Bupropion (/bjuːˈproʊpi.ɒn/ bew-proh-pee-on) (BAN) or bupropion hydrochloride (USAN, BANM), also known as amfebutamone (INN), is a drug of the aminoketone family primarily used as an antidepressant and smoking cessation aid.[8][9][10] Marketed as Wellbutrin and other trade names, it is one of the most frequently prescribed antidepressants in the United States,[11] although in many English-speaking countries, including the United Kingdom, Australia and New Zealand, this is an off-label use.[12] It is also widely used, in a formulation marketed as Zyban, to aid people who are trying to quit smoking.[11] It is taken in the form of tablets, and in the United States and most other countries it is available only with a prescription.[11]
Clinically, bupropion serves as an atypical antidepressant fundamentally different from most commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs).[12] It is an effective antidepressant on its own, but is also popular as an add-on medication in cases of incomplete response to first-line SSRI antidepressants.[13] In contrast to many other antidepressants, it does not cause weight gain or sexual dysfunction.[13] The most important side effect is an increase in risk for epileptic seizures, which caused the drug to be withdrawn from the market for some time and then caused the recommended dosage to be reduced.[13]
Bupropion is known to affect several different biological targets, and its mechanism of action is only partly understood.[13][14] It has been widely described as a weak norepinephrine-dopamine reuptake inhibitor.[14][15] However, studies with humans via the oral administration route have demonstrated that it does not significantly affect dopamine levels in the brain at clinically-used doses, casting doubt on the notion that dopamine is involved in its clinical effects.[14][15] Bupropion is a non-competitive antagonist of neuronal nicotinic acetylcholine receptors (nAChRs), an action which appears to be involved in both its antidepressant benefits and its efficacy in smoking cessation as high and/or altered acetylcholine levels may affect both.[14][16] Chemically, bupropion belongs to the class of aminoketones and is similar in structure to stimulants such as cathinone and amfepramone, and to phenethylamines in general.[13]
Bupropion was synthesized by Nariman Mehta and patented by Burroughs Wellcome in 1969, which later became part of what is now GlaxoSmithKline. It was first approved for clinical use in the United States in 1989. It was originally called by the generic name amfebutamone, before being renamed in 2000.[17] Its chemical name is 3-chloro-N-tert-butyl-β-ketoamphetamine. It is a substituted cathinone (β-ketoamphetamine), as well as a substituted amphetamine.
Medical uses[edit]
Depression[edit]
Bupropion is one of the most widely prescribed antidepressants, and the available evidence indicates that it is effective in clinical depression[18] — as effective as several other widely prescribed drugs, including fluoxetine (Prozac) and paroxetine (Paxil),[19] although trends favoring the efficacy of escitalopram (Lexapro), sertraline (Zoloft) and venlafaxine (Effexor) over bupropion have been observed.[19] Mirtazapine (Remeron), on the other hand is significantly more effective than bupropion.[19] Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction.[20] Bupropion treatment also is not associated with the somnolence or weight gain that may be produced by other antidepressants.[21]
The majority of depressed people suffer from insomnia, but there are some who instead experience constant sleepiness and fatigue. In this subgroup, bupropion has been found to be more effective than selective serotonin reuptake inhibitors (SSRIs) at alleviating the symptoms.[22] There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression.[23]
According to surveys, the addition to a prescribed SSRI is a common strategy when people do not respond to the SSRI, even though this is not an officially approved indication.[24] The addition of bupropion to an SSRI (most commonly fluoxetine or sertraline) may result in an improvement in some people who have an incomplete response to the first-line antidepressant.[24]
In some countries (including Australia, New Zealand and the UK) this is an off-label use.[25][26] Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder.[27]
Smoking cessation[edit]
The next most common use is as an aid for smoking cessation where it reduces the severity of nicotine cravings and withdrawal symptoms.[28] A typical bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. Bupropion approximately doubles the chance of quitting smoking successfully after three months. One year after treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group.[28]
The evidence is clear that bupropion is effective at reducing nicotine cravings. Whether it is more effective than other treatments is not as clear, due to a limited number of studies. The evidence that is available suggests that bupropion is comparable to nicotine replacement therapy, but somewhat less effective than varenicline (Chantix).[28]
In Australia and the UK smoking cessation is the only licensed indication of bupropion.[25][26]
Attention deficit hyperactivity disorder[edit]
