Chemistry:Bupropion

From HandWiki
Short description: Substituted cathinone medication mainly used for depression and smoking cessation
Bupropion
Skeletal formula of bupropion
Ball-and-stick model of the (S) isomer of the bupropion molecule
1 : 1 mixture (racemate)
Clinical data
Pronunciation/bjuːˈproʊpiɒn/
bew-PROH-pee-on
Trade namesWellbutrin, Zyban, others
Other namesAmfebutamone; 3-Chloro-N-tert-butyl-β-keto-α-methylphenethylamine;
3-Chloro-N-tert-butyl-β-ketoamphetamine;
Bupropion hydrochloride[1]
AHFS/Drugs.comMonograph
MedlinePlusa695033
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classNDRI antidepressants
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown[11]
Protein bindingBupropion: 84%[12]
Hydroxybupropion: 77%[12]
Threohydrobupropion: 42%[12]
MetabolismLiver, intestines[11]
Metabolites• Hydroxybupropion
• Threohydrobupropion
• Erythrohydrobupropion
• Others
Elimination half-lifeBupropion: 11–21 h[13][11]
Hydroxybupropion: 20 h[11]
Threohydrobupropion: 37 h[11]
Erythrohydrobupropion: 33 h[11]
ExcretionUrine: 87% (0.5% unchanged)[11]
Feces: 10%[11]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC13H18ClNO
Molar mass239.74 g·mol−1
3D model (JSmol)
  (verify)

Bupropion, sold under the brand name Wellbutrin among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation.[14][15] It is also popular as an add-on medication in the cases of "incomplete response" to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant.[15][16] Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction,[15] it is not associated with weight gain[15] and sleepiness,[17] and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue.[18] Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder.[19]

Common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating.[20][failed verification] Raised blood pressure is notable.[21] Rare but serious side effects include seizure,[20] liver toxicity,[22] psychosis,[23] and risk of overdose.[24] Bupropion use during pregnancy may be associated with increased odds of congenital heart defects.[25]

Bupropion acts as a norepinephrine–dopamine reuptake inhibitor and a nicotinic receptor antagonist.[11] However, its effects on dopamine are weak.[26][27][28][29][30] Chemically, bupropion is an aminoketone that belongs to the class of substituted cathinones and more generally that of substituted amphetamines and substituted phenethylamines.[1][31]

Bupropion was invented by Nariman Mehta, who worked at Burroughs Wellcome, in 1969.[32] It was first approved for medical use in the United States in 1985.[33] Bupropion was originally called by the generic name amfebutamone, before being renamed in 2000.[34] In 2021, it was the eighteenth most commonly prescribed medication in the United States, with more than 29 million prescriptions.[35][36] It is on the World Health Organization's List of Essential Medicines.[37]

Medical uses

Wellbutrin XL

Depression

The evidence overall supports the efficacy of bupropion over placebo for the treatment of depression.[38][15][39] Some peer reviewed studies suggest the quality of evidence is low.[39][15] Some meta-analyses report that bupropion has an at-most small effect size for depression.[40][41][39][42] One meta-analysis reported a large effect size.[15] However, there were methodological limitations with this meta-analysis, including using a subset of only five trials for the effect size calculation, substantial variability in effect sizes between the selected trials—which led the authors to state that their findings in this area should be interpreted with "extreme caution"—and general lack of inclusion of unpublished trials in the meta-analysis.[15] Unpublished trials are more likely to be negative in findings,[43][44] and other meta-analyses have included unpublished trials.[40][41][39][42] Evidence suggests that the efficacy of bupropion for depression is similar to that of other antidepressants.[40][41][15]

Over the autumn and winter months, bupropion prevents development of depression in those who have recurring seasonal affective disorder: 15% of participants on bupropion experienced a major depressive episode vs. 27% of those on placebo.[45] Bupropion also improves depression in bipolar disorder, with the efficacy and risk of affective switch being similar to other antidepressants.[46]

Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo.[15][47] Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants.[15] Bupropion treatment also is not associated with the sleepiness that may be produced by other antidepressants.[17] Bupropion is more effective than selective serotonin reuptake inhibitors (SSRIs) at improving symptoms of hypersomnia and fatigue in depressed patients.[18] Bupropion is effective in the treatment of anxious depression and, contrary to common belief, does not exacerbate anxiety in this context.[48][49] The effectiveness of bupropion for anxious depression is equivalent to that of SSRIs in the case of depression with low or moderate anxiety, whereas SSRIs show a modest effectiveness advantage in terms of response rates for depression with high anxiety.[48]

The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI,[16] and it is supported by clinical trials;[15] however, it appears to be inferior to the addition of atypical antipsychotic aripiprazole.[50][further explanation needed]

Smoking cessation

Prescribed as an aid for smoking cessation, bupropion reduces the severity of craving for nicotine and withdrawal symptoms[51][52][53] such as depressed mood, irritability, difficulty concentrating, and increased appetite.[54] Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible.[54]

The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course.[54][7] After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year.[55] It is unclear whether extending bupropion treatment helps to prevent relapse of smoking.[56]

Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6 fold as compared to placebo. In this respect, bupropion is as effective as nicotine replacement therapy but inferior to varenicline. Combining bupropion and nicotine replacement therapy does not improve the quitting rate.[57]

In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits.[58] The evidence for its use to aid smoking cessation in pregnant women is insufficient.[59]

Attention deficit hyperactivity disorder

In the United States, the treatment of attention deficit hyperactivity disorder (ADHD) is not an approved indication of bupropion, and it is not mentioned in the current (2019) guideline on the ADHD treatment from the American Academy of Pediatrics.[60] Systematic reviews of bupropion for the treatment of ADHD in both adults and children note that bupropion may be effective for ADHD but warn that this conclusion has to be interpreted with caution, because clinical trials were of low quality due to small sizes and risk of bias.[28][61][62][63] Similarly to atomoxetine, bupropion has a delayed onset of action for ADHD, and several weeks of treatment are required for therapeutic effects.[28][64] This is in contrast to stimulants, such as amphetamine and methylphenidate, which have an immediate onset of effect in the condition.[64]

Sexual dysfunction

Bupropion is less likely than other antidepressants to cause sexual dysfunction.[65] A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction[66] including sexual dysfunction induced by SSRI antidepressants.[67] There have also been small studies suggesting that bupropion or a bupropion/trazodone combination may improve some measures of sexual function in women who have hypoactive sexual desire disorder (HSDD) and are not depressed.[68] According to an expert consensus recommendation from the International Society for the Study of Women's Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data.[69] Likewise, a 2022 systematic review and meta-analysis of bupropion for sexual desire disorder in women reported that although data were limited, bupropion appeared to be dose-dependently effective for the condition.[70]

