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Bupropion

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Bupropion
Clinical data
Trade namesWellbutrin, Zyban
AHFS/Drugs.comMonograph
MedlinePlusa695033
License data
Pregnancy
category
  • AU: B2
Dependence
liability		very low
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5 to 20% in animals; no studies in humans
Protein binding84%
MetabolismHepatic—important CYP2B6 and 2D6 involvement
Elimination half-life11 hours [2]
ExcretionRenal (87%), fecal (10%)
Identifiers
  • (±)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO
Molar mass239.74 g/mol g·mol−1
3D model (JSmol)
  • O=C(c1cc(Cl)ccc1)C(NC(C)(C)C)C
  • InChI=1S/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3 checkY
  • Key:SNPPWIUOZRMYNY-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Bupropion (/bjuːˈproʊpi.ɒn/ bew-PROH-pee-on;[3]) is a drug 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.

Medically, bupropion serves as a non-tricyclic antidepressant fundamentally different from most commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs). It is an effective antidepressant on its own, but is also popular as an add-on medication in cases of incomplete response to first-line SSRI antidepressants. In contrast to many other antidepressants, it does not cause weight gain or sexual dysfunction. The most important side effect is an increase in risk for epileptic seizures, which caused the drug to be withdrawn from the market for some time and then caused the recommended dosage to be reduced. 300mg a day (for average body weight) has been shown to maintain the same 0.1% unprovoked seizure rate of the general population.

Bupropion affects a number of neurotransmitter systems, and its mechanisms of action are only partly understood. The primary pharmacological action of the drug is as a mild dopamine reuptake inhibitor and also a much weaker norepinephrine reuptake inhibitor as well as a nicotinic acetylcholine receptor antagonist. Chemically, bupropion belongs to the class of aminoketones and is similar in structure to stimulants such as cathinone and amfepramone, and to phenethylamines in general.

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.[4] Its chemical name is 3-chloro-N-tert-butyl-β-ketoamphetamine. It is a substituted cathinone (β-ketoamphetamine), as well as a substituted amphetamine.

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 treating inflammatory 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]

Contraindications

GlaxoSmithKline advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as alcohol or benzodiazepine withdrawal, anorexia nervosa, bulimia nervosa, or active brain tumors. It should be avoided in individuals who are also taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications.[31] The prescribing information approved by the FDA recommends that caution should be exercised when treating patients with liver damage, severe kidney disease, and severe hypertension, as well as in pediatric patients, adolescents and young adults due to the increased risk of suicidal ideation.[31]

Adverse effects

Epileptic seizures are the most important adverse effect of bupropion. A high incidence of seizures was responsible for the temporary withdrawal of the drug from the market between 1986 and 1989. The risk of seizure is strongly dose-dependent, but also dependent on the preparation. The sustained-release preparation is associated with a seizure incidence of 0.1% at daily dosages of less than 300 mg of bupropion and 0.4% at 300–400 mg.[32] The immediate release preparation is associated with a seizure incidence of 0.4% for dosages below 450 mg; the incidence climbs to 5% for dosages between 450–600 mg per day.[32] 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 0.6% at recommended dosage levels.[33] Given that clinical depression itself has been reported to increase the occurrence of seizures, it has been suggested that low to moderate doses of antidepressants may not actually increase seizure risk at all.[34] However, this same study found that bupropion and clomipramine were unique among antidepressants in that they were associated with increased incidence of seizures.[34]

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 found with placebo.[31] A review of the available data carried out in 2008 indicated that bupropion is safe to use in patients with a variety of serious cardiac conditions.[35]

In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion's approval by the Medicines and Healthcare Products Regulatory Agency as part of the Yellow Card Scheme, which monitored side effects. Approximately 540,000 people were treated with bupropion for smoking cessation during that period. The MHRA received 60 reports of "suspected [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."[36] 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.[37]

The most common adverse effects associated with 12-hour sustained-release bupropion are reported to be dry mouth, nausea, insomnia, tremor, excessive sweating and tinnitus. Those that most often resulted in interruption of the treatment were rash (2.4%) and nausea (0.8%).[31]

Psychiatric

Suicidal thought and behavior are rare in clinical trials, but 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.[38] 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.[38]

Suicidal behavior is less of a concern when bupropion is prescribed for smoking cessation. According to a 2007 Cochrane Database review, there have been four suicides per one million prescriptions and one case of suicidal ideation per ten thousand prescriptions of bupropion for smoking cessation in the UK. The review concludes, "Although some suicides and deaths while taking bupropion have been reported, thus far there is insufficient evidence to suggest they were caused by bupropion."[39]

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 patients, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide.[40] This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years.[41]

