Bupropion
Encyclopedia
Bupropion is an atypical antidepressant
and smoking cessation
aid. The drug is a non-tricyclic antidepressant
and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition
. It binds selectively to the dopamine transporter
, but its behavioural effects have often been attributed to its inhibition of norepinephrine
reuptake
. It also acts as a nicotinic acetylcholine receptor
antagonist
. Bupropion belongs to the chemical class of aminoketone
s and is similar in structure
to stimulants cathinone
and diethylpropion, and to phenethylamine
s in general.
Initially researched and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. With over 20 million retail prescriptions in 2007, it was the fourth-most prescribed antidepressant in the United States retail market after sertraline
, escitalopram
, and fluoxetine
.
Bupropion lowers seizure threshold
, and its potential to cause seizures has been widely publicized. However, at the recommended dose the risk of seizures is comparable to that observed for other antidepressants. Bupropion is an effective antidepressant on its own but it is particularly popular as an add-on medication in the cases of incomplete response to the first-line selective serotonin reuptake inhibitor
(SSRI) antidepressant. In contrast to many other antidepressants, bupropion does not cause weight gain
or sexual dysfunction
; in fact, in most studies, groups placed on bupropion showed statistically significant increases in libido
, and mild to moderate weight loss
.
-controlled double-blind
clinical studies have confirmed the efficacy of bupropion for clinical depression. Comparative clinical studies demonstrated the equivalency of bupropion and sertraline
(Zoloft), fluoxetine
(Prozac), paroxetine
(Paxil) and escitalopram
(Lexapro) as antidepressants. A significantly higher remission rate with bupropion treatment than for venlafaxine
(Effexor) was observed in a recent study. Unlike all other antidepressants, except mirtazapine
(Remeron) and tianeptine
(Stablon), bupropion does not 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, at the end of every study comparing bupropion with placebo or other antidepressants the bupropion group had a lower average weight. Bupropion is more effective than SSRIs at improving symptoms of hypersomnia
and fatigue in depressed patients. In a comparative meta-analysis, there appeared to be a modest advantage for the SSRIs compared to bupropion in the treatment of depression with high anxiety, while these medications were equivalent for the depression with moderate or low anxiety.
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. For example, the combination of bupropion and citalopram
(Celexa) 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. 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. In the STAR*D study, the patients who did not respond to citalopram
(Celexa) were randomly assigned to augmentation by bupropion or buspirone
(Buspar). Approximately 30% of subjects in both groups achieved a remission. However, bupropion augmentation gave better results based on the patients' self-ratings and was much better tolerated. The authors observed that "these findings reveal a consistently more favorable outcome with sustained-release bupropion than with buspirone augmentation of citalopram." The same study indicated a possibility of higher remission rate when the non-responders to citalopram received bupropion augmentation instead of being switched to bupropion (30% vs. 20%).
and anxiety
comorbid with depression, but not panic disorder
with agoraphobia
. Its anxiolytic
potential has been compared to that of sertraline
and doxepin
. However, it can cause agitation in some patients, especially at higher doses, and often increases anxiety, much like methylphenidate
.
cravings and withdrawal
symptoms.
After a seven-week treatment, 27% of subjects who received bupropion reported that an urge to smoke was a problem, versus 56% of those who received placebo
. In the same study, 21% of the bupropion group reported mood swings, versus 32% of the placebo group. The 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 the treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group. The combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison, varenicline (Chantix) showed superior efficacy: after one year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline. 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).
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. Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire disorder, 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 and for orgasmic dysfunction. 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. Bupropion does not adversely affect any measures of sexual functioning in healthy men.
of anti-obesity medication
s 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). 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. Combinations of bupropion and zonisamide
(Empatic
) and of bupropion and naltrexone
(Contrave
) are currently being studied for obesity.
(ADHD) is not an approved indication, bupropion was found to be effective for adult ADHD. There have been many positive case studies and other uncontrolled clinical studies of bupropion for ADHD in minors. However, in the largest to date double-blind study, 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. 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." Similarly, the 2006 guideline from the Texas Department of State Health Services recommends considering bupropion or a tricyclic antidepressant
as a fourth-line treatment after trying two different stimulants and atomoxetine (Strattera).
A study of prophylactic bupropion for the prevention of smoking among teenagers with ADHD yielded unexpected results. The teenagers taking bupropion were two times more likely (close to statistical significance) to begin smoking than the teenagers in the placebo group. However, because significance was not reached, this difference can be attributed entirely to chance. At the same time, the sub-group of patients taking stimulants in addition to bupropion or placebo had a five times lower risk of smoking initiation.
. According to several case studies and a pilot study, bupropion lowers the level of an inflammatory mediator TNF-alpha and may be useful in autoinflammatory conditions such as Crohn's disease
and psoriasis
.
No properly controlled double-blind studies of bupropion for Parkinson's disease
have been conducted. A small 1984 study funded by bupropion's manufacturer found that addition of bupropion to carbidopa
or levodopa
improved Parkinson's symptoms in ten out of twenty patients; however, the side effects, particularly nausea and vomiting, were frequent. The American Psychiatric Association
notes that, "there is no evidence favoring any particular antidepressant medication from the standpoint of therapeutic efficacy in patients with Parkinson's disease complicated by major depressive disorder".
There is considerable disagreement regarding whether it is useful to add an antidepressant, including bupropion, to a mood stabilizer
in patients with bipolar depression.
Bupropion, similarly to other antidepressants, is not efficacious in chronic low back pain. However, it has been found to have surprisingly high efficacy in the treatment of neuropathic pain.
or other conditions that lower the seizure threshold
, such as alcohol or benzodiazepine
withdrawal, anorexia nervosa
, bulimia, or active brain tumors. It should be avoided in individuals who are also taking monoamine oxidase inhibitor
s (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications. 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
.
According to a retrospective
case series
published in 1993, bupropion treatment may exacerbate tic
s in children with co-occurring ADHD
and Tourette syndrome
. No further research of this side effect has been conducted.
is the most controversial side effect of bupropion, and was responsible for its initial withdrawal from the market. The risk of seizure is highly dose-dependent: 0.1% at 100–300 mg of bupropion, 0.4% at 300–450 mg, and 2% at 600 mg. For comparison, the incidence of the first unprovoked seizure in the general population is 0.0003–0.00084%. The risk of seizure for other antidepressants is as follows: 0.1–0.6% for imipramine
, depending on dosage; 0–0.06% for amitriptyline
, depending on dosage; 0.5% for clomipramine
; 0.4% for maprotiline
; and 0.2% for fluoxetine
and fluvoxamine
. Experiments on mice indicate that increased susceptibility to seizure is a general side effect of chronically using antidepressants that inhibit norepinephrine transporters, such as imipramine
, desipramine
and reboxetine
. Clinical depression itself was reported to increase the occurrence of seizures two-to-sevenfold compared with the general population; in this light, the above statistics could indicate that low to moderate doses of antidepressants, including bupropion, may actually have an anti-convulsive action.
