistically significant). Most importantly, considering the higher risk of suicide among older people, antidepressants decrease suicidal thoughts and behavior 2.5-fold for those over 65.[42]

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.[42]

Suicidal behavior is even less likely when bupropion is prescribed for smoking cessation. According to a Cochrane Database review, there have been four suicides per one million prescriptions and one case of suicidal ideation per 10,000 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."[43]

Adverse effects

The common adverse effects associated with sustained-release bupropion (with the greatest difference from placebo) are dry mouth (17% vs 7% for placebo), nausea (13% vs 8% for placebo), insomnia (11% vs 6% for placebo), tremor (6% vs 1% for placebo), excessive sweating (6% vs 2% for placebo) and tinnitus (6% vs 2% for placebo). 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.[41]

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.[44] 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.[45] 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.[46]

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.[41] 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.[39] Moreover, when added to a mood stabilizer, bupropion and sertraline had a twice lower switch risk than venlafaxine.[47]

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.[41] 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.[48] 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.[49] In a study of bupropion for ADHD, a rise of systolic blood pressure by 6 mm Hg and of heartrate by 7 beats per minute (both statistically significant) were observed.[50] 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.[51] 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[52]) 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."[53] 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.[54]

Other isolated adverse affects have been reported. Three cases of liver toxicity have been described in the literature,[55] a very low incidence given the widespread use of the drug. A single case of clitoral priapism (clitorism) has been reported in the literature.[56]

Overdose

GlaxoSmithKline has reported that overdoses of 30 g or more of bupropion resulted in seizure in about one-third of cases. Hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbance or arrhythmia were also reported as consequences of overdose. Multi-drug overdoses that included bupropion resulted in fever, rhabdomyolysis, stupor, hypotension, coma, muscle rigidity, and respiratory failure.[41] Bupropion overdose rarely results in death, although cases have been reported, typically associated with massive overdosage.[57][41]

Mechanism of action

Bupropion is a dopamine and norepinephrine reuptake inhibitor.[58] 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[59] and 12–35% according to GSK researchers.[60] 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 (that is, it is not an MAOI) 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 α3β4 nicotinic antagonist.[61] The degree of inhibition of α3β4 receptors correlates well with the decrease in self-administration of morphine and metamphetamine in rats,[62] and may be relevant to the effect of bupropion on nicotine addiction.

Pharmacokinetics

Important metabolites of bupropion.

Bupropion is metabolized in the liver. It has several active metabolites—R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites are presented in Table 1. Bupropion is known to weakly inhibit the α1 adrenaline receptor, with a 14% potency of its dopamine uptake inhibition, and the histamine H1 receptor, with a 9% potency.[63]

The biological activity of bupropion can be attributed to a significant degree to its active metabolites, in particular to S,S-hydroxybupropion. GSK developed this metabolite as a separate drug called radafaxine,[64] but discontinued development in 2006 due to "an unfavourable risk/benefit assessment".[65]

Bupropion is metabolized to hydroxybupropion by CYP2B6, an isoenzyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. The mechanism of formation of erythro-hydrobupropion and threo-hydrobupropion has not been studied but is probably mediated by one of the carbonyl reductase enzymes. The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (and the half-life from 3 to 16 hours), and of hydroxybupropion by as much as 7.5 times (and the half-life from 12 to 38 hours).[66][67]

There are significant interspecies differences in the metabolism of bupropion, with guinea pigs' metabolism of the drug being closest to that of humans.[68] Particular caution is needed when extrapolating the results of experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.[69]

There have been two reported cases of false-positive urine amphetamine tests in persons taking bupropion. Bupropion metabolites erythro-hydrobupropion and threo-hydrobupropion, which have a phenethylamine structure resembling amphetamine are likely to have been responsible for this reaction. More specific follow-up tests were negative.[70][71]

Table 1. Pharmacology of bupropion and its metabolites.[72][73][74][63][75]
Exposure (concentration over time; bupropion exposure = 100%) and half-life
Bupropion R,R-
Hydroxy
bupropion 		S,S-
Hydroxy
bupropion 		Threo-
hydro
bupropion 		Erythro-
hydro
bupropion
Exposure 100% 800% 160% 310% 90%
Half-life 10 h (IR)
17 h (SR) 		21 h 25 h 26 h 26 h
Inhibition potency (potency of DA uptake inhibition by bupropion = 100%)
DA uptake 100% 0% (rat) 70% (rat) 4% (rat) No data
NE uptake 27% 0% (rat) 106% (rat) 16% (rat) No data
Ser uptake 2% 0% (rat) 4%(rat) 3% (rat) No data
α3β4 nicotinic 53% 15% 10% 7% (rat) No data
α4β2 nicotinic 8% 3% 29% No data No data
α1* nicotinic 12% 13% 13% No data No data
DA = dopamine; NE = norepinephrine; Ser = serotonin.

