Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. Bupropion is an effective antidepressant on its own, but it is also popular as an add-on medication in the cases of incomplete response to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction; it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue. Bupropion does, however, carry a much higher risk of seizure than many other antidepressants and extreme caution must be taken in patients with a history of seizure disorder.
A majority of controlled clinical trials support efficacy of bupropion for the treatment of depression. However, the overall quality of the evidence is low, with one meta-analysis, for example, finding a small effect size of bupropion in depression and another finding a large effect size. Comparative head-to-head clinical trials indicate that bupropion is similar in response rate against depression to fluoxetine, sertraline, paroxetine, and venlafaxine; meanwhile remission rate tends to favor bupropion.
Over the fall and winter months, bupropion prevents development of depression in those who have recurring seasonal affective disorder: 15% of participants on bupropion experienced a major depressive episode vs. 27% of those on placebo. Bupropion also improves depression in bipolar disorder, with the efficacy and risk of affective switch being similar to other antidepressants.
Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo. Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants. Bupropion treatment also is not associated with the sleepiness that may be produced by other antidepressants. Bupropion is more effective than selective serotonin reuptake inhibitors (SSRIs) at improving symptoms of hypersomnia and fatigue in depressed patients. There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of depression with high anxiety; they are equivalent for the depression with moderate or low anxiety.
The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI, and it is supported by clinical trials; however, it appears to be inferior to the addition of atypical antipsychotic aripiprazole.
Prescribed as an aid for smoking cessation bupropion reduces the severity of craving for tobacco and withdrawal symptoms such as depressed
mood, irritability, difficulty concentrating, and increased appetite. Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible.
The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year. It is unclear whether extending bupropion treatment helps to prevent relapse of smoking.
Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6 fold as compared to placebo. In this respect, bupropion is as effective as nicotine replacement therapy but inferior to varenicline. Combining bupropion and nicotine replacement therapy does not improve the quitting rate.
In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits. The evidence for its use to aid smoking cessation in pregnant women is insufficient.
Bupropion is less likely than other antidepressants to cause sexual dysfunction. A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction including sexual dysfunction induced by SSRI antidepressants. There have also been small studies suggesting that bupropion or a bupropion/trazodone combination may improve some measures of sexual function in women who have hypoactive sexual desire disorder (HSDD) and are not depressed. According to an expert consensus recommendation from the International Society for the Study of Women's Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data.
Bupropion is not effective in the treatment of cocaine dependence, but it is showing promise in reducing drug use in light methamphetamine users. Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease, psoriasis, and other autoimmune conditions, but very little clinical evidence is available. Bupropion is not effective in treating chronic low back pain.
Bupropion is available as an oraltablet in a number of different formulations. It is formulated mostly as the hydrochloridesalt but also to a lesser extent as the hydrobromide salt. The available forms of bupropion hydrochloride include IR (instant-release) tablets (50, 75, 100 mg), SR (sustained-release) tablets (50, 100, 150, 200 mg), and XL (extended-release) tablets (150, 300, 450 mg). The only marketed form of bupropion hydrobromide is Aplenzin, an extended-release oral tablet (174, 348, 522 mg). In addition to single-drug formulations, bupropion is formulated in combinations including naltrexone/bupropion (Contrave; 8 mg/90 mg extended-release tablets) and the pending-approval bupropion/dextromethorphan (AXS-05; 105 mg/45 mg tablets).
The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating. Bupropion has the highest incidence of insomnia of all second-generation antidepressants, apart from desvenlafaxine. It is also associated with about 20% increased risk of headache.
Bupropion raises blood pressure in some people. One study showed an average rise of 6 mm Hg in sysolic blood pressure in 10% of patients. The prescribing information notes that hypertension, sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension. Safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remain unclear due to the lack of data.
Seizure is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300–450 mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600 mg. For comparison, the incidence of unprovoked seizure in the general population is 0.07 to 0.09%, and the risk of seizure for a variety of other antidepressants is generally between 0 and 0.5% at the recommended doses.
The FDA requires all antidepressants, including bupropion, to carry a boxed 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 in suicidal thought and behavior in children and adolescents, and 1.5-fold increase in the 18–24 age group. For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.
Bupropion prescribed for smoking cessation results in 25% increase of the risk of psychiatric side effects, in particular, anxiety (about 40% increase) and insomnia (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behavior.
In rare cases, bupropion-induced psychosis may develop. It is associated with higher doses of bupropion; many cases described are at higher than recommended doses. Concurrent antipsychotic medication appears to be protective. In most cases the psychotic symptoms are eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication.
Bupropion is considered moderately dangerous in overdose. According to an analysis of US National Poison Data System, adjusted for the number of prescriptions, bupropion and venlafaxine are the two new generation antidepressants (that is excluding tricyclic antidepressants) that result in the highest mortality and morbidity. For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and abnormal heart rhythms. When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, having had multiple uncontrolled seizures and myocardial infarction.