The prescribing information notes that hypertension
, sometimes severe, was observed in some patients, both with and without pre-existing hypertension. The frequency of this adverse effect was under 1% and not significantly higher than that found with placebo. In a group of cardiac patients with depression, high doses of bupropion (400–500 mg/day) caused a rise in supine
blood pressure but had no effect on pulse rate. No statistically significant changes in blood pressure or heart rate occurred in patients with or without heart conditions at a lower dose of 300 mg/day. In a study of bupropion for ADHD, a rise of systolic
blood pressure by 6 mm Hg and of heart rate by 7 beats per minute (both statistically significant) were observed. A study of smokers hospitalized for heart disease found a 1.5-fold increase (close to being statistically significant) in subsequent cardiovascular events in the bupropion group, compared with the placebo group, but found no difference in blood pressure. Although the cardiovascular side effects of bupropion appear to be mild, it cannot be recommended for patients with heart disease, since the safety comparison with SSRIs (such as sertraline
and fluoxetine
, which may have a preventative effect after a myocardial infarction
) is not in its favor.
In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion's approval by the MHRA
as part of the Yellow Card Scheme
, which monitored side effects. Approximately 540,000 people were treated with bupropion for smoking cessation during that period. The MHRA received 60 reports of "suspected [emphasis MHRA's] adverse reactions to Zyban which had a fatal outcome". The agency concluded that "in the majority of cases the individual's underlying condition may provide an alternative explanation." 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.
Other isolated adverse affects have been reported. Three cases of liver toxicity have been described, a very low incidence given the widespread use of the drug. A single case of clitoral priapism (clitorism
) has been reported in the literature.
The common adverse effects associated with 12-hour sustained-release bupropion (with the greatest difference from placebo) are dry mouth, nausea, insomnia, tremor, excessive sweating and tinnitus
. Those that most often resulted in interruption of the treatment in the same trial were rash (2.4%) and nausea (0.8%).
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 of the suicidal ideation
and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.
Suicidal ideation
and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, bupropion and nine other antidepressants were not statistically different from placebo. Only fluoxetine
caused a significant decrease in suicidal ideation.
Suicidal behavior is less likely 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."
Two years later, the FDA issued a health advisory, which warned that the prescription of bupropion and varenicline for smoking cessation has been associated with reports about unusual behaviour changes, agitation and hostility. Some patients 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 the postmarket review of anti-smoking products, which identified 153 reports of the suicidal adverse events for varenicline over the first year it was marketed and 75 reports for bupropion over ten years. No clear association with suicidality was identified for nicotine patch
products.
Mania
is one of the rare side effects of bupropion. The prescribing information notes that "it is generally believed (though not established in controlled trials)" that, should an episode of depression actually be the first presentation of bipolar disorder
, treating it with antidepressants, including bupropion, may precipitate a manic episode. More recent data indicate that the addition of newer antidepressants, including bupropion, to a mood stabilizer
does not cause the switch to mania more often than the addition of placebo. Moreover, when added to a mood stabilizer, bupropion and sertraline had a twice lower switch risk than venlafaxine.
Like many of the antidepressants, bupropion is associated with the potential risk for causing anxiety as a side effect. How common or severe this anxiety is remains to be fully discovered. Some studies show that it has similar anxiety side effects to the SSRI antidepressants, while others show an elevated risk for akathisia
, or extreme anxiety, as high as 13.9%, or three times that from sertraline.
Psychotic symptoms associated with bupropion are rare. They may include delusions, hallucinations, paranoia
, and confusion. Often, these symptoms can be reduced or eliminated by decreasing the dose or ceasing treatment. In many of these case reports, psychotic symptoms are associated with such risk factors as old age, the history of bipolar disorder or psychosis, and concomitant medications, for example, lithium or benzodiazepines. Most researchers have attributed the psychosis to bupropion's dopaminergic action.
According to several case reports, stopping bupropion abruptly may result in discontinuation syndrome
expressed as dystonia
, irritability, anxiety, mania
, headache, aches and pains. The prescribing information recommends dose tapering after bupropion has been used for seasonal affective disorder
; however it states that dose tapering is not required when discontinuing treatment for smoking cessation.
, hypertension
, drowsiness, lethargy, agitation, nausea and vomiting, and in particular delirium
and seizures. Less commonly additional symptoms include auditory and visual hallucination
s, coma
, and ECG
changes such as conduction disturbance or arrhythmia.
In the majority of childhood exploratory ingestions involving one or two tablets, children will remain asymptomatic. In teenagers and adults seizures are more commonly observed with the seizure rate increasing tenfold with doses of 600 mg daily. One overdose study suggested a dose-dependent relationship with seizures; patients ingesting more than 4.5 g were likely to have a seizure and nearly all patients ingesting more than 9 g had a seizure.
There is no specific antidote for bupropion; treatment is supportive, and focuses on maintaining airway patency and controlling seizures with high dose intravenous benzodiazepine
s or barbiturate
s if seizures are refractory to benzodiazepines. Gastric decontamination may be of little benefit given the risk of seizures and aspiration but activated charcoal is recommended. Additionally, whole bowel irrigation
should be undertaken in those ingesting sustained release formulations. Toxic effects may be delayed in onset, with seizures developing as late as 32 hours. Subsequently patients should undergo electroencephalographic
monitoring for 48 hours.
Bupropion overdose rarely results in death, although cases have been reported. Fatalities are typically associated with large overdosage and related to metabolic acidosis
and hypoxia
as complications of status epilepticus
with associated cardiorespiratory arrest. There is one published case report of successful treatment of refractory cardiac arrest in overdose of bupropion and lamotrigine
using lipid rescue.
enzyme, drug interactions with CYP2B6 inhibitors are possible: this includes medications like paroxetine
, sertraline
, norfluoxetine
(the active metabolite of fluoxetine
), diazepam
, clopidogrel
, and orphenadrine
. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers
, such as carbamazepine
, clotrimazole
, rifampicin
, ritonavir
, St John's Wort
and others.
