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Bupropion

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Bupropion
Clinical data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5 to 20% in animals; no studies in humans
MetabolismHepatic
Elimination half-life20 hours
ExcretionRenal (87%), fecal (10%)
Identifiers
  • (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-
    1-propanone
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO
Molar mass239.74 g/mol g·mol−1

Bupropion (INN; also amfebutamone,[2] brand names Wellbutrin, Zyban, Budeprion and Buproban) is an atypical antidepressant, which acts as a norepinephrine reuptake inhibitor and dopamine reuptake inhibitor,[3] and a nicotinic antagonist.[4][5] Bupropion belongs to the chemical class of aminoketones and is similar in structure to stimulant cathinone, anorectic diethylpropion and to phenethylamines in general. Bupropion is primarily used as an antidepressant and as a smoking cessation aid. In 2006 it was the fourth most prescribed antidepressant on the U.S. retail market with 21,141,000 prescriptions.[6]

History

Bupropion was first synthesized by Burroughs Research in 1966, and patented by Burroughs-Wellcome (now GlaxoSmithKline) in 1974. It was approved by the Food and Drug Administration (FDA) as an antidepressant in 1984 and marketed under the name Wellbutrin. However, a significant incidence of seizures at the originally recommended dosage (400–600 mg) caused in 1986 the removal of the drug from the market. It was shown that the risk of seizures increases from 0.1% at 100–300 mg/day to 0.3–0.4% at 450 mg/day to 2% at 600 mg/day. Reflecting this experience, bupropion was re-introduced to the market in 1989 with the maximum dose of 450 mg/day.

Wellbutrin XL

In 1996 the FDA approved sustained-release (SR) and in 2003 extended release (XL) formulations of Wellbutrin that release bupropion at a slower rate. Wellbutrin SR is taken twice a day and Wellbutrin XL once a day, as compared to three times a day for the immediate release bupropion. Wellbutrin SR and XL are now available in generic form. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. In late 2006, Wellbutrin XL was approved for use by the FDA as treatment for seasonal affective disorder.

In the UK, bupropion was approved in 2000 as a smoking cessation aid, and has not been approved for the treatment of depression.[7]

Indications

Depression

Multiple placebo-controlled studies have confirmed efficacy of bupropion for depression.[8] Equivalent antidepressant potency of bupropion and sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil)[9] and escitalopram (Lexapro)[10] was demonstrated in comparative clinical studies. A significantly higher remission rate for bupropion than for venlafaxine (Effexor) treatment was observed in a recent study.[11] Unlike most other antidepressants, with the exception of mirtazapine (Remeron) and maprotiline (Ludiomil), bupropion does not cause sexual dysfunction and its rate of sexual side-effects is not different from placebo.[12][13] Bupropion treatment is not associated with weight gain; on the contrary, in every study comparing bupropion with placebo or other antidepressants the bupropion group ended up with lower average weight.[14] Bupropion is more effective than SSRIs at improving the symptoms of hypersomnia and fatigue in depressed patients.[15]

According to several surveys, the augmentation of bupropion to a currently prescribed SSRI is the preferred strategy among clinicians when the patient does not respond to the SSRI (treatment resistant depression). Although no placebo-controlled studies of bupropion augmentation have been conducted, multiple open-label trials and case reports generally support this strategy.[16] For example, combination of bupropion and citalopram was observed to be more effective than switch to a single antidepressant. 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 corresponding first line antidepressant.[17][18] Bupropion improved "energy" ratings, which originally decreased under the influence of the SSRI; improvements in mood and motivation, and some improvement of cognitive and sexual functions were also noted. Interestingly, sleep quality and anxiety in most cases stayed unchanged.[18]

Smoking cessation

Bupropion reduces the severity of nicotine cravings and addiction/withdrawal symptoms. Urge to smoke was a problem for 27% of subjects receiving bupropion vs 56% receiving placebo at the end of a 7-week treatment. 21% of the bupropion group reported mood swings vs 32% of the placebo group in the same study.[19] Bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco around ten days into the course. The efficacy of bupropion is similar to that of nicotine replacement therapy. Bupropion approximately doubles the chance of quitting smoking successfully after 3 months. 1 year after the treatment the odds of sustaining smoking cessation are still 1.5 higher in the bupropion group than in the placebo group.[20] Combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison, recently approved varenicline (Chantix) showed superior efficacy. After 1 year the rate of continuous abstinency was 10% for placebo, 15% for bupropion, and 23% for varenicline.[21] Bupropion slows down the weight gain occurring in the first weeks after quitting smoking (after 7 weeks, the placebo group had an average 2.7 kg increase in weight vs 1.5 kg for the bupropion group). However, with time this effect becomes negligible (after 26 weeks, both placebo and bupropion group recorded 4.8 kg weight gain).[19]

Sexual dysfunction

Although it is not an FDA-approved indication, a large body of evidence exists in favor of bupropion's use for sexual dysfunction. According to a survey, bupropion is the drug of choice among psychiatrists for the treatment of serotonin reuptake inhibitor (SSRI) induced sexual dysfunction. In that survey, 36 percent of the responding psychiatrists said they preferred switching their patients with sexual dysfunction to bupropion; however, 43 percent said they favored the augmentation of bupropion to the current medication.[22] There are studies demonstrating efficacy of both approaches, with improvement of desire and orgasm components of the sexual function being the most often noted. For the augmentation approach, indications exist that the addition of at least 200 mg/day of bupropion to the SSRI medication is necessary to achieve a statistically significant improvement. The addition of 150 mg/day of bupropion to the SSRI regimen of the patients with sexual dysfunction did not produce a statistically significant difference from that of placebo.[23][24][25][26][27][28]