Obesity

Bupropion, when used for treating obesity over a period of 6 to 12 months, results in an average weight loss of 2.7 kg (5.9 lbs) over placebo.[71] This is not much different from the weight loss produced by several other weight-loss medications such as sibutramine or orlistat.[71] The combination drug naltrexone/bupropion has been approved by the US Food and Drug Administration (FDA) for the treatment of obesity.[72][73]

Other uses

Bupropion is not effective in the treatment of cocaine dependence,[74] but it is showing promise in reducing drug use in light methamphetamine users.[75] 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, psoriasis, and other autoimmune conditions, but very little clinical evidence is available.[76][77][78] Bupropion is not effective in treating chronic low back pain.[79]

Available forms

Bupropion is available as an oral tablet in a number of different formulations.[80] It is formulated mostly as the hydrochloride salt but also to a lesser extent as the hydrobromide salt.[80] The available forms of bupropion hydrochloride include IR (instant-release) tablets (50, 75, 100 mg), SR (sustained-release) tablets (50, 100, 150, 200 mg), and XL (extended-release) tablets (150, 300, 450 mg).[80] The IR formulation is generally administered thrice daily, the SR formultion twice daily, and the XL formulation once daily. The only marketed form of bupropion hydrobromide is Aplenzin, an extended-release oral tablet taken once daily (174, 348, 522 mg, equivalent to 150, 300, and 450 mg of bupropion hydrochloride).[80] In addition to single-drug formulations, bupropion is formulated in combinations including naltrexone/bupropion (Contrave; 8 mg/90 mg extended-release tablets) for obesity[80] and dextromethorphan/bupropion (Auvelity; 45 mg/105 mg tablets) for depression.[81][82]

Contraindications

The drug label 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, benzodiazepine or alcohol withdrawal. It should be avoided in individuals who are taking monoamine oxidase inhibitors (MAOIs). The label recommends that caution should be exercised when treating people with liver damage, severe kidney disease, and severe hypertension, and in children, adolescents and young adults due to the increased risk of suicidal ideation.[7]

Side effects

The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating.[20] Bupropion has the highest incidence of insomnia of all second-generation antidepressants, apart from desvenlafaxine.[83] It is also associated with about 20% increased risk of headache.[84]

Bupropion raises blood pressure in some people. One study showed an average rise of 6 mm Hg in systolic blood pressure in 10% of patients.[21] The prescribing information notes that hypertension, sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension.[20] Safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remain unclear due to the lack of data.[85][86]

Seizure is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300–450 mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600 mg.[20] For comparison, the incidence of unprovoked seizure in the general population is 0.07 to 0.09%, and the risk of seizure for a variety of other antidepressants is generally between 0 and 0.5% at the recommended doses.[87]

Cases of liver toxicity leading to death or liver transplantation have been reported for bupropion. It is considered to be one of several antidepressants with greater risk of hepatotoxicity.[22]

The prescribing information warns about bupropion triggering an angle-closure glaucoma attack.[7] On the other hand, bupropion may decrease the risk of development of open angle glaucoma.[88]

Bupropion use by mothers in the first trimester of pregnancy is associated with 23% increase of the odds in congenital heart defects in their children.[25]

Bupropion has rarely been associated with instances of Stevens–Johnson syndrome.[89][90]

Psychiatric

The FDA requires all antidepressants, including bupropion, to carry a boxed warning stating that antidepressants may increase the risk of suicide in people younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in suicidal thought and behavior in children and adolescents, and 1.5-fold increase in the 18–24 age group.[91] For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.[91]

Bupropion prescribed for smoking cessation results in 25% increase of the risk of psychiatric side effects, in particular, anxiety (about 40% increase) and insomnia (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behavior.[52]

In rare cases, bupropion-induced psychosis may develop. It is associated with higher doses of bupropion; many cases described are at higher than recommended doses. Concurrent antipsychotic medication appears to be protective.[23] In most cases the psychotic symptoms are eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication.[7][23]

Although studies are lacking, a handful of case reports suggest that abrupt discontinuation of bupropion may cause antidepressant discontinuation syndrome.[92]

Overdose

Bupropion is considered moderately dangerous in overdose.[93][94] According to an analysis of US National Poison Data System, adjusted for the number of prescriptions, bupropion and venlafaxine are the two new generation antidepressants (that is excluding tricyclic antidepressants) that result in the highest mortality and morbidity.[24] For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and abnormal heart rhythms. When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, having had multiple uncontrolled seizures and myocardial infarction.[7]

Interactions

Since bupropion is metabolized to hydroxybupropion by the enzyme CYP2B6, drug interactions with CYP2B6 inhibitors are possible: this includes such medications as paroxetine, sertraline, norfluoxetine (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 phenobarbital.[95] Indeed, carbamazepine decreases exposure to bupropion by 90% and increases exposure to hydroxybupropion by 94%.[96] Ritonavir, lopinavir/ritonavir, and efavirenz have been shown to decrease levels of bupropion and/or its metabolites.[97] Ticlopidine and clopidogrel, both potent CYP2B6 inhibitors, have been found to considerably increase bupropion levels as well as decrease levels of its metabolite hydroxybupropion.[97]

Bupropion and its metabolites are inhibitors of CYP2D6, with hydroxybupropion responsible for most of the inhibition. Additionally, bupropion and its metabolites may decrease expression of CYP2D6 in the liver. The end effect is a significant slowing of the clearance of other drugs metabolized by this enzyme.[11] For instance, bupropion has been found to increase area-under-the-curve of desipramine, a CYP2D6 substrate, by 5-fold.[97] Bupropion has also been found to increase levels of atomoxetine by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold.[98] As another example, the ratio of dextromethorphan (a drug that is mainly metabolized by CYP2D6) to its major metabolite dextrorphan increased approximately 35-fold when it was administered to people being treated with 300 mg/day bupropion.[95] When people on bupropion are given MDMA, about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased heart rate effects of MDMA.[99][100] Interactions with other CYP2D6 substrates, such as metoprolol, imipramine, nortriptyline,[100] venlafaxine,[95] and nebivolol[11] have also been reported. However, in a notable exception, bupropion does not seem to affect the concentrations of CYP2D6 substrates fluoxetine and paroxetine.[95][101]

Bupropion lowers the seizure threshold, and therefore can potentially interact with other medications that also lower it, such as antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids.[7] The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance.[7]

Caution should be observed when combining bupropion with a monoamine oxidase inhibitor (MAOI), as it may result in hypertensive crisis.[102]