Bupropion is an inhibitor of CYP2D6
. Hydroxybupropion is an inhibitor of that enzyme. A significant increase in the concentration of some drugs metabolized by CYP2D6 (venlafaxine
, desipramine
and dextromethorphan
, but not fluoxetine or paroxetine) has been observed when they are taken with bupropion.
Bupropion lowers the seizure threshold; accordingly, extreme care should be taken when prescribing bupropion with other medications that also lower it, such as antipsychotics, theophylline
, steroid
s, and some tricyclic antidepressant
s. Its combination with nicotine replacement therapies
can elevate blood pressure; since this combination is no more effective than either a nicotine patch or bupropion alone, it is not recommended.
The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold. A small study conducted by GlaxoSmithKline indicated that bupropion (100 mg) may counteract the subjective effects of small doses of alcohol (16–32 mL, slightly less than 1–2 standard US drinks). The volunteers reported feeling more sober and clear-headed and less sedated. Bupropion also reduced the detrimental effect of alcohol on auditory vigilance. The combination of bupropion (100 mg) and two drinks of alcohol increased heart rate by six beats per minute, a statistically significant increase.
and norepinephrine reuptake inhibitor
and releaser. It is about twice as potent an inhibitor of dopamine reuptake than of norepinephrine reuptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without reference to its metabolism. The occupancy of dopamine transporter
(DAT) by bupropion and its metabolites in the human brain as measured by positron emission tomography
was 6–22% in an independent study and 12–35% according to GlaxoSmithKline researchers. 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. 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.
Bupropion does not inhibit monoamine oxidase
or serotonin reuptake. However, it has been shown to indirectly enhance the firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive nicotinic antagonist
. The degree of inhibition of α3β4 receptors correlates well with the decrease in self-administration of morphine and methamphetamine in rats, and may be relevant to the effect of bupropion on nicotine addiction. The drug is supplied as a racemic
mixture, and the activities of the individual enantiomers were not found to differ.
Two SAR
studies date from 2009 and 2010.
s: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites are presented in Table 1. Bupropion is known to weakly inhibit the α1 adrenergic receptor
, with a 14% potency of its dopamine uptake inhibition, and the H1 receptor, with a 9% potency.
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
, but discontinued development in 2006 due to "an unfavourable risk/benefit
assessment".
Bupropion is metabolized to hydroxybupropion by CYP2B6
, an isoenzyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. The mechanism of formation of erythro-hydrobupropion and threo-hydrobupropion has not been studied but is probably mediated by one of the carbonyl reductase enzymes. The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (and the half-life from 3 to 16 hours), and of hydroxybupropion by as much as 7.5 times (and the half-life from 12 to 38 hours). Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.
There are significant interspecies differences in the metabolism of bupropion, with guinea pig
s' metabolism of the drug being closest to that of humans compared to mice and rats. Particular caution is needed when extrapolating the results of experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.
There have been two reported cases of false-positive urine amphetamine tests in persons taking bupropion. Bupropion metabolites erythro-hydrobupropion and threo-hydrobupropion, which have a phenethylamine
structure resembling amphetamine are likely to have been responsible for this reaction. More specific follow-up tests were negative.
with t-butylamine. It is a substituted cathinone
, or in other words, a derivative of cathinone
.
of Burroughs Wellcome (now GlaxoSmithKline
) in 1969, and the US patent for it was granted in 1974. It was approved by the United States Food and Drug Administration
(FDA) as an antidepressant on December 30, 1985 and marketed under the name Wellbutrin. However, a significant incidence of seizures at the originally recommended dosage (400–600 mg) 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 maximum recommended dose of 450 mg/day.
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). 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. In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder
.
(Wellbutrin SR), and extended release (Wellbutrin XL or XR). "Sustained release" and "extended release" are generally interchangeable terms, but in this case Wellbutrin SR is intended for twice-daily dosing and Wellbutrin XL is intended for once-daily dosing. Not all generics have retained this naming scheme, and the United States Pharmacopeia
requires all prolonged-release drug formulations (including generics for Wellbutrin SR) to be labeled "extended release", which has caused confusion and medication errors. According to GlaxoSmithKline, the SR tablets should not be split. Merck indicates that splitting a 150 mg Wellbutrin SR tablet decreases the time to peak levels, but that it will retain its sustained-release characteristics.
Efficacy cannot be determined early in treatment as, with most antidepressants, the medication must reach maximum blood plasma concentration for some time to be effective (2–4 weeks in some cases). Some prescribers may also prescribe a small dose of a benzodiazepine
to offset the initial side effects some patients encounter when starting bupropion treatment. These initial side effects, similar to stimulant side effects such as anxiety, agitation, nervousness, insomnia, etc. generally subside within the first 2 weeks and do not occur in every patient. People taking other products that manipulate norepinephrine
and/or its reuptake (for example antidepressants like venlafaxine
(Effexor, Pristiq), smoking cessation aids like Zyban, or pain medications like tramadol
) should surely let their doctor know they also take these medications; however, in proper dosages, concurrent use of norepinephrine
manipulating medications is usually not an issue.
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. 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 the Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also noted 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.
In France, marketing authorization was granted on August 3, 2001, also solely as a smoking cessation aid, and with a maximum daily dose of 300 mg; only sustained-release bupropion is available. Bupropion was granted a licence for use in adults with major depression in the Netherlands in early 2007, with GlaxoSmithKline expecting subsequent approval in other European countries.
In the United States, a newer formulation using the hydrobromide salt instead of the more classic hydrochloride salt has been released under the brand name Aplenzin by Sanofi-Aventis beginning in April 2008.
There is no generic equivalent at this time. This is a once-a-day formula that is taken in slightly higher dosages due to the difference in the salts (e.g. 348 mg Aplenzin Bupropion HBr is equivalent to 300 mg Bupropion HCl). In some patients the hydrobromide salt may metabolize in a more (or less) consistent fashion than the classic hydrochloride salt, delivering the medication in a more (or less) consistent manner. This is just one more option available to the prescriber of once-a-day Bupropion treatments.