Interactions

Since bupropion is metabolized to hydroxybupropion by the CYP2B6 enzyme, drug interactions with CYP2B6 inhibitors are possible: this includes medications like paroxetine, sertraline, norfluoxetine (the active metabolite of fluoxetine), diazepam, clopidogrel, and orphenadrine. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers, such as carbamazepine, clotrimazole, rifampicin, ritonavir, St John's Wort and others.[76]

Hydroxybupropion (but not bupropion) is itself an inhibitor of CYP2D6, as well as a substrate of that enzyme. A significant increase in the concentration of some drugs metabolized by CYP2D6 (venlafaxine, desipramine and dextromethorphan, but not fluoxetine or paroxetine) has been observed when they are taken with bupropion.[76][77]

Bupropion lowers the seizure threshold; accordingly, extreme care should be taken when prescribing bupropion with other medications that also lower it, such as antipsychotics, theophylline, steroids, and some tricyclic antidepressants.[41] Its combination with nicotine replacement therapies can elevate blood pressure; since this combination is no more effective than either a nicotine patch or bupropion alone, it is not recommended.

The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold.[41] A small study conducted by GSK indicated that bupropion (100 mg) may counteract the subjective effects of small doses of alcohol (16–32 mL, slightly less than 1–2 standard US drinks). The volunteers reported feeling more sober and clear-headed and less sedated. Bupropion also reduced the detrimental effect of alcohol on auditory vigilance. The combination of bupropion (100 mg) and two drinks of alcohol increased heart rate by six beats per minute, a statistically significant increase.[78]

Availability

Brand and generic pills are available in three forms: immediate release, sustained release (SR), and extended release (XL, ER). According to GSK, a 150 mg bupropion SR tablet can be split in two and retain its sustained-release characteristics.[79]

In the United Kingdom and Australia, bupropion was approved as a smoking cessation aid in 2000, but has not been approved for the treatment of depression.[80][81] Zyban is available via prescription in the UK only with a letter from a smoking cessation clinic to the patient's physician confirming that he or she is a heavy smoker who has not benefited from nicotine replacement therapies.

In France, marketing authorization was granted on August 3 2001, also solely as a smoking cessation aid, and with a maximum daily dose of 300 mg;[82] only sustained-release bupropion is available. Bupropion was granted a licence for use in adults with major depression in the Netherlands in early 2007, with GlaxoSmithKline expecting subsequent approval in other European countries.[83]

Bupropion is available internationally under the following brand names:

Abuse liability

According to the US government classification of psychiatric medications, bupropion is not abusable[84] or has low abuse potential.[85] In animal studies, however, squirrel monkeys[86] and rats[87] maintained the intravenous self-administration of bupropion, which may indicate abuse potential—though important differences of bupropion metabolism in rats and humans make any extrapolations invalid.

Two studies on drug abusers indicated that the subjective effects of bupropion are markedly different from those of amphetamine.[88][89] Healthy volunteers trained to discriminate amphetamine and placebo recognized bupropion (400 mg) as amphetamine 20% of the time, compared to 10% for placebo and 75% for methylphenidate (20 mg). They also reported feeling alert, vigorous, elated and energetic, reflecting the general stimulating properties of bupropion. In contrast to amphetamine and methylphenidate, there was no feeling of "liking the drug" and no desire to take it again.[90] A comparison of bupropion SR (150 mg) and caffeine (178 mg) indicated that caffeine may have higher abuse liability since it resulted in more reports of pleasant feelings and a "high" than bupropion.[91]

There have been only three reports of bupropion abuse in the literature. All three cases described teenagers crushing and insufflating (snorting) the drug, one of them resulting in seizures.[92] An article on medication abuse in prisons mentions bupropion as one of the psychotropic medications commonly abused by inmates.[93]

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External links

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