Pharmacology

Pharmacology of bupropion and its metabolites.
  Bupropion R,R-
Hydroxy
bupropion 		S,S-
Hydroxy
bupropion 		Threo-
hydro
bupropion 		Erythro-
hydro
bupropion
Exposure and half-life
AUC relative
to bupropion[103][104] 		1 23.8 0.6 11.2 2.5
Half-life[13] 11 h 19 h 15 h 31 h 22 h
Inhibition IC50 (μM) in human cells, unless noted otherwise. (Smaller is more potent)
DAT, uptake[105] 0.66 inactive 0.63 47 (rat)[106] no data
NET, uptake[105] 1.85 9.9 0.24 16 (rat)[106] no data
SERT, uptake[105] inactive inactive inactive 67 (rat)[106] no data
α3β4 nicotinic[105] 1.8 6.5 11 14 (rat)[107] no data
α4β2 nicotinic[108] 12 31 3.3 no data no data
α1β1γδ nicotinic[108] 7.9 7.6 28 no data no data
5-HT3A[109][110] 87 (mouse) no data no data no data no data

Pharmacodynamics

The mechanism of action of bupropion in the treatment of depression and for other indications is unclear.[11] However, it is thought to be related to the fact that bupropion is a norepinephrine–dopamine reuptake inhibitor (NDRI) and antagonist of several nicotinic acetylcholine receptors.[11] It is uncertain whether bupropion is a norepinephrine–dopamine releasing agent.[11] Pharmacological actions of bupropion, to a substantial degree, are due to its active metabolites hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion that are present in the blood plasma at comparable or much higher levels.[11] In fact, bupropion could accurately be conceptualized as a prodrug of these metabolites.[11] Overall action of these metabolites, and particularly one enantiomer S,S-hydroxybupropion, is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic antagonism (see the chart on the right).[11] Bupropion has no meaningful direct activity at a variety of receptors, including α- and β-adrenergic, dopamine, serotonin, histamine, and muscarinic acetylcholine receptors.[17]

The occupancy of dopamine transporter (DAT) by bupropion (300 mg/day) and its metabolites in the human brain as measured by several positron emission tomography (PET) studies is approximately 20%, with a mean occupancy range of about 14 to 26%.[26][27][28] For comparison, the NDRI methylphenidate at therapeutic doses is thought to occupy greater than 50% of DAT sites.[28] In accordance with its low DAT occupancy, no measurable dopamine release in the human brain was detected with bupropion (one 150 mg dose) in a PET study.[26][27][111] Bupropion has also been shown to increase striatal VMAT2, though it is unknown if this effect is more pronounced than other DRIs.[112] These findings raise questions about the role of dopamine reuptake inhibition in the pharmacology of bupropion, and suggest that other actions may be responsible for its therapeutic effects.[26][28][27] More research is needed in this area.[26] No data are available on occupancy of the norepinephrine transporter (NET) by bupropion and its metabolites.[26] However, due to the increased exposure of hydroxybupropion over bupropion itself, which has higher affinity for the NET than the DAT,[105] bupropion's overall pharmacological profile in humans may end up making it effectively more of a norepinephrine reuptake inhibitor than a dopamine reuptake inhibitor.[29][30] Accordingly, the clinical effects of bupropion are more consistent with noradrenergic activity than with dopaminergic actions.[29][30]

Bupropion has been found to have a mixture of anti-inflammatory and pro-inflammatory activity through modulation of the immune system.[113][114][115][116][117][118][119] One such mechanism underlying these effects may be reduced levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα).[113][119][120] The catecholaminergic actions of bupropion may be involved in its immunomodulatory effects.[120]

Pharmacokinetics

Principal pathways of bupropion metabolism

After oral administration, bupropion is rapidly and completely absorbed reaching the peak blood plasma concentration after 1.5 hours (tmax). Sustained release (SR) and extended release (XL) formulations have been designed to slow down absorption resulting in tmax of 3 hours and 5 hours, respectively.[95] Absolute bioavailability of bupropion is unknown but is presumed to be low, at 5–20%, due to the first-pass metabolism. As for the relative bioavailability of the formulations, XL formulation has lower bioavailability (68%) compared to SR formulation and immediate release bupropion.[11]

Bupropion is metabolized in the body by a variety of pathways. The oxidative pathways are by cytochrome P450 isoenzymes CYP2B6 leading to R,R- and S,S-hydroxybupropion and, to a lesser degree, CYP2C19 leading to 4'-hydroxybupropion. The reductive pathways are by 11β-hydroxysteroid dehydrogenase type 1 in the liver and AKR7A2/AKR7A3 in the intestine leading to threo-hydrobupropion and by yet unknown enzyme leading to erythro-hydrobupropion.[11]

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 (with a half-life of 12–30 hours), while the effective doses of hydroxybupropion may differ by as much as 7.5 times (with a half-life of 15–25 hours).[7][121][122] Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.[123]

Chemistry

Bupropion is an aminoketone that belongs to the class of substituted cathinones and the more general class of substituted phenethylamines.[1][31] The clinically used bupropion is racemic, that is a mixture of two enantiomers: S-bupropion and R-bupropion. Although the optical isomers on bupropion can be separated, they rapidly racemize under physiological conditions.[11][124]

There have been reported cases of false-positive urine amphetamine tests in persons taking bupropion.[125][126][127]

Synthesis

It is synthesized in two chemical steps starting from 3'-chloro-propiophenone. The alpha position adjacent to the ketone is first brominated followed by nucleophilic displacement of the resulting alpha-bromoketone with t-butylamine and treated with hydrochloric acid to give bupropion as the hydrochloride salt in 75–85% overall yield.[32][128]

Bupropion synthesis diagram
3'-chloro-propiophenone
3'-chloro-2-bromopropiophenone
bupropion hydrochloride
This diagram shows the synthesis of bupropion via 3'-chloro-propiophenone.

History

Comparison of steady-state plasma bupropion levels with bupropion IR 100 mg t.i.d. (3x/day), bupropion SR 150 mg b.i.d. (2x/day), and bupropion XL 300 mg q.d. (1x/day)[129][95]

Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974.[32] It was approved by the US Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin.[33][130] However, a significant incidence of seizures at the originally recommended dosage (400–600 mg/day) caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose of 450 mg/day.[131]

In 1996, the FDA approved a sustained-release formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin).[132] In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing.[133] Wellbutrin SR and XL are available in generic form in the United States and Canada. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban.[134][132] In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.[135][136]

In October 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.[137] 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."[138] The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL.[139] On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg."[140] The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013.[140] (As of October 2013) the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.[140]

In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by Sanofi-Aventis.[141][142][9]

In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide.[143] This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years.[144] Based on the results of follow-up trials this warning was removed in 2016.[145]

In 2012, the US Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.[146]

In 2017, the European Medicines Agency (EMA) recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India.[147] The products recommended for suspension included several 300 mg modified-release bupropion tablets.[148]

Following EMA's call for an industry-wide review of medicines for the possible presence of nitrosamines,[149] GlaxoSmithKline paused batch release and distribution of bupropion 150 mg tablets in November 2022. In July 2023, EMA raised the acceptable daily intake of nitrosamines impurities, leading GlaxoSmithKline to announce that distribution of bupropion 150 mg tablets would resume "across the EU and Europe" by the end of 2023.[150]

Society and culture

Recreational use

While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of its pharmacology.[151] Case reports describe misuse of bupropion as producing a "high" similar to cocaine or amphetamine usage but with less intensity. Bupropion misuse is uncommon.[151] 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 when taken orally are markedly different from those of addictive stimulants such as cocaine or amphetamine.[152] However, bupropion, by non-conventional routes of administration like injection or insufflation, has been reported to be misused in the United States and Canada, notably in prisons.[153][154][155][156]

Legal status

In Russia bupropion is banned as a narcotic drug, yet not per se but rather as a derivative of methcathinone.[157] In Australia, France, and the UK, smoking cessation is the only licensed use of bupropion, and no generics are marketed.[158][159][160]

Brand names

Brand names include Wellbutrin, Aplenzin, Budeprion, Buproban, Forfivo, Voxra, Zyban, Bupron, Bupisure, Bupep, Smoquite, Elontril, and Buxon.