There have been numerous reports of positive results for bupropion as a treatment for attention deficit hyperactivity disorder (ADHD),[29] both in minors and adults.[30] However, in a double-blind study of children, while aggression and hyperactivity as rated by the children's teachers were significantly improved in comparison to placebo, parents and clinicians could not distinguish between the effects of bupropion and placebo.[30] 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."[31] Similarly, the Texas Department of State Health Services guideline recommends considering bupropion or a tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and atomoxetine.[32]
Sexual dysfunction[edit]
Bupropion is one of few antidepressants that do not cause sexual dysfunction.[33] A range of studies demonstrate that bupropion not only produces fewer sexual side effects than other antidepressants, but can actually help to alleviate sexual dysfunction.[34] 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. There have also been a few studies suggesting that bupropion can improve sexual function in women who are not depressed, if they have hypoactive sexual desire disorder.[35]
Obesity[edit]
Bupropion, when used for treating obesity over a period of 6 to 12 months, may result in weight loss of 2.7 kg over placebo.[36] This is not much different from the weight loss produced by several other medications, such as sibutramine, orlistat and amfepramone.[36]
It has been studied in combination with naltrexone.[37] Concerns from bupropion include an increase in blood pressure and heart rate and thus as of 2013 it has not been approved in the United States for this use.[37]
Other[edit]
There has been controversy about whether it is useful to add an antidepressant such as bupropion to a mood stabilizer in patients with bipolar depression, but recent reviews have concluded that bupropion in this situation does no significant harm and may sometimes give significant benefit.[38][39]
Bupropion has shown no effectiveness in the treatment of cocaine dependence, but there is weak evidence that it may be useful in treating methamphetamine dependence.[40]
Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease or other autoimmune conditions, but very little clinical evidence is available.[41]
Bupropion—like other antidepressants, with the exception of duloxetine (Cymbalta)[42]—is not effective in treating chronic low back pain.[43] It does, however, show some promise in the treatment of neuropathic pain.[44]
Recreational use[edit]
According to the US government classification of psychiatric medications, bupropion is "non-abusable".[45] However, in animal studies, squirrel monkeys and rats could be induced to self-administer bupropion via the injection route, which is often taken as a sign of addiction potential; however, there are significant interspecies differences in bupropion metabolism.[46] There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion via the oral route are markedly different from those of addictive stimulants such as cocaine or amphetamine.[47] In any case, bupropion, via non-conventional routes of administration (e.g., injection, insufflation), is reported to be abused in Canada,[48] and in recent years in United States prisons.[49][50]
Contraindications[edit]
GlaxoSmithKline advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as anorexia nervosa, bulimia nervosa, active brain tumors, or concurrent alcohol and/or benzodiazepine use and/or withdrawal. It should be avoided in individuals who are also taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications.[51] 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.
Clinically, bupropion serves as an atypical antidepressant fundamentally different from most commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs).[12] It is an effective antidepressant on its own, but is also popular as an add-on medication in cases of incomplete response to first-line SSRI antidepressants.[13] In contrast to many other antidepressants, it does not cause weight gain or sexual dysfunction.[13] The most important side effect is an increase in risk for epileptic seizures, which caused the drug to be withdrawn from the market for some time and then caused the recommended dosage to be reduced.[13]
Bupropion is known to affect several different biological targets, and its mechanism of action is only partly understood.[13][14] It has been widely described as a weak norepinephrine-dopamine reuptake inhibitor.[14][15] However, studies with humans via the oral administration route have demonstrated that it does not significantly affect dopamine levels in the brain at clinically-used doses, casting doubt on the notion that dopamine is involved in its clinical effects.[14][15] Bupropion is a non-competitive antagonist of neuronal nicotinic acetylcholine receptors (nAChRs), an action which appears to be involved in both its antidepressant benefits and its efficacy in smoking cessation as high and/or altered acetylcholine levels may affect both.[14][16] Chemically, bupropion belongs to the class of aminoketones and is similar in structure to stimulants such as cathinone and amfepramone, and to phenethylamines in general.[13]
Bupropion was synthesized by Nariman Mehta and patented by Burroughs Wellcome in 1969, which later became part of what is now GlaxoSmithKline. It was first approved for clinical use in the United States in 1989. It was originally called by the generic name amfebutamone, before being renamed in 2000.[17] Its chemical name is 3-chloro-N-tert-butyl-β-ketoamphetamine. It is a substituted cathinone (β-ketoamphetamine), as well as a substituted amphetamine.
