Bupropion
Bupropion (/bjuːˈproʊpi.ɒn/ bew-proh-pee-on;[2] ) is a drug that is primarily used as an atypical antidepressant and smoking cessation aid. Marketed as Wellbutrin, Budeprion, Prexaton, Elontril, Aplenzin, or other trade names, it is one of the most frequently prescribed antidepressants in the United States. Marketed in lower-dose formulations as Zyban, Voxra, or other names, it is also widely used to reduce nicotine cravings by people who are trying to quit smoking. It is taken in the form of pills, and in the United States is available only by prescription.
Bupropion lowers seizure threshold, and its potential to cause seizures has been widely publicized. Bupropion is an effective antidepressant on its own, but it is also popular as an add-on medication in cases of incomplete response to first-line SSRI antidepressants. In contrast to many other antidepressants, bupropion does not cause weight gain or sexual dysfunction.
Bupropion was patented in 1969 by Burroughs Wellcome, which later became part of what is now GlaxoSmithKline. It was originally called amfebutamone, before being renamed in 2000.[3] Its chemical name is 3-chloro-N-tert-butyl-β-ketoamphetamine. It is asubstituted cathinone (β-ketoamphetamine), as well as a substituted amphetamine.
The drug is a mild psychostimulant. Its primary pharmacological action is as a dopamine reuptake inhibitor, and also to a lesser extent a norepinephrine reuptake inhibitor. Bupropion affects a number of neurotransmitter systems, and its mechanisms of action are only partly understood. It binds selectively to the dopamine transporter and makes dopamine reuptake inhibition twice as potent as norepinephrine reuptake inhibition.[4]
It also acts as a nicotinic acetylcholine receptor antagonist. Bupropion belongs to the chemical class of aminoketones and is similar in structure to stimulants such as cathinone and amfepramone, and to phenethylamines in general. Medically, bupropion serves as a non-tricyclic antidepressant fundamentally different from most commonly prescribed antidepressants such asselective serotonin reuptake inhibitors (SSRIs).
Medical uses
Depression
The most common use for bupropion is in the treatment of depression, where it is marketed by GlaxoSmithKline under the trade name Wellbutrin, or as a generic version under a variety of other names.
Bupropion is one of the most widely prescribed antidepressants, and the available evidence indicates that it is effective in clinical depression[5] — as effective as several other widely prescribed drugs, including sertraline (Zoloft), fluoxetine (Prozac), paroxetine(Paxil)[6] and escitalopram (Lexapro).[7] It has several features that distinguish it from other antidepressants. Unlike the majority of antidepressants, bupropion does not usually cause sexual dysfunction.[8] Bupropion treatment also is not associated with the somnolence or weight gain that may be produced by other antidepressants.[9]
The majority of depressed people suffer from insomnia, but there are some who instead experience constant sleepiness and fatigue. In this subgroup, bupropion has been found to be more effective than selective serotonin reuptake inhibitors (SSRIs) at alleviating the symptoms.[10] There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression.[11]
According to surveys, the augmentation of a prescribed SSRI with bupropion is a common strategy among clinicians when the patient does not respond to the SSRI, even though this is not an officially approved indication for prescription.[12] The addition of bupropion to an SSRI (most commonly fluoxetine or sertraline) results in a significant improvement in the majority of patients who have an incomplete response to the first-line antidepressant.[12]
Smoking cessation
The next most common use is as an aid for smoking cessation, where it is marketed by GlaxoSmithKline under the trade name Zyban, or by other makers as a generic equivalent.
Numerous studies have provided evidence that bupropion substantially reduces the severity of nicotine cravings and withdrawal symptoms.[13] For example, in one large-scale study, 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.[14] A typical bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. Bupropion approximately doubles the chance of quitting smoking successfully after three months. One year after treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group.[13]
The evidence is clear that bupropion is effective at reducing nicotine cravings. Whether it is more effective than other treatments is not as clear, due to a limited number of studies. The evidence that is available suggests that bupropion is comparable to nicotine replacement therapy, but somewhat less effective than varenicline (Chantix).[13]
Seasonal Affective Disorder
Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder.[15]It was the first drug approved specifically for this condition.