Bupropion and its metabolites are inhibitors of CYP2D6, with hydroxybupropion responsible for most of the inhibition. Additionally, bupropion and its metabolites may decrease expression of CYP2D6 in the liver. The end effect is a significant slowing of the clearance of other drugs metabolized by this enzyme. For instance, bupropion has been found to increase area-under-the-curve of desipramine, a CYP2D6 substrate, by 5-fold. Bupropion has also been found to increase levels of atomoxetine by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold. As another example, the ratio of dextromethorphan (a drug that is mainly metabolized by CYP2D6) to its major metabolitedextrorphan increased approximately 35-fold when it was administered to people being treated with 300 mg/day bupropion. When people on bupropion are given MDMA, about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased heart rate effects of MDMA. Interactions with other CYP2D6 substrates, such as metoprolol, imipramine, nortriptyline,venlafaxine, and nebivolol have also been reported. However, in a notable exception, bupropion does not seem to affect the concentrations of CYP2D6 substrates fluoxetine and paroxetine.
The occupancy of dopamine transporter (DAT) by bupropion (300 mg/day) and its metabolites in the human brain as measured by several positron emission tomography (PET) studies is approximately 20%, with a mean occupancy range of about 14 to 26%. For comparison, the NDRI methylphenidate at therapeutic doses is thought to occupy greater than 50% of DAT sites. In accordance with its low DAT occupancy, no measurable dopamine release in the human brain was detected with bupropion (150 mg/day) in a PET study. These findings raise questions about the role of dopamine reuptake inhibition in the pharmacology of bupropion, and suggest that other actions may be responsible for its therapeutic effects. More research is needed in this area. No data are available on occupancy of the norepinephrine transporter (NET) by bupropion and its metabolites. However, due to the increased exposure of hydroxybupropion over bupropion itself, which has higher affinity to NET than DAT (R,R- has no DAT affinity at all, and S,S- has ~3x higher affinity to NET over DAT), bupropion's overall pharmacological profile in humans may end up making it effectively more of an NRI than a DRI.
Principal pathways of bupropion metabolism.
After oral administration, bupropion is rapidly and completely absorbed reaching the peak blood plasma concentration after 1.5 hours (tmax). Sustained release (SR) and extended release (XL) formulations have been designed to slow down absorption resulting in tmax of 3 hours and 5 hours, respectively. Absolute bioavailability of bupropion is unknown but is presumed to be low, at 5–20%, due to the first-pass metabolism. As for the relative biovailability of the formulations, XL formulation has lower bioavailability (68%) compared to SR formulation and immediate release bupropion.
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 (with a half-life of 12–30 hours), while the effective doses of hydroxybupropion may differ by as much as 7.5 times (with a half-life of 15–25 hours). Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.
This diagram shows the synthesis of bupropion via 3'-chloro-propiophenone.
Comparison of steady-state plasma bupropion levels with bupropion IR 100 mg t.i.d. (3x/day), bupropion SR 150 mg b.i.d. (2x/day), and bupropion XL 300 mg q.d. (1x/day).
Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974. It was approved by the U.S. Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin. However, a significant incidence of seizures at the originally recommended dosage (400–600 mg/day) 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 lower maximum recommended daily dose of 450 mg/day.
In 1996, the FDA approved a sustained-release formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin). In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing. Wellbutrin SR and XL are available in generic form in the United States and Canada. 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.
In France, marketing authorization was granted for Zyban on 3 August 2001, with a maximum daily dose of 300 mg; only sustained-release bupropion is available, and only as a smoking cessation aid.
On 11 October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People's Pharmacy, released the results of comparative tests of different brands of bupropion. The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that "one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab." The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg." The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. As of October 2013[update] the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.
In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by Sanofi-Aventis.
In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide. This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years. Based on the results of follow-up trials this warning was removed in 2016.
In 2012, the U.S. Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3-billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.
In 2017, the European Medicines Agency recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India. The products recommended for suspension included several 300 mg modified-release bupropion tablets.
Society and culture
While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of its pharmacology. Bupropion misuse is uncommon. There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion when taken orally are markedly different from those of addictive stimulants such as cocaine or amphetamine. However, bupropion, by non-conventional routes of administration like injection or insufflation has been reported to be misused in the United States and Canada, notably in prisons.
In Russia bupropion is banned as a narcotic drug, yet not per se but rather as a derivative of methcathinone.
In Australia and the UK, smoking cessation is the only licensed use of bupropion.
^ abc"Compound Summary". Bupropion. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 28 July 2018. Archived from the original on 29 July 2018. Retrieved 29 July 2018.
^ abWilens TE, Hammerness PG, Biederman J, Kwon A, Spencer TJ, Clark S, et al. (February 2005). "Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder". The Journal of Clinical Psychiatry. 66 (2): 253–259. doi:10.4088/jcp.v66n0215. PMID15705013.