Psychotic symptoms associated with bupropion are rare. They may include delusions, hallucinations, paranoia, and confusion. In most cases these symptoms can be reduced or eliminated by decreasing the dose or ceasing treatment.[31][42] In many of these case reports, psychotic symptoms are associated with risk factors such as old age, a history of bipolar disorder or psychosis, and concomitant medications, for example, lithium or benzodiazepines.[43]

According to several case reports, stopping bupropion abruptly may result in a "discontinuation syndrome" expressed as dystonia, irritability, anxiety, mania, headache, aches and pains.[44] The prescribing information recommends dose tapering after bupropion has been used for seasonal affective disorder;[31] however it states that dose tapering is not required when discontinuing treatment for smoking cessation.[45]

Overdose

Bupropion is considered relatively safe in overdose. The most commonly reported symptom is epileptic seizures; other common symptoms include heart rhythm abnormalities, increased blood pressure, agitation, and hallucinations.[22][46]

In the majority of childhood exploratory ingestions involving one or two tablets, children show no apparent symptoms.[47] In teenagers and adults seizures are more commonly observed, with the seizure rate increasing tenfold with doses of 600 mg daily.[48]

Bupropion overdose rarely results in death, although some cases have been reported.[49] Fatalities are typically associated with large overdosage and related to metabolic acidosis and hypoxia as complications of status epilepticus with associated cardiac arrest.

Interactions

Since bupropion is metabolized to hydroxybupropion by the CYP2B6 enzyme, drug interactions with CYP2B6 inhibitors are possible: this includes medications like paroxetine, sertraline, 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, phenobarbital, phenytoin and others.[50] Conversely, because bupropion is itself an inhibitor of CYP2D6,[51] it can slow the clearance of other drugs metabolized by that enzyme.[50]

Bupropion lowers the threshold for epileptic seizures, and therefore can potentially interact with other medications that also lower it, such as theophylline, steroids, and some tricyclic antidepressants.[31] 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.[31]

Pharmacology

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) sites by bupropion and its metabolites in the human brain as measured by positron emission tomography was 6–22% in an independent study[52] and 12–35% according to GlaxoSmithKline researchers.[53] 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. By contrast, approximately 65% occupancy or greater of DAT is required to achieve euphoria and reach abuse potential.[54] However recent research indicates that dopamine is inactivated by norepinephrine reuptake in the frontal cortex, which largely lacks dopamine transporters, therefore bupropion can increase dopamine neurotransmission in this part of the brain, and this may be one possible explanation for any additional dopaminergic effects.[55]

Bupropion has also been shown to act as a noncompetitive nicotinic antagonist.[56]

Outside the nervous system, both bupropion and its primary metabolite hydrobupropion act in the liver as potent inhibitors of the enzyme CYP2D6, which metabolizes not only bupropion itself but also a variety of other drugs and biologically active substances.[51] This mechanism creates the potential for a variety of drug interactions.

Pharmacokinetics

Metabolites of bupropion.

Bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6.[32] 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 shown in the table. Bupropion is known to weakly inhibit the α1 adrenergic receptor, with a 14% potency of its dopamine uptake inhibition, and the H1 receptor, with a 9% potency.[57]

Pharmacology of bupropion and its metabolites.[57][58][59][60][61]
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
5HT 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; 5HT = serotonin.

The biological activity of bupropion can be attributed to a significant degree to its active metabolites, in particular to S,S-hydroxybupropion. GlaxoSmithKline developed this metabolite as a separate drug called radafaxine,[62] but discontinued development in 2006 due to "an unfavourable risk/benefit assessment".[63]

Bupropion is metabolized to hydroxybupropion by CYP2B6, an isozyme 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).[64] Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.[65]

There are significant interspecies differences in the metabolism of bupropion, with the metabolism in humans being more similar to guinea pigs than to mice and rats.[66] In fact hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.[67]

There have been two reported cases of false-positive urine amphetamine tests in persons taking bupropion. More specific follow-up tests were negative.[68][69]

Synthesis

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 first brominated 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.[70][71]

Regulatory history

Wellbutrin XL

Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974.[70] 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.[72] However, a significant incidence of epileptic seizures at the originally recommended dosage 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.[73]

In 1996, the FDA approved a sustained-release formulation of bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin).[74] 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, while in Canada, only the SR formulation is available in generic form. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban.[74] In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.[75]

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.[76]

On October 11, 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.[77] 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."[78] 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.[79] On October 3, 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg."[80] 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.[80]

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.[81]

In France, marketing authorization was granted for Zyban on August 3, 2001, with a maximum daily dose of 300 mg;[82] only sustained-release bupropion is available, and only as a smoking cessation aid. 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]

Recreational use

According to the US government classification of psychiatric medications, bupropion is "non-abusable".[84] In animal studies, squirrel monkeys and rats could be induced to self-administer bupropion, which is often taken as a sign of addiction potential; however, there are significant interspecies differences in bupropion metabolism.[51] 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 are markedly different from those of addictive stimulants such as cocaine or amphetamine.[85]

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