Attention deficit hyperactivity disorder
There have been numerous reports of positive results for bupropion as a treatment for attention deficit hyperactivity disorder (ADHD), both in minors and adults.[16] However, in the largest to date double-blind study of children, 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.[16] 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.”[17] Similarly, the Texas Department of State Health Services guideline recommends considering bupropion or a tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and atomoxetine.[18]
Sexual dysfunction
Bupropion is one of few antidepressants that do not cause sexual dysfunction.[19] A range of studies demonstrate that bupropion not only produces fewer sexual side effects than other antidepressants, but can actually help to alleviate sexual dysfunction.[20] According to a survey of psychiatrists, it is the drug of choice for the treatment of SSRI-induced sexual dysfunction, although this is not an indication approved by the U.S. Food and Drug Administration. 36% of psychiatrists preferred switching patients with SSRI-induced sexual dysfunction to bupropion, and 43% favored the augmentation of the current medication with bupropion.[21] There have also been a few studies suggesting that bupropion can improve sexual function in women who are not depressed, if they have hypoactive sexual desire disorder.[22]
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) was significantly greater than in the placebo group (1.7 kg). It was not, however, significantly different from the weight loss produced by several other established medications, such as sibutramine, orlistat and amfepramone.[23]
Other uses
There has been controversy about whether it is useful to add an antidepressant such as bupropion to a mood stabilizer in patients with bipolar depression, but recent reviews have concluded that bupropion in this situation does no significant harm and may sometimes give significant benefit.[24][25]
Bupropion has shown no effectiveness in the treatment of cocaine dependence, but there is weak evidence that it may be useful in treating methamphetamine dependence.[26]
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 treatinginflammatory bowel disease or other autoimmune conditions, but very little clinical evidence is available.[27]
Bupropion—like other antidepressants, with the exception of duloxetine (Cymbalta)[28]—is not effective in treating chronic low back pain.[29] It does, however, show some promise in the treatment of neuropathic pain.[30]
Bupropion is a substituted cathinone. It is synthesized in two chemical steps starting from 3′-chloro-propiophenone. The alpha position adjacent to the ketone is firstbrominated followed by nucleophilic displacement of the resulting alpha-bromoketone with t-butylamine and treated with hydrochloric acid to give bupropion as the hydrochloride salt in 75–85% overall yield.a, b a Mehta NB (June 25, 1974). “United States Patent 3,819,706: Meta-chloro substituted α-butylamino-propiophenones”. USPTO. Retrieved June 2, 2008. b, ^ Perrine DM, Ross JT, Nervi SJ, Zimmerman RH (2000). “A Short, One-Pot Synthesis of Bupropion (Zyban, Wellbutrin)”. Journal of Chemical Education 77 (11): 1479.Bibcode:2000JChEd..77.1479P. doi:10.1021/ed077p1479.
Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
^ entry “Bupropion (By mouth)” at “PubMed Health” (from the US government agency NIH, National Institutes of Health, retrieved March 31, 2013.
^ The INN originally assigned in 1974 by the World Health Organization was “amfebutamone”. In 2000, the INN was reassigned as bupropion. See World Health Organization (2000). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 83″ (PDF). WHO Drug Information 14 (2). Archived from the original on May 31, 2011. Retrieved June 22, 2009.
^ Arias HR, Santamaría A, Ali SF (2009). “Pharmacological and neurotoxicological actions mediated by bupropion and diethylpropion”. Int. Rev. Neurobiol. International Review of Neurobiology 88: 223–55. doi:10.1016/S0074-7742(09)88009-4. ISBN 978-0-12-374504-0. PMID 19897080.
^ Moreira R (October 2011). “The efficacy and tolerability of bupropion in the treatment of major depressive disorder”. Clin Drug Investig. 31 Suppl 1: 5–17.doi:10.2165/1159616-S0-000000000-00000. PMID 22015858.
^ Thase ME, Haight BR, Richard N, Rockett CB, Mitton M, Modell JG, VanMeter S, Harriett AE, Wang Y (August 2005). “Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials”. J Clin Psychiatry 66 (8): 974–81.doi:10.4088/JCP.v66n0803. PMID 16086611.
^ Clayton AH, Croft HA, Horrigan JP, Wightman DS, Krishen A, Richard NE, Modell JG (May 2006). “Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies”. J Clin Psychiatry 67 (5): 736–46. doi:10.4088/JCP.v67n0507.PMID 16841623.
^ Clayton AH (2003). “Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge”. Primary Psychiatry 10 (1): 55–61.
^ Dhillon S, Yang LP, Curran MP (2008). “Bupropion: a review of its use in the management of major depressive disorder”. Drugs 68 (5): 653–89.doi:10.2165/00003495-200868050-00011. PMID 18370448.
^ Baldwin DS, Papakostas GI (2006). “Symptoms of fatigue and sleepiness in major depressive disorder”. J Clin Psychiatry. 67 Suppl 6 (Suppl 6): 9–15. PMID 16848671.
^ 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”. J Clin Psychiatry 69 (8): 1287–92.doi:10.4088/JCP.v69n0812. PMID 18605812.