References

  1. ↑ 1.0 1.1 1.2 "Bupropion". PubChem. United States National Library of Medicine – National Center for Biotechnology Information. 28 July 2018. https://pubchem.ncbi.nlm.nih.gov/compound/444. 
  2. ↑ "Bupropion Use During Pregnancy". https://www.drugs.com/pregnancy/bupropion.html. 
  3. ↑ "TGA eBS - Product and Consumer Medicine Information Licence". https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01138-1. 
  4. ↑ "Wellbutrin Product information". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61183. 
  5. ↑ "Zyban Product information". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61860. 
  6. ↑ "Zyban 150 mg prolonged release tablets - Summary of Product Characteristics (SmPC)". 21 April 2022. https://www.medicines.org.uk/emc/product/3827/smpc. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 "Wellbutrin SR - bupropion hydrochloride tablet, film coated". 5 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbc8c074-f080-4489-a5ae-207b5fadeba3. 
  8. ↑ "Wellbutrin XL- bupropion hydrochloride tablet, extended release". 4 March 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a435da9d-f6e8-4ddc-897d-8cd2bf777b21. 
  9. ↑ 9.0 9.1 "Aplenzin - bupropion hydrobromide tablet, extended release". 2 June 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6494d2d9-0ce4-4126-b1c7-49684395942b. 
  10. ↑ "Bupropion hydrochloride EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/referrals/bupropion-hydrochloride. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 11.19 "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metabolism Reviews 51 (3): 293–313. August 2019. doi:10.1080/03602532.2019.1620763. PMID 31124380. 
  12. ↑ 12.0 12.1 12.2 "Zyban 150 mg prolonged release film-coated tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. GlaxoSmithKline UK. 1 August 2013. http://www.medicines.org.uk/emc/medicine/2948/SPC/Zyban+150+mg+prolonged+release+film-coated+tablets/. 
  13. ↑ 13.0 13.1 "Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers". The Journal of Pharmacology and Experimental Therapeutics 358 (2): 230–238. August 2016. doi:10.1124/jpet.116.232876. PMID 27255113. 
  14. ↑ Martindale: The Complete Drug Reference (37th ed.). Pharmaceutical Press. 2011. p. 402. ISBN 9780853699828. 
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 "Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant". Therapeutic Advances in Psychopharmacology 6 (2): 99–144. April 2016. doi:10.1177/2045125316629071. PMID 27141292. 
  16. ↑ 16.0 16.1 "Clinicians' Views on Treatment-Resistant Depression: 2016 Survey Reports". The American Journal of Geriatric Psychiatry 24 (10): 913–917. October 2016. doi:10.1016/j.jagp.2016.05.010. PMID 27591914. 
  17. ↑ 17.0 17.1 17.2 "Bupropion: a review of its use in the management of major depressive disorder". Drugs 68 (5): 653–689. 2008. doi:10.2165/00003495-200868050-00011. PMID 18370448. 
  18. ↑ 18.0 18.1 "Symptoms of fatigue and sleepiness in major depressive disorder". The Journal of Clinical Psychiatry 67 (Suppl 6): 9–15. 2006. PMID 16848671. 
  19. ↑ "Epileptic Seizures Under Antidepressive Drug Treatment: Systematic Review". Pharmacopsychiatry 51 (4): 121–135. July 2018. doi:10.1055/s-0043-117962. PMID 28850959. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 "Wellbutrin XL® Prescribing Information". GlaxoSmithKline. June 2006. http://us.gsk.com/products/assets/us_wellbutrinXL.pdf. 
  21. ↑ 21.0 21.1 "Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder". The Journal of Clinical Psychiatry 66 (2): 253–259. February 2005. doi:10.4088/jcp.v66n0215. PMID 15705013. 
  22. ↑ 22.0 22.1 "Antidepressant-induced liver injury: a review for clinicians". The American Journal of Psychiatry 171 (4): 404–415. April 2014. doi:10.1176/appi.ajp.2013.13050709. PMID 24362450. 
  23. ↑ 23.0 23.1 23.2 "Bupropion-induced psychosis: folklore or a fact? A systematic review of the literature". General Hospital Psychiatry 33 (6): 612–617. November–December 2011. doi:10.1016/j.genhosppsych.2011.07.001. PMID 21872337. 
  24. ↑ 24.0 24.1 "Morbidity and Mortality Associated With Medications Used in the Treatment of Depression: An Analysis of Cases Reported to U.S. Poison Control Centers, 2000-2014". The American Journal of Psychiatry 174 (5): 438–450. May 2017. doi:10.1176/appi.ajp.2016.16050523. PMID 28135844. 
  25. ↑ 25.0 25.1 "A Systematic Review and Meta-Analysis Considering the Risk for Congenital Heart Defects of Antidepressant Classes and Individual Antidepressants". Drug Safety 44 (3): 291–312. March 2021. doi:10.1007/s40264-020-01027-x. PMID 33354752. https://unisa.alma.exlibrisgroup.com/view/delivery/61USOUTHAUS_INST/12212569530001831. Retrieved 17 May 2022. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 "Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants". The World Journal of Biological Psychiatry 22 (8): 561–628. October 2021. doi:10.1080/15622975.2021.1878427. PMID 33977870. https://serval.unil.ch/resource/serval:BIB_6FD14CC75A02.P001/REF.pdf. Retrieved 10 April 2022. 
  27. ↑ 27.0 27.1 27.2 27.3 "Bupropion and bupropion analogs as treatments for CNS disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. 69. Academic Press. 2014. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 9780124201187. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 28.5 "Bupropion for attention deficit hyperactivity disorder (ADHD) in adults". The Cochrane Database of Systematic Reviews 2017 (10): CD009504. October 2017. doi:10.1002/14651858.CD009504.pub2. PMID 28965364. 
  29. ↑ 29.0 29.1 29.2 "Other Antidepressants: Bupropion, Mirtazapine, and Trazodone". The American Psychiatric Association Publishing Textbook of Mood Disorders, Second Edition. American Psychiatric Pub. 16 June 2022. pp. 365–374. ISBN 978-1-61537-331-4. OCLC 1249799493. https://books.google.com/books?id=VAJ8EAAAQBAJ&pg=PA365. Retrieved 27 August 2022. 
  30. ↑ 30.0 30.1 30.2 "Practice patterns of bupropion co-prescription with antipsychotic medications". J Addict Dis 40 (4): 481–488. January 2022. doi:10.1080/10550887.2022.2028531. PMID 35068363. 
