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Bupropion

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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 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 and 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.

Bupropion is primarily used as an antidepressant and 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]

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 in 1984 and marketed under the name Wellbutrin. 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, 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 (SR) formulation, and in 2003 an extended-release (XL) formulation of Wellbutrin, both of which release bupropion at a slower rate. Wellbutrin SR is taken twice a day and Wellbutrin XL once a day, as compared to three times daily for the regular formulation. Wellbutrin SR and XL are available 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.

In the United Kingdom, bupropion was approved as a smoking cessation aid in 2000, but has not been approved for the treatment of depression.[6]

Therapeutic uses

Depression

Placebo-controlled studies have confirmed the efficacy of bupropion for clinical depression.[7] Comparative clinical studies demonstrated the equivalency of bupropion and sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil)[8] and escitalopram (Lexapro)[9] as antidepressants. A significantly higher remission rate for bupropion treatment than for venlafaxine (Effexor) was observed in a recent study.[10] Unlike most other antidepressants, with the exceptions of mirtazapine (Remeron) and maprotiline (Ludiomil), bupropion does not cause sexual dysfunction and the occurrence of sexual side effects is not different from placebo.[11][12] 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.[13] Bupropion is more effective than SSRIs at improving symptoms of hypersomnia and fatigue in depressed patients.[14]

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.[15] 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.[16][17] 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.[17]

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.[18] 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.[19] 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.[20] 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).[18]

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.[21] 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 mg/day of bupropion to the SSRI is necessary to achieve a statistically significant improvement. The addition of 150 mg/day of bupropion to the SSRI regimen did not produce a statistically significant difference from placebo.[22][23][24][25][26][27]

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.[28] Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire,[29][30] 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[31] and for orgasmic dysfunction.[32] 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.[33] Bupropion does not affect any measures of sexual functioning in healthy men.[34]

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.[35]

Other uses

Bupropion is also effective for adult attention-deficit hyperactivity disorder[36] and for the prevention of seasonal affective disorder,[37] and has been approved by the FDA for the latter indication.[38] The combination of bupropion with a mood stabilizer in patients with bipolar depressions was shown to have the same effectiveness as placebo.[39]

Contraindications

Bupropion should be avoided in 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 also be avoided in individuals that are also taking MAO inhibitors. When switching from a MAOI to bupropion it is important to include a short period of about two weeks between the medications.[40]

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 (see below).[40]

Suicide risk

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 generic 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."[40]

FDA analysts also found that the risk of suicidal thoughts and behavior strongly depends on age of a person. In addition to increasing this risk in children and adolescents, antidepressants may increase it as much as 1.5 times in young (age 18–24) adults (data close to statistical significance). However, they decrease the suicidal thoughts and behavior for persons aged 31 to 64 years by 23% (statistically significant). Most importantly, considering the high risk of suicide among older people, antidepressants decrease suicidal thoughts and behavior 2.5-fold for persons 65 or more years old.[41]

The suicidal ideation/behavior in clinical trials is rare. For the above analysis, the FDA had to combine the results of 295 recent trials of 11 different antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, bupropion and 9 other antidepressants were not statistically different from placebo. Only fluoxetine caused a significant decrease in suicidal ideation/behavior.[41]

The suicidal behavior is even less likely when bupropion is prescribed for quitting smoking. According to Cochrane Database review, there have been 4 suicides per 1,000,000 prescriptions and 1 case of suicidal behavior/ideation per 10,000 prescriptions of bupropion for smoking cessation in the UK. The review concludes that, "Although some suicides and deaths while taking bupropion have been reported, thus far there is insufficient evidence to suggest they were caused by bupropion."[42]

Abuse liability

According to the US government classification of psychiatric medications, bupropion is non-abusable[43] or has low abuse potential.[44] However, in animal studies bupropion maintained intravenous self-administration by squirrel monkeys[45] and rats,[46] which may indicate abuse potential. On the other hand, important differences of bupropion metabolism in rats and humans make any extrapolation of rats' results to humans invalid (see Pharmacokinetics).