^ a b Zisook S, Rush AJ, Haight BR, Clines DC, Rockett CB (February 2006). “Use of bupropion in combination with serotonin reuptake inhibitors”. Biol. Psychiatry 59 (3): 203–10. doi:10.1016/j.biopsych.2005.06.027. PMID 16165100.
^ a b c Wu P, Wilson K, Dimoulas P, Mills EJ (2006). “Effectiveness of smoking cessation therapies: a systematic review and meta-analysis”. BMC Public Health 6: 300. doi:10.1186/1471-2458-6-300. PMC 1764891. PMID 17156479.
^ Tønnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel PI, Hider A, Sweet R, Townsend J (August 2003). “A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation”. J. Intern. Med. 254(2): 184–92. doi:10.1046/j.1365-2796.2003.01185.x. PMID 12859700.
^ ”First drug for seasonal depression”. FDA Consum 40 (5): 7. 2006.PMID 17328102.
^ a b Cantwell DP (1998). “ADHD through the life span: the role of bupropion in treatment”. J Clin Psychiatry. 59 Suppl 4: 92–4. PMID 9554326.
^ Pliszka S; AACAP Work Group on Quality Issues (July 2007). “Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder”. J Am Acad Child Adolesc Psychiatry 46 (7): 894–921.doi:10.1097/chi.0b013e318054e724. PMID 17581453.
^ Pliszka SR, Crismon ML, Hughes CW, Corners CK, Emslie GJ, Jensen PS, McCracken JT, Swanson JM, Lopez M (June 2006). “The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder”. J Am Acad Child Adolesc Psychiatry 45 (6): 642–57.doi:10.1097/01.chi.0000215326.51175.eb. PMID 16721314.
^ Serretti A, Chiesa A (June 2009). “Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis”. J Clin Psychopharmacol 29 (3): 259–66.doi:10.1097/JCP.0b013e3181a5233f. PMID 19440080.
^ Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S (2004). “A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor”. Prim Care Companion J Clin Psychiatry 6 (4): 159–166. doi:10.4088/PCC.v06n0403. PMC 514842. PMID 15361919.
^ Dording CM, Mischoulon D, Petersen TJ, Kornbluh R, Gordon J, Nierenberg AA, Rosenbaum JE, Fava M (September 2002). “The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists”. Ann Clin Psychiatry 14 (3): 143–7.doi:10.3109/10401230209147450. PMID 12585563.
^ a b Foley KF, DeSanty KP, Kast RE (September 2006). “Bupropion: pharmacology and therapeutic applications”. Expert Rev Neurother 6 (9): 1249–65.doi:10.1586/14737175.6.9.1249. PMID 17009913.
^ Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC (April 2005). “Meta-analysis: pharmacologic treatment of obesity”. Ann. Intern. Med. 142 (7): 532–46. doi:10.7326/0003-4819-142-7-200504050-00012. PMID 15809465.
^ Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM (September 2004). “Antidepressants for bipolar depression: a systematic review of randomized, controlled trials”. Am J Psychiatry 161 (9): 1537–47. doi:10.1176/appi.ajp.161.9.1537.PMID 15337640.
^ Yatham LN, Kennedy SH, O’Donovan C, Parikh SV, MacQueen G, McIntyre RS, Sharma V, Beaulieu S (December 2006). “Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007″. Bipolar Disord 8 (6): 721–39. doi:10.1111/j.1399-5618.2006.00432.x.PMID 17156158.
^ Kampman KM (June 2008). “The search for medications to treat stimulant dependence”. Addict Sci Clin Pract 4 (2): 28–35. doi:10.1151/ascp084228.PMC 2797110. PMID 18497715.
^ Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ (2006). “Antidepressants and inflammatory bowel disease: a systematic review”.Clin Pract Epidemiol Ment Health 2: 24. doi:10.1186/1745-0179-2-24.PMC 1599716. PMID 16984660.
^ “FDA clears Cymbalta to treat chronic musculoskeletal pain”. FDA Press Announcements. Food and Drug Administration. November 4, 2010. Retrieved August 19, 2013. “The U.S. Food and Drug Administration … approved Cymbalta (duloxetine hydrochloride) to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.”
^ Urquhart DM, Hoving JL, Assendelft WW, Roland M, van Tulder MW (2008). “Antidepressants for non-specific low back pain”. In Urquhart DM. Cochrane Database Syst Rev (1): CD001703. doi:10.1002/14651858.CD001703.pub3. PMID 18253994.
^ Shah TH, Moradimehr A (August 2010). “Bupropion for the treatment of neuropathic pain”. Am J Hosp Palliat Care 27 (5): 333–6. doi:10.1177/1049909110361229.PMID 20185402.
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