Two studies on drug abusers indicated that the subjective effects of bupropion are markedly different from those of amphetamine
. Healthy volunteers trained to discriminate amphetamine and placebo recognized bupropion (400 mg) as amphetamine 20% of the time, compared to 10% for placebo and 75% for methylphenidate
(20 mg). They also reported feeling alert, vigorous, elated and energetic, reflecting the general stimulating properties of bupropion. In contrast to amphetamine and methylphenidate, there was no feeling of "liking the drug" and no desire to take it again. A comparison of bupropion SR (150 mg) and caffeine
(178 mg) indicated that caffeine may have higher abuse liability since it resulted in more reports of pleasant feelings and a "high" than bupropion.
There have been four reports of bupropion abuse in the literature. Three cases described teenagers crushing and insufflating
(snorting) the drug, two of them resulting in seizures. An additional case was reported where a teenager ingested bupropion believing the drug to be a stimulant. A newspaper article on medication abuse in prisons mentioned bupropion as one of the psychotropic medications commonly abused by inmates.
s and rats maintained the intravenous self-administration of bupropion. Significant interspecies differences of bupropion metabolism exist, particularly between rats and humans.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
and smoking cessation
Smoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
aid. The drug is a non-tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition
Norepinephrine-dopamine reuptake inhibitor
A norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
. It binds selectively to the dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
, but its behavioural effects have often been attributed to its inhibition of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
reuptake
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
. It also acts as a nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
. Bupropion belongs to the chemical class of aminoketone
Aminoketone
Aminoketones are compounds containing both a ketone group and an amine. An example is the phenethylamine stimulant cathinone....
s and is similar in structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
to stimulants cathinone
Cathinone
Cathinone, or Benzoylethanamine, is a monoamine alkaloid found in the shrub Catha edulis and is chemically similar to ephedrine, cathine and other amphetamines. Cathinone induces the release of dopamine from striatal preparations that are prelabelled either with dopamine or its precursors. It is...
and diethylpropion, and to phenethylamine
Substituted phenethylamine
The substituted phenethylamines are chemical compounds with the 2-phenethylamine chemical structure modified at the phenyl ring, sidechain, and/or amino group. Some of them are psychoactive drugs, including stimulants, psychedelics, opioids, and entactogens, which exert their effects primarily...
s in general.
Initially researched and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. With over 20 million retail prescriptions in 2007, it was the fourth-most prescribed antidepressant in the United States retail market after sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
, escitalopram
Escitalopram
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
, and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
.
Bupropion lowers seizure threshold
Seizure threshold
A seizure threshold is the balance between excitatory and inhibitory forces in the brain which affects how susceptible one is to seizures. Those diagnosed with epilepsy or certain other neurological conditions are vulnerable to sudden new seizures if the threshold is upset, and so must be...
, and its potential to cause seizures has been widely publicized. However, at the recommended dose the risk of seizures is comparable to that observed for other antidepressants. Bupropion is an effective antidepressant on its own but it is particularly popular as an add-on medication in the cases of incomplete response to the first-line selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) antidepressant. In contrast to many other antidepressants, bupropion does not cause weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
or sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
; in fact, in most studies, groups placed on bupropion showed statistically significant increases in libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
, and mild to moderate weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
.
Depression
PlaceboPlacebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
-controlled double-blind
Double-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
clinical studies have confirmed the efficacy of bupropion for clinical depression. Comparative clinical studies demonstrated the equivalency of bupropion and sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft), fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac), paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil) and escitalopram
Escitalopram
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
(Lexapro) as antidepressants. A significantly higher remission rate with bupropion treatment than for venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor) was observed in a recent study. Unlike all other antidepressants, except mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
(Remeron) and tianeptine
Tianeptine
Tianeptine was discovered by The French Society of Medical Research in the 1960s. Under the trade-names it is a drug used for treating major depressive episodes ....
(Stablon), bupropion does not 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, at the end of every study comparing bupropion with placebo or other antidepressants the bupropion group had a lower average weight. Bupropion is more effective than SSRIs at improving symptoms of hypersomnia
Hypersomnia
Hypersomnia is a disorder characterized by excessive amounts of sleepiness.There are two main categories of hypersomnia: primary hypersomnia and recurrent hypersomnia...
and fatigue in depressed patients. In a comparative meta-analysis, there appeared to be a modest advantage for the SSRIs compared to bupropion in the treatment of depression with high anxiety, while these medications were equivalent for the depression with moderate or low anxiety.
According to several surveys, the augmentation
Augmentation (psychiatry)
Augmentation is the combination of two or more drugs to achieve better treatment results....
of a prescribed SSRI with bupropion is the preferred strategy among clinicians when the patient does not respond to the SSRI. For example, the combination of bupropion and citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa) 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. 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. In the STAR*D study, the patients who did not respond to citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa) were randomly assigned to augmentation by bupropion or buspirone
Buspirone
Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
(Buspar). Approximately 30% of subjects in both groups achieved a remission. However, bupropion augmentation gave better results based on the patients' self-ratings and was much better tolerated. The authors observed that "these findings reveal a consistently more favorable outcome with sustained-release bupropion than with buspirone augmentation of citalopram." The same study indicated a possibility of higher remission rate when the non-responders to citalopram received bupropion augmentation instead of being switched to bupropion (30% vs. 20%).
Anxiety
Bupropion has shown some success in treating social anxiety disorderSocial anxiety disorder
Social anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
comorbid with depression, but not panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
with agoraphobia
Agoraphobia
Agoraphobia is an anxiety disorder defined as a morbid fear of having a panic attack or panic-like symptoms in a situation from which it is perceived to be difficult to escape. These situations can include, but are not limited to, wide-open spaces, crowds, or uncontrolled social conditions...
. Its anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
potential has been compared to that of sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
and doxepin
Doxepin
Doxepin is a psychotropic agent with tricyclic antidepressant and anxiolytic properties, known under many brand-names such as Aponal, the original preparation by Boehringer-Mannheim, now part of the Roche group; Adapine, Doxal , Deptran, Sinquan and Sinequan...
. However, it can cause agitation in some patients, especially at higher doses, and often increases anxiety, much like methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
.
Smoking cessation
Bupropion reduces the severity of nicotineNicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
cravings and withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
symptoms.
After a seven-week treatment, 27% of subjects who received bupropion reported that an urge to smoke was a problem, versus 56% of those who received placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. In the same study, 21% of the bupropion group reported mood swings, versus 32% of the placebo group. The 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 the treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group. The combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison, varenicline (Chantix) showed superior efficacy: after one year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline. 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).