Two studies on drug abusers indicated that subjective effects of bupropion are markedly different from those of amphetamine.[47][48] Healthy volunteers trained to discriminate amphetamine and placebo, recognized bupropion (400 mg) as amphetamine in 20% of cases as compared to 10% for placebo and 75% for methylphenidate (20 mg). They also reported feeling alert, vigorous, elated and energetic, reflecting general stimulating properties of bupropion. However, in contrast to amphetamine and methylphenidate, there was no feeling of "liking the drug" and desire to take it again.[49] A comparison of bupropion SR (150 mg) and caffeine (178 mg) indicated that caffeine may have higher abuse liability since caffeine resulted in greater frequency of reports of pleasant feelings and "high" than bupropion.[50]

There have been only three reports of bupropion abuse in the literature. All three cases were teenagers crushing and insufflating (snorting) bupropion, one of them ending up with seizures.[51] An article on abuse of medications in prisons mostly concerned with the recreational use of quetiapine (Seroquel) mentions bupropion as one of the psychotropic medications commonly abused by inmates. Other such medications are gabapentin (Neurontin), tricyclic antidepressants and trihexyphenidyl.[52]

Dosage and forms

For the treatment of depression, the target dose is 300 mg daily, starting with 150 mg in the first few days. If indicated and directed by physician, the dose may be increased to a maximum of 450 mg daily. To treat tobacco withdrawal, bupropion is prescribed at 150 mg initially, and may be increased to 300 mg if indicated and directed by physician. In patients also receiving insulin, sympathomimetic anorectical drugs, or antimalaria agents, the daily dose of bupropion should not exceed 150 mg.

Due to the high variability of bupropion's pharmacokinetics, the recommended starting dose of 150 mg for some patients may be equivalent to 450–500 mg for an average patient. Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.[53] Because this is infeasible in routine clinical practice, a lower starting dose of 75 mg may be considered. This dose can be increased gradually based on individual tolerability up to the maximum dose of 450 mg.

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.[40]

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.[54] Zyban is available via prescription in the United Kingdom 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.

Mechanism of action

Bupropion is a dopamine and norepinephrine reuptake inhibitor.[55] It is about twice as potent an inhibitor of dopamine uptake than norepinephrine uptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without understanding its metabolism. Occupancy of dopamine transporter (DAT) by bupropion and its metabolites in human brain measured by positron emission tomography was 6–22% according to an independent study[56] and 12–35% according to GSK researchers.[57] Based on the 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 bupropion action. Bupropion does not inhibit monoamine oxidase (i.e. is not a MAOI) or serotonin reuptake. However, it has been shown to indirectly enhance firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive α3β4 nicotinic antagonist.[58] The degree of inhibition of α3β4 receptors correlates well with the decrease of self-administration of morphine and metamphetamine in rats,[59] 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. These active metabolites are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites combined from several sources are presented in the Table below. In addition, bupropion is known to weakly inhibit the α1 adrenaline receptor, with a 14% potency of its dopamine uptake inhibition, as well as the histamine H1 receptor, with 9% potency of dopamine uptake inhibition.[60]

Thus, the biological activity of bupropion can be attributed to a great degree to its active metabolites, in particular to S,S-hydroxybupropion. GSK developed this metabolite as a separate drug radafaxine,[61] but discontinued development in 2006 due to "poor test results".

Bupropion is metabolized to hydroxybupropion by a cytochrome P450 enzyme CYP2B6. Alcohol causes 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 probably it is mediated by one of the carbonyl reductase enzymes. The metabolism of bupropion is highly variable: the effective dose of bupropion received by different individuals, who ingested the same amount of the drug, may differ as much as 5.5 times (and half-life time from 3 to 16 hours), and of hydroxybupropion as much as 7.5 times (and half-life time from 12 to 38 h).[62][63]

Significant interspecies differences in metabolism of bupropion exist, with guinea pigs' metabolism of the drug being closest to the human metabolism.[64] Particular caution is needed when extrapolating the results of the experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.[65]

There have been two cases reported of false-positive urine amphetamine tests in persons taking bupropion. This is likely due to the bupropion metabolites erythro-hydrobupropion and threo-hydrobupropion, which have phenethylamine structure resembling amphetamine, were responsible for this reaction. More specific tests conducted afterwards were negative.[66][67]

Table. Pharmacology of bupropion and its metabolites.[68][69][70][60][71]
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