^ abcKumar S, Kodela S, Detweiler JG, Kim KY, Detweiler MB (November–December 2011). "Bupropion-induced psychosis: folklore or a fact? A systematic review of the literature". General Hospital Psychiatry. 33 (6): 612–617. doi:10.1016/j.genhosppsych.2011.07.001. PMID21872337.
^World Health Organization (2000). "International nonproprietary names for pharmaceutical substances (INN) : proposed international nonproprietary names : list 83". WHO Drug Information. 14 (2). hdl:10665/58135.
^Papakostas GI, Stahl SM, Krishen A, Seifert CA, Tucker VL, Goodale EP, Fava M (August 2008). "Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies". The Journal of Clinical Psychiatry. 69 (8): 1287–1292. doi:10.4088/JCP.v69n0812. PMID18605812. S2CID25267685.
^Ng QX (March 2017). "A Systematic Review of the Use of Bupropion for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents". Journal of Child and Adolescent Psychopharmacology. 27 (2): 112–116. doi:10.1089/cap.2016.0124. PMID27813651.
^Cao DN, Shi JJ, Hao W, Wu N, Li J (June 2016). "Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction". European Journal of Pharmacology. 780: 129–135. doi:10.1016/j.ejphar.2016.03.040. PMID27018393.
^Majeed A, Xiong J, Teopiz KM, Ng J, Ho R, Rosenblat JD, et al. (March 2021). "Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials". Expert Opinion on Emerging Drugs. 26 (1): 63–74. doi:10.1080/14728214.2021.1898588. PMID33682569. S2CID232141396.
^Alberti S, Chiesa A, Andrisano C, Serretti A (June 2015). "Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis". Journal of Clinical Psychopharmacology. 35 (3): 296–303. doi:10.1097/JCP.0000000000000329. PMID25874915. S2CID33102792.
^Grandi SM, Shimony A, Eisenberg MJ (December 2013). "Bupropion for smoking cessation in patients hospitalized with cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials". The Canadian Journal of Cardiology. 29 (12): 1704–1711. doi:10.1016/j.cjca.2013.09.014. PMID24267809.
^Schmid Y, Rickli A, Schaffner A, Duthaler U, Grouzmann E, Hysek CM, Liechti ME (April 2015). "Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects". The Journal of Pharmacology and Experimental Therapeutics. 353 (1): 102–111. doi:10.1124/jpet.114.222356. PMID25655950. S2CID14761997.
^ abProtti M, Mandrioli R, Marasca C, Cavalli A, Serretti A, Mercolini L (September 2020). "New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others". Medicinal Research Reviews. 40 (5): 1794–1832. doi:10.1002/med.21671. PMID32285503. S2CID215758102.
^Spina E, Santoro V, D'Arrigo C (July 2008). "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update". Clinical Therapeutics. 30 (7): 1206–1227. doi:10.1016/s0149-2918(08)80047-1. PMID18691982.
^Feinberg SS (November 2004). "Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication". The Journal of Clinical Psychiatry. 65 (11): 1520–1524. doi:10.4088/jcp.v65n1113. PMID15554766.
^Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ (November 2020). "Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults". Clinical Pharmacology and Therapeutics. 108 (5): 1036–1048. doi:10.1002/cpt.1888. PMID32386065. S2CID218563059.
^ abcSánchez C, Hyttel J (August 1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology. 19 (4): 467–489. doi:10.1023/a:1006986824213. PMID10379421. S2CID19490821.
^Bondarev ML, Bondareva TS, Young R, Glennon RA (August 2003). "Behavioral and biochemical investigations of bupropion metabolites". European Journal of Pharmacology. 474 (1): 85–93. doi:10.1016/S0014-2999(03)02010-7. PMID12909199.
^ abDamaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, et al. (September 2004). "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors". Molecular Pharmacology. 66 (3): 675–682. doi:10.1124/mol.104.001313. PMID15322260. S2CID1577336.
^ abcCarroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Adv Pharmacol. Advances in Pharmacology. Vol. 69. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN9780124201187. PMID24484978.
^Gründer G, Hiemke C, Paulzen M, Veselinovic T, Vernaleken I (September 2011). "Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging". Pharmacopsychiatry. 44 (6): 236–248. doi:10.1055/s-0031-1286282. PMID21959785.
^Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, et al. (April 2004). "Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes". Pharmacogenetics. 14 (4): 225–238. doi:10.1097/00008571-200404000-00002. PMID15083067.
^Preskorn SH (1991). "Should bupropion dosage be adjusted based upon therapeutic drug monitoring?". Psychopharmacology Bulletin. 27 (4): 637–643. PMID1813908.
^Musso DL, Mehta NB, Soroko FE, Ferris RM, Hollingsworth EB, Kenney BT (1993). "Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion". Chirality. 5 (7): 495–500. doi:10.1002/chir.530050704. PMID8240925.