Sexual dysfunction
Bupropion is one of few antidepressants that does not cause sexual dysfunction. 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 (FDA). 36% of psychiatrists preferred switching patients with SSRI-induced sexual dysfunction to bupropion, and 43% favored the augmentation of the current medication with bupropion. There are studies demonstrating the efficacy of both approaches; improvement of the desire and orgasm components of sexual function were the most often noted. For the augmentation approach, the addition of at least 200 mg/day of bupropion to the SSRI regimen may be necessary to achieve an improvement since the addition of 150 mg/day of bupropion did not produce a statistically significant difference from placebo.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. Two studies, one of which was placebo-controlled, demonstrated the efficacy of bupropion for women with hypoactive sexual desire disorder, resulting in significant improvement of arousal, orgasm and overall satisfaction. Bupropion also showed promise as a treatment for sexual dysfunction caused by chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
for breast cancer and for orgasmic dysfunction. 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. Bupropion does not adversely affect any measures of sexual functioning in healthy men.
Obesity
A recent meta-analysisMeta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of anti-obesity medication
Anti-obesity drug
Anti-obesity medication or weight loss drugs are all pharmacological agents that reduce or control weight. These drugs alter one of the fundamental processes of the human body, weight regulation, by either altering appetite, metabolism, or absorption of calories. It is common for them to be tried...
s 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
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. 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). The same review found the differences in weight loss between bupropion and other established weight-loss medications, such as sibutramine
Sibutramine
Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...
, orlistat
Orlistat
Orlistat , also known as tetrahydrolipstatin, is a drug designed to treat obesity. Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake...
and diethylpropion, to be statistically insignificant. Combinations of bupropion and zonisamide
Zonisamide
Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome, myoclonic, and generalized tonic clonic seizure.-History:...
(Empatic
Empatic
Bupropion/zonisamide is an experimental drug combination for the treatment of obesity.It is being developed by Orexigen Therapeutics. It has undergone phase 2 tests and is currently waiting for phase 3 testing to commence. The combination consists of two already US FDA approved prescription...
) and of bupropion and naltrexone
Naltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...
(Contrave
Contrave
Bupropion/naltrexone is an experimental treatment for obesity in phase III clinical trials. Currently being developed by Orexigen in a sustained-release formulation, it is a combination of two approved drugs, bupropion and naltrexone...
) are currently being studied for obesity.
Attention-deficit hyperactivity disorder
Although attention-deficit hyperactivity disorderAttention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
(ADHD) is not an approved indication, bupropion was found to be effective for adult ADHD. There have been many positive case studies and other uncontrolled clinical studies of bupropion for ADHD in minors. However, in the largest to date double-blind study, 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. 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." Similarly, the 2006 guideline from the Texas Department of State Health Services recommends considering bupropion or a tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
as a fourth-line treatment after trying two different stimulants and atomoxetine (Strattera).
A study of prophylactic bupropion for the prevention of smoking among teenagers with ADHD yielded unexpected results. The teenagers taking bupropion were two times more likely (close to statistical significance) to begin smoking than the teenagers in the placebo group. However, because significance was not reached, this difference can be attributed entirely to chance. At the same time, the sub-group of patients taking stimulants in addition to bupropion or placebo had a five times lower risk of smoking initiation.
Other uses
Bupropion was approved by the U.S. Food and Drug Administration (FDA) for the prevention of seasonal affective disorderSeasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
. According to several case studies and a pilot study, bupropion lowers the level of an inflammatory mediator TNF-alpha and may be useful in autoinflammatory conditions such as Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
and psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
.
No properly controlled double-blind studies of bupropion for Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
have been conducted. A small 1984 study funded by bupropion's manufacturer found that addition of bupropion to carbidopa
Carbidopa
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...
or levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
improved Parkinson's symptoms in ten out of twenty patients; however, the side effects, particularly nausea and vomiting, were frequent. The American Psychiatric Association
American Psychiatric Association
The American Psychiatric Association is the main professional organization of psychiatrists and trainee psychiatrists in the United States, and the most influential worldwide. Its some 38,000 members are mainly American but some are international...
notes that, "there is no evidence favoring any particular antidepressant medication from the standpoint of therapeutic efficacy in patients with Parkinson's disease complicated by major depressive disorder".
There is considerable disagreement regarding whether it is useful to add an antidepressant, including bupropion, to a mood stabilizer
Mood stabilizer
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
in patients with bipolar depression.
Bupropion, similarly to other antidepressants, is not efficacious in chronic low back pain. However, it has been found to have surprisingly high efficacy in the treatment of neuropathic pain.
Contraindications
GlaxoSmithKline advises that bupropion should not be prescribed to individuals with epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
or other conditions that lower the seizure threshold
Seizure threshold
A seizure threshold is the balance between excitatory and inhibitory forces in the brain which affects how susceptible one is to seizures. Those diagnosed with epilepsy or certain other neurological conditions are vulnerable to sudden new seizures if the threshold is upset, and so must be...
, such as alcohol or benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
withdrawal, anorexia nervosa
Anorexia nervosa
Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
, bulimia, or active brain tumors. It should be avoided in individuals who are also taking monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications. 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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, as well as in pediatric patients, adolescents and young adults due to the increased risk of suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
.
According to a retrospective
Retrospective
Retrospective generally means to take a look back at events that already have taken place. For example, the term is used in medicine, describing a look back at a patient's medical history or lifestyle.-Music:...
case series
Case series
A case series is a medical research descriptive study that tracks patients with a known exposure given similar treatment or examines their medical records for exposure and outcome. It can be retrospective or prospective and usually involves a smaller number of patients than more powerful...
published in 1993, bupropion treatment may exacerbate tic
Tic
A tic is a sudden, repetitive, nonrhythmic, stereotyped motor movement or vocalization involving discrete muscle groups. Tics can be invisible to the observer, such as abdominal tensing or toe crunching. Common motor and phonic tics are, respectively, eye blinking and throat clearing...
s in children with co-occurring ADHD
Attention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
and Tourette syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
. No further research of this side effect has been conducted.
Adverse effects
SeizureSeizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
is the most controversial side effect of bupropion, and was responsible for its initial withdrawal from the market. The risk of seizure is highly dose-dependent: 0.1% at 100–300 mg of bupropion, 0.4% at 300–450 mg, and 2% at 600 mg. For comparison, the incidence of the first unprovoked seizure in the general population is 0.0003–0.00084%. The risk of seizure for other antidepressants is as follows: 0.1–0.6% for imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, depending on dosage; 0–0.06% for amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
, depending on dosage; 0.5% for clomipramine
Clomipramine
Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
; 0.4% for maprotiline
Maprotiline
Maprotiline is a tetracyclic antidepressant . It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake....