Side effects

For Bupropion SR (300 mg/day) common side effects 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). The two side effects which 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 by simply prescribing a different color pill. [40]

Seizure is the most controversial side effect of bupropion, which caused its earlier mentioned 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: imipramine 0.1–0.6% depending on dosage, amitriptiline 0–0.06% depending on dosage, clomipramine 0.5%, maprotiline 0.4%, fluoxetine and fluvoxamine 0.2%.[72] Experiments on mice indicate that increased susceptibility to seizure is a general side effect of antidepressants inhibiting norepinephrine transporter, such as imipramine, desipramine and reboxetine, given chronically.[73] On the other hand, depression was reported to increase occurrence of seizures 2–7 fold as compared to 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.[74] Nevertheless, patients using bupropion should still be screened for pre-disposing factors that could contribute to and/or indicate a low seizure threshold. A prescriber may also review all other medications/substances the patient is using and make dosing decisions based on the results.

Three cases of liver toxicity of bupropion have been reported in the literature.[75] This is extremely rare considering the widespread use of the drug.

The prescribing information notes that hypertension, sometimes severe, was observed in some patients, both with and without pre-existing hypertension, treated with bupropion. At the same time, the frequency of this side effect was under 1% and not significantly higher than for placebo.[40] In a group of cardiac patients with depression, high doses of bupropion (400–500 mg/day) caused a rise of supine blood pressure but no effect on pulse rate.[76] No statistically significant changes in blood pressure or heart rate occurred in patients both with and without heart conditions at a lower dose (300 mg/day) .[77] In a study of bupropion for ADHD, a rise of systolic blood pressure by 6 mm Hg and heartbeat rate by 7 bits per minute (both statistically significant) was observed.[78] A study of smokers hospitalized for heart disease found a 1.5–fold increase (close to being statistically significant) in the subsequent cardiovascular events in bupropion group as compared to the placebo group but no difference in blood pressure.[79] Although cardiovascular side effects of bupropion appear to be mild, it can not be recommended for patients with heart disease since the safety comparison with SSRI antidepressants (such as sertraline and fluoxetine which may have a preventative effect after a myocardial infarction[80]) is not in its favor.

A single case of clitoral priapism (clitorism) has been reported in the literature.[81]

In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion's approval by MHRA as a part of the Yellow Card Scheme which monitored side effects. Approximately 540,000 people were treated by bupropion for smoking cessation during that period. 60 reports of "suspected (emphasis by MHRA) adverse reactions to Zyban which had a fatal outcome" were received. The agency concluded that "in the majority of cases the individual’s underlying condition may provide an alternative explanation."[82] This is consistent with a large (9300 patients) safety study, which indicated that mortality of smokers taking bupropion is not higher than natural mortality of smokers of the same age.[83]

Interactions

As bupropion is metabolized to hydroxybupropion by CYP2B6, drug interactions with CYP2B6 inhibitors (paroxetine, sertraline, norfluoxetine—the active metabolite of fluoxetine—, diazepam, clopidogrel, orphenadrine and others) are possible. 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.[84]

Hydroxybupropion (but not bupropion) is itself an inhibitor of CYP2D6, as well as a substrate of that enzyme. Significant increase of the concentration of some drugs metabolized by CYP2D6 (venlafaxine, desipramine and dextromethorphan, but not fluoxetine or paroxetine) when taken with bupropion has been observed.[84][85]

Bupropion lowers the seizure threshold; therefore, extreme care should be taken when prescribing bupropion with other medications that also lower the seizure threshold (antipsychotics, theophylline, steroids, some tricyclic antidepressants).[40] Combination with nicotine replacement therapies can elevate blood pressure; it is also no more effective than either a nicotine patch or bupropion alone, so it should not be recommended.

The prescribing information recommends to minimize the use of alcohol, since in rare cases bupropion reduced alcohol tolerance, and also because the excessive use of alcohol may lower the seizure threshold.[40] 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 partially neutralized the detrimental effect of alcohol on auditory vigilance. In addition, the combination of bupropion (100 mg) and two drinks of alcohol increased the heart rate by 6 beats/min, a statistically significant increase.[86]

Trade names

References

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