  31. ↑ 31.0 31.1 Case Studies in Medical Toxicology: From the American College of Medical Toxicology. Springer. 2017. p. 85. ISBN 9783319564494. https://books.google.com/books?id=cEFEDwAAQBAJ&pg=PA85. Retrieved 5 June 2020. 
  32. ↑ 32.0 32.1 32.2 "United States Patent 3,819,706: Meta-chloro substituted α-butylamino-propiophenones". USPTO. 25 June 1974. http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=3819706.PN.&OS=PN/3819706&RS=PN/3819706. 
  33. ↑ 33.0 33.1 "Wellbutrin approval package". 30 December 1985. https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018644Orig1s000rev.pdf. 
  34. ↑ "International nonproprietary names for pharmaceutical substances (INN) : proposed international nonproprietary names : list 83". WHO Drug Information 14 (2). 2000. 
  35. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  36. ↑ "Bupropion - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Bupropion. 
  37. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  38. ↑ "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis". Lancet 373 (9665): 746–758. February 2009. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342. 
  39. ↑ 39.0 39.1 39.2 39.3 "The comparative evidence basis for the efficacy of second-generation antidepressants in the treatment of depression in the US: A Bayesian meta-analysis of Food and Drug Administration reviews". Journal of Affective Disorders 235: 393–398. August 2018. doi:10.1016/j.jad.2018.04.040. PMID 29677603. https://orca.cardiff.ac.uk/110777/1/Morey.%20The%20comparative.pdf. Retrieved 13 December 2021. 
  40. ↑ 40.0 40.1 40.2 "Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis". Lancet 391 (10128): 1357–1366. April 2018. doi:10.1016/S0140-6736(17)32802-7. PMID 29477251. 
  41. ↑ 41.0 41.1 41.2 "Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials". PLOS ONE 15 (2): e0229381. 2020. doi:10.1371/journal.pone.0229381. PMID 32101579. Bibcode: 2020PLoSO..1529381H. 
  42. ↑ 42.0 42.1 "Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis". BMJ 378: e067606. August 2022. doi:10.1136/bmj-2021-067606. PMID 35918097. 
  43. ↑ "Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials". PLOS Med 19 (1): e1003886. January 2022. doi:10.1371/journal.pmed.1003886. PMID 35045113. 
  44. ↑ "Selective publication of antidepressant trials and its influence on apparent efficacy". N Engl J Med 358 (3): 252–60. January 2008. doi:10.1056/NEJMsa065779. PMID 18199864. 
  45. ↑ "Second-generation antidepressants for preventing seasonal affective disorder in adults". The Cochrane Database of Systematic Reviews 3 (4): CD011268. March 2019. doi:10.1002/14651858.CD011268.pub3. PMID 30883669. 
  46. ↑ "Significant Treatment Effect of Bupropion in Patients With Bipolar Disorder but Similar Phase-Shifting Rate as Other Antidepressants: A Meta-Analysis Following the PRISMA Guidelines". Medicine 95 (13): e3165. March 2016. doi:10.1097/MD.0000000000003165. PMID 27043678. 
  47. ↑ "Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge". Primary Psychiatry 10 (1): 55–61. 2003. http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1362. Retrieved 21 March 2013. 
  48. ↑ 48.0 48.1 "Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies". The Journal of Clinical Psychiatry 69 (8): 1287–1292. August 2008. doi:10.4088/JCP.v69n0812. PMID 18605812. 
  49. ↑ "Bupropion-myth-busting!". CNS Spectr 27 (5): 545–546. October 2022. doi:10.1017/S1092852921000365. PMID 33843549. 
  50. ↑ "Pharmacological Treatments for Patients with Treatment-Resistant Depression". Pharmaceuticals 13 (6): 116. June 2020. doi:10.3390/ph13060116. PMID 32512768. 
  51. ↑ "The use of bupropion SR in cigarette smoking cessation". International Journal of Chronic Obstructive Pulmonary Disease 3 (1): 45–53. 2008. doi:10.2147/copd.s1121. PMID 18488428. 
  52. ↑ 52.0 52.1 "Antidepressants for smoking cessation". The Cochrane Database of Systematic Reviews 2023 (5): CD000031. May 2023. doi:10.1002/14651858.CD000031.pub6. PMID 37230961. 
  53. ↑ "Effectiveness of smoking cessation therapies: a systematic review and meta-analysis". BMC Public Health 6: 300. December 2006. doi:10.1186/1471-2458-6-300. PMID 17156479. 
  54. ↑ 54.0 54.1 54.2 "Bupropion for the treatment of nicotine withdrawal and craving". Expert Review of Neurotherapeutics 6 (7): 965–981. July 2006. doi:10.1586/14737175.6.7.965. PMID 16831112. 
  55. ↑ "Diminishing benefit of smoking cessation medications during the first year: a meta-analysis of randomized controlled trials". Addiction 113 (5): 805–816. May 2018. doi:10.1111/add.14134. PMID 29377409. 
  56. ↑ "Relapse prevention interventions for smoking cessation". The Cochrane Database of Systematic Reviews 2019 (10). October 2019. doi:10.1002/14651858.CD003999.pub6. PMID 31684681. 
  57. ↑ "Interventions for Tobacco Cessation in Adults, Including Pregnant Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force". JAMA 325 (3): 280–298. January 2021. doi:10.1001/jama.2020.23541. PMID 33464342. 
  58. ↑ "Primary Care-Relevant Interventions for Tobacco and Nicotine Use Prevention and Cessation in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force". JAMA 323 (16): 1599–1608. April 2020. doi:10.1001/jama.2020.3332. PMID 32343335. 
  59. ↑ "Pharmacological interventions for promoting smoking cessation during pregnancy". The Cochrane Database of Systematic Reviews 2020 (3): CD010078. March 2020. doi:10.1002/14651858.CD010078.pub3. PMID 32129504. 
  60. ↑ "Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents". Pediatrics 144 (4): e20192528. October 2019. doi:10.1542/peds.2019-2528. PMID 31570648. 
  61. ↑ "Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis". PLOS ONE 15 (10): e0240584. 2020. doi:10.1371/journal.pone.0240584. PMID 33085721. Bibcode: 2020PLoSO..1540584E. 
  62. ↑ "Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis". The Lancet. Psychiatry 5 (9): 727–738. September 2018. doi:10.1016/S2215-0366(18)30269-4. PMID 30097390. 
  63. ↑ "A Systematic Review of the Use of Bupropion for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents". Journal of Child and Adolescent Psychopharmacology 27 (2): 112–116. March 2017. doi:10.1089/cap.2016.0124. PMID 27813651. 
  64. ↑ 64.0 64.1 "An update on the pharmacotherapy of attention-deficit/hyperactivity disorder in adults". Expert Review of Neurotherapeutics 11 (10): 1443–1465. October 2011. doi:10.1586/ern.11.137. PMID 21955201. 