; and 0.2% for fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
and fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
. Experiments on mice indicate that increased susceptibility to seizure is a general side effect of chronically using antidepressants that inhibit norepinephrine transporters, such as imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
and reboxetine
Reboxetine
Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...
. Clinical depression itself was reported to increase the occurrence of seizures two-to-sevenfold compared with the general population; in this light, the above statistics could indicate that low to moderate doses of antidepressants, including bupropion, may actually have an anti-convulsive action.
The prescribing information notes that hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, sometimes severe, was observed in some patients, both with and without pre-existing hypertension. The frequency of this adverse effect was under 1% and not significantly higher than that found with placebo. In a group of cardiac patients with depression, high doses of bupropion (400–500 mg/day) caused a rise in supine
Supine position
The supine position is a position of the body: lying down with the face up, as opposed to the prone position, which is face down, sometimes with the hands behind the head or neck. When used in surgical procedures, it allows access to the peritoneal, thoracic and pericardial regions; as well as the...
blood pressure but had no effect on pulse rate. No statistically significant changes in blood pressure or heart rate occurred in patients with or without heart conditions at a lower dose of 300 mg/day. In a study of bupropion for ADHD, a rise of systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
blood pressure by 6 mm Hg and of heart rate by 7 beats per minute (both statistically significant) were observed. A study of smokers hospitalized for heart disease found a 1.5-fold increase (close to being statistically significant) in subsequent cardiovascular events in the bupropion group, compared with the placebo group, but found no difference in blood pressure. Although the cardiovascular side effects of bupropion appear to be mild, it cannot be recommended for patients with heart disease, since the safety comparison with SSRIs (such as sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, which may have a preventative effect after a myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
) is not in its favor.
In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion's approval by the MHRA
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
as part of the Yellow Card Scheme
Yellow Card Scheme
The Yellow Card Scheme is the UK system for collecting information on suspected Adverse Drug Reactions to medicines. The Scheme was founded in 1964 after the thalidomide disaster, and was developed by Dr Bill Inman....
, 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." 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.
Other isolated adverse affects have been reported. Three cases of liver toxicity have been described, a very low incidence given the widespread use of the drug. A single case of clitoral priapism (clitorism
Clitorism
Clitorism is a continued, painful condition in the female with recurring erection of the clitoris. The word is also used to describe an abnormal enlargement of the clitoris. Clitorism is painful, much like its male counterpart, priapism....
) has been reported in the literature.
The common adverse effects associated with 12-hour sustained-release bupropion (with the greatest difference from placebo) are dry mouth, nausea, insomnia, tremor, excessive sweating and tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
. Those that most often resulted in interruption of the treatment in the same trial were rash (2.4%) and nausea (0.8%).
Psychiatric
The FDA requires all antidepressants, including bupropion, to carry a black box warningBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
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 of the suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.
Suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, bupropion and nine other antidepressants were not statistically different from placebo. Only fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
caused a significant decrease in suicidal ideation.
Suicidal behavior is less likely when bupropion is prescribed for smoking cessation. According to a 2007 Cochrane Database
Cochrane Library
The Cochrane Library is a collection of databases in medicine and other healthcare specialties provided by the Cochrane Collaboration and other organisations. At its core is the collection of Cochrane Reviews, a database of systematic reviews and meta-analyses which summarize and interpret the...
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."
Two years later, the FDA issued a health advisory, which warned that the prescription of bupropion and varenicline for smoking cessation has been associated with reports about unusual behaviour changes, agitation and hostility. Some patients 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 the postmarket review of anti-smoking products, which identified 153 reports of the suicidal adverse events for varenicline over the first year it was marketed and 75 reports for bupropion over ten years. No clear association with suicidality was identified for nicotine patch
Nicotine patch
A nicotine patch is a transdermal patch that releases nicotine into the body through the skin. It is used as an aid in nicotine replacement therapy , a process for smoking cessation. The first published study of the pharmacokinetics of a transdermal nicotine patch in humans was authored by Jed E....
products.
Mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
is one of the rare side effects of bupropion. The prescribing information notes that "it is generally believed (though not established in controlled trials)" that, should an episode of depression actually be the first presentation of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, treating it with antidepressants, including bupropion, may precipitate a manic episode. More recent data indicate that the addition of newer antidepressants, including bupropion, to a mood stabilizer
Mood stabilizer
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
does not cause the switch to mania more often than the addition of placebo. Moreover, when added to a mood stabilizer, bupropion and sertraline had a twice lower switch risk than venlafaxine.
Like many of the antidepressants, bupropion is associated with the potential risk for causing anxiety as a side effect. How common or severe this anxiety is remains to be fully discovered. Some studies show that it has similar anxiety side effects to the SSRI antidepressants, while others show an elevated risk for akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
, or extreme anxiety, as high as 13.9%, or three times that from sertraline.
Psychotic symptoms associated with bupropion are rare. They may include delusions, hallucinations, paranoia
Paranoia
Paranoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
, and confusion. Often, these symptoms can be reduced or eliminated by decreasing the dose or ceasing treatment. In many of these case reports, psychotic symptoms are associated with such risk factors as old age, the history of bipolar disorder or psychosis, and concomitant medications, for example, lithium or benzodiazepines. Most researchers have attributed the psychosis to bupropion's dopaminergic action.
According to several case reports, stopping bupropion abruptly may result in discontinuation syndrome
Withdrawal syndrome
A withdrawal syndrome, also called a discontinuation syndrome, occurs when a person suddenly stops taking or reduces the dosage of some types of medications...
expressed as dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
, irritability, anxiety, mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
, headache, aches and pains. The prescribing information recommends dose tapering after bupropion has been used for seasonal affective disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
; however it states that dose tapering is not required when discontinuing treatment for smoking cessation.
Overdose
Overdose of bupropion results in significant clinical effects in over one-third of cases. The most common symptoms include sinus tachycardiaSinus tachycardia
Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, drowsiness, lethargy, agitation, nausea and vomiting, and in particular delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
and seizures. Less commonly additional symptoms include auditory and visual hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s, coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
, and ECG
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
changes such as conduction disturbance or arrhythmia.
In the majority of childhood exploratory ingestions involving one or two tablets, children will remain asymptomatic. In teenagers and adults seizures are more commonly observed with the seizure rate increasing tenfold with doses of 600 mg daily. One overdose study suggested a dose-dependent relationship with seizures; patients ingesting more than 4.5 g were likely to have a seizure and nearly all patients ingesting more than 9 g had a seizure.