Medical uses[edit]
Depression[edit]
Bupropion is one of the most widely prescribed antidepressants, and the available evidence indicates that it is effective in clinical depression[18] — as effective as several other widely prescribed drugs, including fluoxetine (Prozac) and paroxetine (Paxil),[19] although trends favoring the efficacy of escitalopram (Lexapro), sertraline (Zoloft) and venlafaxine (Effexor) over bupropion have been observed.[19] Mirtazapine (Remeron), on the other hand is significantly more effective than bupropion.[19] Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction.[20] Bupropion treatment also is not associated with the somnolence or weight gain that may be produced by other antidepressants.[21]
The majority of depressed people suffer from insomnia, but there are some who instead experience constant sleepiness and fatigue. In this subgroup, bupropion has been found to be more effective than selective serotonin reuptake inhibitors (SSRIs) at alleviating the symptoms.[22] There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression.[23]
According to surveys, the addition to a prescribed SSRI is a common strategy when people do not respond to the SSRI, even though this is not an officially approved indication.[24] The addition of bupropion to an SSRI (most commonly fluoxetine or sertraline) may result in an improvement in some people who have an incomplete response to the first-line antidepressant.[24]
In some countries (including Australia, New Zealand and the UK) this is an off-label use.[25][26] Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder.[27]
Smoking cessation[edit]
The next most common use is as an aid for smoking cessation where it reduces the severity of nicotine cravings and withdrawal symptoms.[28] A typical bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. Bupropion approximately doubles the chance of quitting smoking successfully after three months. One year after treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group.[28]
The evidence is clear that bupropion is effective at reducing nicotine cravings. Whether it is more effective than other treatments is not as clear, due to a limited number of studies. The evidence that is available suggests that bupropion is comparable to nicotine replacement therapy, but somewhat less effective than varenicline (Chantix).[28]
In Australia and the UK smoking cessation is the only licensed indication of bupropion.[25][26]
Attention deficit hyperactivity disorder[edit]
There have been numerous reports of positive results for bupropion as a treatment for attention deficit hyperactivity disorder (ADHD),[29] both in minors and adults.[30] However, in a double-blind study of children, while aggression and hyperactivity as rated by the children's teachers were significantly improved in comparison to placebo, parents and clinicians could not distinguish between the effects of bupropion and placebo.[30] 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."[31] Similarly, the Texas Department of State Health Services guideline recommends considering bupropion or a tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and atomoxetine.[32]
Sexual dysfunction[edit]
Bupropion is one of few antidepressants that do not cause sexual dysfunction.[33] A range of studies demonstrate that bupropion not only produces fewer sexual side effects than other antidepressants, but can actually help to alleviate sexual dysfunction.[34] 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. There have also been a few studies suggesting that bupropion can improve sexual function in women who are not depressed, if they have hypoactive sexual desire disorder.[35]
Obesity[edit]
Bupropion, when used for treating obesity over a period of 6 to 12 months, may result in weight loss of 2.7 kg over placebo.[36] This is not much different from the weight loss produced by several other medications, such as sibutramine, orlistat and amfepramone.[36]
It has been studied in combination with naltrexone.[37] Concerns from bupropion include an increase in blood pressure and heart rate and thus as of 2013 it has not been approved in the United States for this use.[37]
Other[edit]
There has been controversy about whether it is useful to add an antidepressant such as bupropion to a mood stabilizer in patients with bipolar depression, but recent reviews have concluded that bupropion in this situation does no significant harm and may sometimes give significant benefit.[38][39]
Bupropion has shown no effectiveness in the treatment of cocaine dependence, but there is weak evidence that it may be useful in treating methamphetamine dependence.[40]
Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease or other autoimmune conditions, but very little clinical evidence is available.[41]
Bupropion—like other antidepressants, with the exception of duloxetine (Cymbalta)[42]—is not effective in treating chronic low back pain.[43] It does, however, show some promise in the treatment of neuropathic pain.[44]
Recreational use[edit]
According to the US government classification of psychiatric medications, bupropion is "non-abusable".[45] However, in animal studies, squirrel monkeys and rats could be induced to self-administer bupropion via the injection route, which is often taken as a sign of addiction potential; however, there are significant interspecies differences in bupropion metabolism.[46] There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion via the oral route are markedly different from those of addictive stimulants such as cocaine or amphetamine.[47] In any case, bupropion, via non-conventional routes of administration (e.g., injection, insufflation), is reported to be abused in Canada,[48] and in recent years in United States prisons.[49][50]
Contraindications[edit]
GlaxoSmithKline advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as anorexia nervosa, bulimia nervosa, active brain tumors, or concurrent alcohol and/or benzodiazepine use and/or withdrawal. It should be avoided in individuals who are also taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications.[51] 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.
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