  65. ↑ "Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis". Journal of Clinical Psychopharmacology 29 (3): 259–266. June 2009. doi:10.1097/JCP.0b013e3181a5233f. PMID 19440080. 
  66. ↑ "A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor". Primary Care Companion to the Journal of Clinical Psychiatry 6 (4): 159–166. 2004. doi:10.4088/PCC.v06n0403. PMID 15361919. 
  67. ↑ "Women's sexual dysfunction associated with psychiatric disorders and their treatment". Women's Health 14: 1745506518762664. 2018. doi:10.1177/1745506518762664. PMID 29649948. 
  68. ↑ "Evaluation and Management of Hypoactive Sexual Desire Disorder". Sexual Medicine 6 (2): 59–74. June 2018. doi:10.1016/j.esxm.2018.01.004. PMID 29523488. 
  69. ↑ "Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review". Mayo Clinic Proceedings 92 (1): 114–128. January 2017. doi:10.1016/j.mayocp.2016.09.018. PMID 27916394. 
  70. ↑ "The Role of Bupropion in the Treatment of Women with Sexual Desire Disorder: A Systematic Review and Meta-Analysis". Curr Neuropharmacol 20 (10): 1941–1955. February 2022. doi:10.2174/1570159X20666220222145735. PMID 35193485. 
  71. ↑ 71.0 71.1 "Meta-analysis: pharmacologic treatment of obesity". Annals of Internal Medicine 142 (7): 532–546. April 2005. doi:10.7326/0003-4819-142-7-200504050-00012. PMID 15809465. 
  72. ↑ "Drug Approval Package: Contrave (naltrexone hydrochloride/bupropion hydrochloride) Extended-Release Tablets NDA #200063". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000TOC.cfm. 
  73. ↑ "Contrave Extended-Release - naltrexone hydrochloride and bupropion hydrochloride tablet, extended release". 26 April 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b. 
  74. ↑ "The search for medications to treat stimulant dependence". Addiction Science & Clinical Practice 4 (2): 28–35. June 2008. doi:10.1151/ascp084228. PMID 18497715. 
  75. ↑ "Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction". European Journal of Pharmacology 780: 129–135. June 2016. doi:10.1016/j.ejphar.2016.03.040. PMID 27018393. 
  76. ↑ "Antidepressants and inflammatory bowel disease: a systematic review". Clinical Practice and Epidemiology in Mental Health 2: 24. September 2006. doi:10.1186/1745-0179-2-24. PMID 16984660. 
  77. ↑ "Empirically Supported Use of Psychiatric Medications in Adolescents and Adults with IBD". Inflammatory Bowel Diseases 22 (6): 1509–1522. June 2016. doi:10.1097/MIB.0000000000000734. PMID 27167571. 
  78. ↑ "Antidepressants have Anti-inflammatory Effects that may be Relevant to Dermatology: A Systematic Review". Acta Dermato-Venereologica 97 (8): 897–905. August 2017. doi:10.2340/00015555-2702. PMID 28512664. 
  79. ↑ "Antidepressants for non-specific low back pain". The Cochrane Database of Systematic Reviews 2008 (1): CD001703. January 2008. doi:10.1002/14651858.CD001703.pub3. PMID 18253994. 
  80. ↑ 80.0 80.1 80.2 80.3 80.4 "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/daf/. 
  81. ↑ "Bupropion/Dextromethorphan - Axsome Therapeutics". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800044221. 
  82. ↑ "Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials". Expert Opinion on Emerging Drugs 26 (1): 63–74. March 2021. doi:10.1080/14728214.2021.1898588. PMID 33682569. 
  83. ↑ "Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis". Journal of Clinical Psychopharmacology 35 (3): 296–303. June 2015. doi:10.1097/JCP.0000000000000329. PMID 25874915. http://journals.lww.com/psychopharmacology. Retrieved 13 November 2022. 
  84. ↑ "Meta-analysis: Second generation antidepressants and headache". Journal of Affective Disorders 236: 60–68. August 2018. doi:10.1016/j.jad.2018.04.047. PMID 29715610. 
  85. ↑ "Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort". Clinical Cardiology 40 (10): 899–906. October 2017. doi:10.1002/clc.22744. PMID 28605035. 
  86. ↑ "Bupropion for smoking cessation in patients hospitalized with cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials". The Canadian Journal of Cardiology 29 (12): 1704–1711. December 2013. doi:10.1016/j.cjca.2013.09.014. PMID 24267809. 
  87. ↑ "Effects of psychotropic drugs on seizure threshold". Drug Safety 25 (2): 91–110. 2002. doi:10.2165/00002018-200225020-00004. PMID 11888352. 
  88. ↑ "A review of systemic medications that may modulate the risk of glaucoma". Eye 34 (1): 12–28. January 2020. doi:10.1038/s41433-019-0603-z. PMID 31595027. 
  89. ↑ "Naltrexone + bupropion (Mysimba). Too risky for only modest weight loss". Prescrire International 24 (164): 229–233. October 2015. PMID 26594724. 
  90. ↑ "Severe skin complications in patients treated with antidepressants: a literature review". Postepy Dermatologii I Alergologii 31 (2): 92–97. May 2014. doi:10.5114/pdia.2014.40930. PMID 25097474. 
  91. ↑ 91.0 91.1 "Antidepressants and suicidality in adults: statistical evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)". U.S. Food and Drug Administration (FDA). https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt. 
  92. ↑ "Antidepressant Withdrawal and Rebound Phenomena". Deutsches Ärzteblatt International 116 (20): 355–361. May 2019. doi:10.3238/arztebl.2019.0355. PMID 31288917. 
  93. ↑ The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. 2012. ISBN 978-0-470-97969-3. 
  94. ↑ "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. December 2008. doi:10.1007/BF03161207. PMID 19031375. 
  95. ↑ 95.0 95.1 95.2 95.3 95.4 95.5 "Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations". Clinical Therapeutics 27 (11): 1685–1695. November 2005. doi:10.1016/j.clinthera.2005.11.011. PMID 16368442. 
  96. ↑ "Carbamazepine but not valproate induces bupropion metabolism". Journal of Clinical Psychopharmacology 15 (5): 327–333. October 1995. doi:10.1097/00004714-199510000-00004. PMID 8830063. 
  97. ↑ 97.0 97.1 97.2 "Highlight os Prescribing Information: CONTRAVE (naltrexone hydrochloride and bupropion hydrochloride) extended-release tablets, for oral use". Currax Pharmaceuticals LLC. U.S. Food and Drug Administration. August 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/200063s015lbl.pdf. 