There is no specific antidote for bupropion; treatment is supportive, and focuses on maintaining airway patency and controlling seizures with high dose intravenous benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s or barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s if seizures are refractory to benzodiazepines. Gastric decontamination may be of little benefit given the risk of seizures and aspiration but activated charcoal is recommended. Additionally, whole bowel irrigation
Whole bowel irrigation
Whole bowel irrigation is a medical process involving the rapid administration of large volumes of an osmotically balanced polyethylene glycol solution , either orally or via a nasogastric tube, to flush out the entire gastrointestinal tract.-History:Whole bowel irrigation was originally developed...
should be undertaken in those ingesting sustained release formulations. Toxic effects may be delayed in onset, with seizures developing as late as 32 hours. Subsequently patients should undergo electroencephalographic
Electroencephalography
Electroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
monitoring for 48 hours.
Bupropion overdose rarely results in death, although cases have been reported. Fatalities are typically associated with large overdosage and related to metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
and hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
as complications of status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
with associated cardiorespiratory arrest. There is one published case report of successful treatment of refractory cardiac arrest in overdose of bupropion and lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
using lipid rescue.
Interactions
Since bupropion is metabolized to hydroxybupropion by the CYP2B6CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
enzyme, drug interactions with CYP2B6 inhibitors are possible: this includes medications like paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
, norfluoxetine
Norfluoxetine
Seproxetine, also known as -norfluoxetine, is a selective serotonin reuptake inhibitor . It is an active metabolite of fluoxetine. Seproxetine was being investigated by Eli Lilly and Company as an antidepressant but development was never completed and the drug was never marketed.-Synthesis:Fuller,...
(the active metabolite of fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
), diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
, and orphenadrine
Orphenadrine
Orphenadrine is an anticholinergic drug of the ethanolamine antihistamine class with prominent CNS and peripheral actions used to treat painful muscle spasms, other similar conditions, as well as the treatment...
. 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
Enzyme induction and inhibition
Enzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
, such as carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, clotrimazole
Clotrimazole
Clotrimazole is an antifungal medication commonly used in the treatment of fungal infections such as vaginal yeast infections, oral thrush, and ringworm...
, rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
, St John's Wort
St John's wort
St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
and others.
Bupropion is an inhibitor of CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. Hydroxybupropion is an inhibitor of that enzyme. A significant increase in the concentration of some drugs metabolized by CYP2D6 (venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
, desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
and dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
, but not fluoxetine or paroxetine) has been observed when they are taken with bupropion.
Bupropion lowers the seizure threshold; accordingly, extreme care should be taken when prescribing bupropion with other medications that also lower it, such as antipsychotics, theophylline
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
, steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s, and some tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s. Its combination with nicotine replacement therapies
Nicotine replacement therapy
Nicotine replacement therapy is the remedial administration of nicotine to the body by means other than tobacco, usually as part of smoking cessation. Common forms of nicotine replacement therapy are nicotine patches and nicotine gum...
can elevate blood pressure; since this combination is no more effective than either a nicotine patch or bupropion alone, it is not recommended.
The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold. A small study conducted by GlaxoSmithKline indicated that bupropion (100 mg) may counteract the subjective effects of small doses of alcohol (16–32 mL, slightly less than 1–2 standard US drinks). The volunteers reported feeling more sober and clear-headed and less sedated. Bupropion also reduced the detrimental effect of alcohol on auditory vigilance. The combination of bupropion (100 mg) and two drinks of alcohol increased heart rate by six beats per minute, a statistically significant increase.
Detection in biological fluids
Bupropion may be quantitated in blood, plasma or serum to monitor therapeutic use, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. The drug is unstable in biological fluids at room temperature and therefore specimens should be maintained at the coldest possible temperature prior to analysis.Mechanism of action
Bupropion is a dopamineDopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
and norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
and releaser. It is about twice as potent an inhibitor of dopamine reuptake than of norepinephrine reuptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without reference to its metabolism. The occupancy of dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT) by bupropion and its metabolites in the human brain as measured by positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
was 6–22% in an independent study and 12–35% according to GlaxoSmithKline researchers. 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. 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.
Bupropion does not inhibit monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
or serotonin reuptake. However, it has been shown to indirectly enhance the firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive nicotinic antagonist
Nicotinic antagonist
A nicotinic antagonist is a type of anticholinergic that inhibits the action at nicotinic acetylcholine receptors. These compounds are mainly used for peripheral muscle paralysis in surgery, but some centrally acting compounds such as bupropion, mecamylamine, and 18-methoxycoronaridine block...
. The degree of inhibition of α3β4 receptors correlates well with the decrease in self-administration of morphine and methamphetamine in rats, and may be relevant to the effect of bupropion on nicotine addiction. The drug is supplied as a racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture, and the activities of the individual enantiomers were not found to differ.
Two SAR
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
studies date from 2009 and 2010.
Pharmacokinetics
Bupropion is metabolized in the liver. It has several active metaboliteMetabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites are presented in Table 1. Bupropion is known to weakly inhibit the α1 adrenergic receptor
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
, with a 14% potency of its dopamine uptake inhibition, and the H1 receptor, with a 9% potency.
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
Radafaxine
Radafaxine is drug candidate designated GW-353,162 by GlaxoSmithKline, investigated for treatment of restless leg syndrome and as an NDRI antidepressant...
, but discontinued development in 2006 due to "an unfavourable risk/benefit
assessment".
Bupropion is metabolized to hydroxybupropion by CYP2B6
CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
, an isoenzyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. The mechanism of formation of erythro-hydrobupropion and threo-hydrobupropion has not been studied but is probably mediated by one of the carbonyl reductase enzymes. The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (and the half-life from 3 to 16 hours), and of hydroxybupropion by as much as 7.5 times (and the half-life from 12 to 38 hours). Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.
There are significant interspecies differences in the metabolism of bupropion, with guinea pig
Guinea pig
The guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...
s' metabolism of the drug being closest to that of humans compared to mice and rats. Particular caution is needed when extrapolating the results of experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.