  98. ↑ "Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers". Journal of Pharmacy & Pharmaceutical Sciences 19 (2): 198–207. 2016. doi:10.18433/J3H03R. PMID 27518170. 
  99. ↑ "Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects". The Journal of Pharmacology and Experimental Therapeutics 353 (1): 102–111. April 2015. doi:10.1124/jpet.114.222356. PMID 25655950. 
  100. ↑ 100.0 100.1 "New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others". Medicinal Research Reviews 40 (5): 1794–1832. September 2020. doi:10.1002/med.21671. PMID 32285503. 
  101. ↑ "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update". Clinical Therapeutics 30 (7): 1206–1227. July 2008. doi:10.1016/s0149-2918(08)80047-1. PMID 18691982. 
  102. ↑ "Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication". The Journal of Clinical Psychiatry 65 (11): 1520–1524. November 2004. doi:10.4088/jcp.v65n1113. PMID 15554766. 
  103. ↑ "Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial". Clinical Pharmacology and Therapeutics 105 (5): 1164–1174. May 2019. doi:10.1002/cpt.1309. PMID 30460996. 
  104. ↑ "Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults". Clinical Pharmacology and Therapeutics 108 (5): 1036–1048. November 2020. doi:10.1002/cpt.1888. PMID 32386065. 
  105. ↑ 105.0 105.1 105.2 105.3 105.4 "Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation". Journal of Medicinal Chemistry 53 (12): 4731–4748. June 2010. doi:10.1021/jm1003232. PMID 20509659. 
  106. ↑ 106.0 106.1 106.2 "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology 19 (4): 467–489. August 1999. doi:10.1023/a:1006986824213. PMID 10379421. 
  107. ↑ "Behavioral and biochemical investigations of bupropion metabolites". European Journal of Pharmacology 474 (1): 85–93. August 2003. doi:10.1016/S0014-2999(03)02010-7. PMID 12909199. 
  108. ↑ 108.0 108.1 "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors". Molecular Pharmacology 66 (3): 675–682. September 2004. doi:10.1124/mol.104.001313. PMID 15322260. 
  109. ↑ "Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations". Molecular Pharmacology 97 (3): 171–179. March 2020. doi:10.1124/mol.119.118349. PMID 31871303. 
  110. ↑ "The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors". Neuropharmacology 113 (Pt A): 89–99. February 2017. doi:10.1016/j.neuropharm.2016.09.021. PMID 27671323. 
  111. ↑ "Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: an [11Craclopride PET study"]. NeuroImage 50 (1): 260–266. March 2010. doi:10.1016/j.neuroimage.2009.11.077. PMID 19969097. 
  112. ↑ "Bupropion increases striatal vesicular monoamine transport". Neuropharmacology. New Perspectives in Neurotransmitter Transporter Biology 49 (6): 820–830. November 2005. doi:10.1016/j.neuropharm.2005.05.004. PMID 16005476. 
  113. ↑ 113.0 113.1 "Peripheral inflammatory effects of different interventions for treatment-resistant depression: A systematic review". Neuroscience Applied (Elsevier BV) 2: 101014. 2023. doi:10.1016/j.nsa.2022.101014. ISSN 2772-4085. 
  114. ↑ "Analgesic and anti-inflammatory activities of bupropion in animal models". Res Pharm Sci 9 (4): 251–7. 2014. PMID 25657796. 
  115. ↑ "Revisiting bupropion anti-inflammatory action: involvement of the TLR2/TLR4 and JAK2/STAT3". Inflammopharmacology 29 (4): 1101–1109. August 2021. doi:10.1007/s10787-021-00829-4. PMID 34218389. 
  116. ↑ "Anti-inflammatory activity of bupropion through immunomodulation of the macrophages". Naunyn Schmiedebergs Arch Pharmacol 396 (9): 2087–2093. September 2023. doi:10.1007/s00210-023-02462-0. PMID 36928557. 
  117. ↑ "Bupropion for interferon-alpha-induced depression in patients with hepatitis C viral infection: an open-label study". Psychiatry Investig 12 (1): 142–5. January 2015. doi:10.4306/pi.2015.12.1.142. PMID 25670957. 
  118. ↑ "Bupropion reduces the inflammatory response and intestinal injury due to ischemia-reperfusion". Transplant Proc 45 (6): 2502–5. 2013. doi:10.1016/j.transproceed.2013.04.010. PMID 23953570. 
  119. ↑ 119.0 119.1 "Bupropion monotherapy alters neurotrophic and inflammatory markers in patients of major depressive disorder". Pharmacol Biochem Behav 200: 173073. January 2021. doi:10.1016/j.pbb.2020.173073. PMID 33186562. 
  120. ↑ 120.0 120.1 "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice". Int Immunopharmacol 6 (6): 903–7. June 2006. doi:10.1016/j.intimp.2005.12.007. PMID 16644475. https://www.arca.fiocruz.br/handle/icict/2741. Retrieved 25 October 2023. 
  121. ↑ Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. 2010. ISBN 978-0-07-162442-8. [page needed]
  122. ↑ "Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes". Pharmacogenetics 14 (4): 225–238. April 2004. doi:10.1097/00008571-200404000-00002. PMID 15083067. 
  123. ↑ "Should bupropion dosage be adjusted based upon therapeutic drug monitoring?". Psychopharmacology Bulletin 27 (4): 637–643. 1991. PMID 1813908. 
  124. ↑ "Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion". Chirality 5 (7): 495–500. 1993. doi:10.1002/chir.530050704. PMID 8240925. 
  125. ↑ "Amphetamine positive toxicology screen secondary to bupropion". Depression and Anxiety 12 (1): 53–54. 2000. doi:10.1002/1520-6394(2000)12:1<53::AID-DA8>3.0.CO;2-4. PMID 10999247. 
  126. ↑ "Bupropion metabolites produce false-positive urine amphetamine results". Clinical Chemistry 41 (6 Pt 1): 955–956. June 1995. doi:10.1093/clinchem/41.6.955. PMID 7768026. 
  127. ↑ "Frequency of false positive amphetamine screens due to bupropion using the Syva EMIT II immunoassay". Journal of Medical Toxicology 7 (2): 105–108. June 2011. doi:10.1007/s13181-010-0131-5. PMID 21191682. 
  128. ↑ "A Short, One-Pot Synthesis of Bupropion (Zyban, Wellbutrin)". Journal of Chemical Education 77 (11): 1479. 2000. doi:10.1021/ed077p1479. Bibcode: 2000JChEd..77.1479P. 
  129. ↑ "15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL". Primary Care Companion to the Journal of Clinical Psychiatry 7 (3): 106–113. 2005. doi:10.4088/pcc.v07n0305. PMID 16027765. 
  130. ↑ "Wellbutrin entry in the Orange Book". U.S. Food and Drug Administration Center for Drug Evaluation and Research. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=018644&TABLE1=OB_Rx. 
  131. ↑ "Bupropion (Wellbutrin)". eMedExpert.com. 31 March 2008. http://www.emedexpert.com/facts/bupropion-facts.shtml. 
  132. ↑ 132.0 132.1 "Bupropion helps people with schizophrenia quit smoking". National Institute on Drug Abuse Research Findings 20 (5). April 2006. http://drugabuse.gov/NIDA_notes/NNvol20N5/Bupropion.html. Retrieved 27 May 2013. 
  133. ↑ "Drug Approval Package: Wellbutrin XL (Bupropion HCI) NDA #021515". 22 April 2005. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021515_Wellbutrin.cfm. 
  134. ↑ "Drug Approval Package: Zyban NDA# 020711". 8 August 2003. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020711_zyban_toc.cfm. 
  135. ↑ "FDA approval letter". 6 December 2006. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021515s010,021515s018LTR.pdf. 
  136. ↑ "Seasonal affective disorder drug Wellbutrin XL wins approval". CNN. 14 June 2006. http://www.cnn.com/HEALTH/library/DI/00069.html. 
  137. ↑ "Generic drug equality questioned". 12 October 2007. http://www.peoplespharmacy.com/archives/generic_drug_problems/generic_drug_equality_questioned.php. 
  138. ↑ "Report questions generic antidepressant". NBC News. 12 October 2007. http://www.nbcnews.com/id/21142869. 
  139. ↑ "Review of therapeutic equivalence: generic bupropion XL 300 mg and Wellbutrin XL 300 mg". https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm. 
  140. ↑ 140.0 140.1 140.2 "Budeprion XL 300 mg not therapeutically equivalent to Wellbutrin XL 300 mg". U.S. Food and Drug Administration (FDA). 3 October 2012. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/update-bupropion-hydrochloride-extended-release-300-mg-bioequivalence-studies.  This article incorporates text from this source, which is in the public domain.
  141. ↑ "FDA Approvals: Advair, Relistor, Aplenzin". Medscape. 8 May 2008. http://www.medscape.com/viewarticle/574187. 
  142. ↑ "Drug Approval Package: Aplenzin (Bupropion Hydrobromide) NDA 22108". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022108s000TOC.cfm. 
  143. ↑ "Public Health Advisory: FDA requires new boxed warnings for the smoking cessation drugs Chantix and Zyban". U.S. Food and Drug Administration (FDA). 1 July 2009. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm. 
  144. ↑ "The smoking cessation aids varenicline (marketed as Chantix) and bupropion (marketed as Zyban and generics) suicidal ideation and behavior". Drug Safety Newsletter 2 (1): 1–4. 2009. https://www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/UCM107318.pdf. Retrieved 16 December 2019. 
  145. ↑ "Safety Alerts for Human Medical Products - Chantix (varenicline) and Zyban (bupropion)". Drug Safety Communication – Mental Health Side Effects Revised. U.S. Food and Drug Administration (FDA). 16 December 2016. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm533517.htm. 
  146. ↑ "Glaxo agrees to pay $3 billion in fraud settlement". The New York Times. 2 July 2012. https://www.nytimes.com/2012/07/03/business/glaxosmithkline-agrees-to-pay-3-billion-in-fraud-settlement.html. 
  147. ↑ Committee for Medicinal Products for Human Use (CHMP) (24 March 2017). "EMA recommends suspension of medicines due to unreliable studies from Micro Therapeutic Research Labs". European Medicines Agency. https://www.ema.europa.eu/en/news/ema-recommends-suspension-medicines-due-unreliable-studies-micro-therapeutic-research-labs. 
  148. ↑ Committee for Medicinal Products for Human Use (CHMP) (23 March 2017). "Products for which the marketing authorisations are recommended for suspension and marketing authorisation applications which do not satisfy the criteria for authorisation as adopted by the CHMP". European Medicines Agency. https://www.ema.europa.eu/en/documents/referral/micro-therapeutic-research-article-31-referral-products-which-marketing-authorisations-are_en.pdf. 
  149. ↑ EMA (26 September 2019). "EMA advises companies on steps to take avoid nitrosamines in human medicines" (in en). https://www.ema.europa.eu/en/news/ema-advises-companies-steps-take-avoid-nitrosamines-human-medicines. 
  150. ↑ Lipanovic, David (6 September 2023). "Bupropion to be made available in the UK again from December 2023, says manufacturer" (in en-US). https://pharmaceutical-journal.com/article/news/bupropion-to-be-made-available-in-the-uk-again-from-december-2023-says-manufacturer. 
  151. ↑ 151.0 151.1 "Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential". The American Journal of Drug and Alcohol Abuse 45 (4): 341–354. 2019. doi:10.1080/00952990.2018.1545023. PMID 30601027. 
  152. ↑ "The abuse liability and therapeutic potential of drugs evaluated for cocaine addiction as predicted by animal models". Current Neuropharmacology 1: 21–46. 2003. doi:10.2174/1570159033360566. 
  153. ↑ Antidepressant Wellbutrin becomes 'poor man's cocaine' on Toronto streets Global News 18 September 2013.
  154. ↑ "Wellbutrin®: misuse and abuse by incarcerated individuals". Journal of Addictions Nursing 23 (1): 65–69. February 2012. doi:10.3109/10884602.2011.647838. PMID 22468662. 
  155. ↑ "Intravenous bupropion: a previously undocumented method of abuse of a commonly prescribed antidepressant agent". Journal of Addiction Medicine 7 (3): 216–217. May–June 2013. doi:10.1097/ADM.0b013e3182824863. PMID 23519045. 
  156. ↑ "Bupropion "Abuse" Reported to US Poison Centers". Journal of Addiction Medicine 10 (5): 357–362. 2016. doi:10.1097/ADM.0000000000000249. PMID 27504927. 
  157. ↑ "Постановление Правительства РФ от 30 июня 1998 г. N 681 "Об утверждении перечня наркотических средств, психотропных веществ и их прекурсоров, подлежащих контролю в Российской Федерации" (с изменениями и дополнениями)" (in ru). Гарант. http://base.garant.ru/12112176/. "Эфедрон (меткатинон) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень" 
  158. ↑ Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  159. ↑ "Autorisation - ZYBAN L.P. 150 mg, comprimé à libération prolongée". http://agence-prd.ansm.sante.fr/php/ecodex/extrait.php?specid=64556383. 
  160. ↑ Joint Formulary Committee (2015). British National Formulary (BNF) (69 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-156-2. 

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