There have been two reported cases of false-positive urine amphetamine tests in persons taking bupropion. Bupropion metabolites erythro-hydrobupropion and threo-hydrobupropion, which have a phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
structure resembling amphetamine are likely to have been responsible for this reaction. More specific follow-up tests were negative.
| 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 Dopamine Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their... ; NE = norepinephrine Norepinephrine Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter... ; 5HT = serotonin Serotonin Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans... . |
|||||
Synthesis
Bupropion is synthesized by brominating 3'-chloropropiophenone, followed by nucleophilic substitutionNucleophilic substitution
In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...
with t-butylamine. It is a substituted cathinone
Substituted cathinone
Substituted cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions...
, or in other words, a derivative of cathinone
Cathinone
Cathinone, or Benzoylethanamine, is a monoamine alkaloid found in the shrub Catha edulis and is chemically similar to ephedrine, cathine and other amphetamines. Cathinone induces the release of dopamine from striatal preparations that are prelabelled either with dopamine or its precursors. It is...
.
History
Bupropion was invented by Nariman MehtaNariman Mehta
Nariman B. Mehta was born in Bombay, India on April 8, 1920. He began his schooling at the St. Xavier's College,where he received a B.S. in Chemistry/Physics and a B.A. in English/Economics....
of Burroughs Wellcome (now GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) in 1969, and the US patent for it was granted in 1974. It was approved by the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) as an antidepressant on December 30, 1985 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. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a maximum recommended dose of 450 mg/day.
In 1996, the FDA approved a sustained-release
Sustained release
Time release technology, also known as sustained-release , sustained-action , extended-release , time-release or timed-release, controlled-release , modified release , or continuous-release , is a mechanism used in pill tablets or capsules to...
formulation of 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
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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. In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
.
Availability and dose forms
Brand-name and generic bupropion tablets are available in three forms, each as the hydrochloride salt: immediate release (Wellbutrin), sustained releaseSustained release
Time release technology, also known as sustained-release , sustained-action , extended-release , time-release or timed-release, controlled-release , modified release , or continuous-release , is a mechanism used in pill tablets or capsules to...
(Wellbutrin SR), and extended release (Wellbutrin XL or XR). "Sustained release" and "extended release" are generally interchangeable terms, but in this case Wellbutrin SR is intended for twice-daily dosing and Wellbutrin XL is intended for once-daily dosing. Not all generics have retained this naming scheme, and the United States Pharmacopeia
United States Pharmacopeia
The United States Pharmacopeia is the official pharmacopeia of the United States, published dually with the National Formulary as the USP-NF. The United States Pharmacopeial Convention is the nonprofit organization that owns the trademark and copyright to the USP-NF and publishes it every year...
requires all prolonged-release drug formulations (including generics for Wellbutrin SR) to be labeled "extended release", which has caused confusion and medication errors. According to GlaxoSmithKline, the SR tablets should not be split. Merck indicates that splitting a 150 mg Wellbutrin SR tablet decreases the time to peak levels, but that it will retain its sustained-release characteristics.
Efficacy cannot be determined early in treatment as, with most antidepressants, the medication must reach maximum blood plasma concentration for some time to be effective (2–4 weeks in some cases). Some prescribers may also prescribe a small dose of a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
to offset the initial side effects some patients encounter when starting bupropion treatment. These initial side effects, similar to stimulant side effects such as anxiety, agitation, nervousness, insomnia, etc. generally subside within the first 2 weeks and do not occur in every patient. People taking other products that manipulate norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and/or its reuptake (for example antidepressants like venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor, Pristiq), smoking cessation aids like Zyban, or pain medications like tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
) should surely let their doctor know they also take these medications; however, in proper dosages, concurrent use of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
manipulating medications is usually not an issue.
On October 11, 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com
ConsumerLab.com
ConsumerLab.com is a provider of independent test results and information to help consumers and healthcare professionals evaluate health, wellness, and nutrition products. ConsumerLab.com was founded in 1999. It is subscription fee based....
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 the Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also noted 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.
In France, marketing authorization was granted on August 3, 2001, also solely as a smoking cessation aid, and with a maximum daily dose of 300 mg; only sustained-release bupropion is available. Bupropion was granted a licence for use in adults with major depression in the Netherlands in early 2007, with GlaxoSmithKline expecting subsequent approval in other European countries.
In the United States, a newer formulation using the hydrobromide salt instead of the more classic hydrochloride salt has been released under the brand name Aplenzin by Sanofi-Aventis beginning in April 2008.
There is no generic equivalent at this time. This is a once-a-day formula that is taken in slightly higher dosages due to the difference in the salts (e.g. 348 mg Aplenzin Bupropion HBr is equivalent to 300 mg Bupropion HCl). In some patients the hydrobromide salt may metabolize in a more (or less) consistent fashion than the classic hydrochloride salt, delivering the medication in a more (or less) consistent manner. This is just one more option available to the prescriber of once-a-day Bupropion treatments.
Recreational use
According to the US government classification of psychiatric medications, bupropion is "non-abusable".Two studies on drug abusers indicated that the subjective effects of bupropion are markedly different from those of amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
. Healthy volunteers trained to discriminate amphetamine and placebo recognized bupropion (400 mg) as amphetamine 20% of the time, compared to 10% for placebo and 75% for methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
(20 mg). They also reported feeling alert, vigorous, elated and energetic, reflecting the general stimulating properties of bupropion. In contrast to amphetamine and methylphenidate, there was no feeling of "liking the drug" and no desire to take it again. A comparison of bupropion SR (150 mg) and caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
(178 mg) indicated that caffeine may have higher abuse liability since it resulted in more reports of pleasant feelings and a "high" than bupropion.
There have been four reports of bupropion abuse in the literature. Three cases described teenagers crushing and insufflating
Insufflation (medicine)
Insufflation is the practice of inhaling a substance. Insufflation has limited medical use, but is a common route of administration with many respiratory drugs used to treat conditions in the lungs and paranasal sinus .The technique is common for many recreational drugs and is also used for some...
(snorting) the drug, two of them resulting in seizures. An additional case was reported where a teenager ingested bupropion believing the drug to be a stimulant. A newspaper article on medication abuse in prisons mentioned bupropion as one of the psychotropic medications commonly abused by inmates.
Animal research
In animal studies squirrel monkeySquirrel monkey
The squirrel monkeys are the New World monkeys of the genus Saimiri. They are the only genus in the subfamily Saimirinae.Squirrel monkeys live in the tropical forests of Central and South America in the canopy layer. Most species have parapatric or allopatric ranges in the Amazon, while S...
s and rats maintained the intravenous self-administration of bupropion. Significant interspecies differences of bupropion metabolism exist, particularly between rats and humans.