Several studies have indicated that bupropion also relieves sexual dysfunction among non-depressed patients. After a 12-weeks course in a mixed male/female double-blind study, 63% of subjects on bupropion rated their condition as improved or much improved vs. only 3% of subjects on placebo.[29] Two studies, one of which was placebo-controlled, demonstrated efficacy of bupropion for women with hypoactive sexual desire[30][31] 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[32] and for orgasmic dysfunction.[33] As with the treatment of SSRI-induced sexual disorder, a higher dose of bupropion (300 mg) may be necessary, since a randomized study, which employed a lower dose (150 mg), failed to find any significant difference between bupropion, sexual therapy or combined treatment.[34] Interestingly, bupropion does not affect any measures of sexual functioning in healthy males.[35]

Obesity

A recent review/meta-analysis of anti-obesity medications pooled the results of three double-blind, placebo-controlled trials of bupropion. This meta-analysis confirmed the efficacy of bupropion—given at 400 mg per day—for obesity. Over a period of 6 to 12 months, weight loss in the bupropion group (4.4 kg, 10 lb) was significantly greater than in the placebo group (1.7 kg, 4 lb). The same review found the differences in weight loss between bupropion and other established weight loss medications, such as sibutramine, orlistat and diethylpropion, to be statistically insignificant.[36]

Other indications

Bupropion is also effective for adult attention-deficit hyperactivity disorder[37] and for the prevention of seasonal affective disorder,[38] and was approved by the FDA for the latter indication.[39]

Mode of action

Bupropion is a dopamine and norepinephrine reuptake inhibitor. It is about twice as potent an inhibitor of dopamine uptake than norepinephrine uptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without understanding its metabolism. Occupancy of dopamine transporter (DAT) by bupropion and its metabolites in human brain measured by positron emission tomography was 6–22% according to an independent study[40] and 12–35% according to GSK researchers.[41] Based on the analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of bupropion action. Bupropion does not inhibit monoamine oxidase (i.e. is not a MAOI) or serotonin reuptake. However, it has been shown to indirectly enhance firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive α3β4 nicotinic antagonist.[42] The degree of inhibition of α3β4 receptors correlates well with the decrease of self-administration of morphine and metamphetamine in rats,[43] and may be relevant to the effect of bupropion on nicotine addiction.

Pharmacokinetics

File:Bupropion metabolism.svg
Important metabolites of bupropion

Bupropion is metabolized in the liver. It has several active metabolites: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion. These active metabolites are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites combined from several sources are presented in the Table below. In addition, bupropion is known to weakly inhibit the α1 adrenaline receptor, with a 14% potency of its dopamine uptake inhibition, as well as the histamine H1 receptor, with 9% potency of dopamine uptake inhibition.[44]

Table. Pharmacology of bupropion and its metabolites.[45][46][47][44][48]

Exposure (concentration over time; bupropion exposure = 100%) and half-life
Bupropion R,R-
Hydroxy
bupropion 		S,S-
Hydroxy
bupropion 		Threo-
hydro
bupropion 		Erythro-
hydro
bupropion
Exposure 100% 800% 160% 310% 90%
Half-life 10 h (IR)
17 h (SR) 		21 h 25 h 26 h 26 h
Inhibition potency (potency of DA uptake inhibition by bupropion = 100%)
DA uptake 100% 0% (rat) 70% (rat) 4% (rat) No data
NE uptake 27% 0% (rat) 106% (rat) 16% (rat) No data
Ser uptake 2% 0% (rat) 4%(rat) 3% (rat) No data
α3β4 nicotinic 53% 15% 10% 7% (rat) No data
α4β2 nicotinic 8% 3% 29% No data No data
α1* nicotinic 12% 13% 13% No data No data

Thus, the biological activity of bupropion can be attributed to a great degree to its active metabolites, in particular to S,S-hydroxybupropion. GSK developed this metabolite as a separate drug radafaxine,[49] but discontinued development in 2006 due to "poor test results".

Bupropion is metabolized to hydroxybupropion by a cytochrome P450 enzyme CYP2B6. Alcohol causes increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. The mechanism of formation of erythro-hydrobupropion and threo-hydrobupropion has not been studied but probably it is mediated by one of the carbonyl reductase enzymes. The metabolism of bupropion is highly variable: the effective dose of bupropion received by different individuals, who ingested the same amount of the drug, may differ as much as 5.5 times (and half-life time from 3 to 16 hours), and of hydroxybupropion as much as 7.5 times (and half-life time from 12 to 38 h)[50][51]

Significant interspecies differences in metabolism of bupropion exist, with guinea pigs' metabolism of the drug being closest to the human metabolism.[52] Particular caution is needed when extrapolating the results of the experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.[53]

Contraindications and warnings

Bupropion is contraindicated in individuals with the following conditions:

  • Epilepsy and other conditions that lower the seizure threshold (such as alcohol or

benzodiazepine discontinuation, anorexia nervosa and bulimia, active brain tumors, etc.);

  • Concomitant treatment with MAO inhibitors. When switching from a MAO to bupropion it is important that there be a short period of about two weeks between the medications.[54]

Caution should be exercised when treating patients with:

  • Liver damage (e.g. cirrhosis) as the drug levels may be higher than in other patients;
  • Severe kidney disease as in such patients the levels of hydroxybupropion and threo-hydrobupropion are 2–3 times higher than in normal subjects;
  • Severe hypertension as bupropion is known to cause hypertension;
  • Pediatric patients, adolescents and young adults (see below).[54]

Suicide risk

The FDA requires all antidepressants, including bupropion, to carry a black box warning that states, "Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders... The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%." Further generic warnings in the prescribing information say, "It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults... Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases."[54]

FDA analysts also found that the risk of suicidal thoughts and behavior strongly depends on age of a person. In addition to increasing this risk in children and adolescents, antidepressants may increase it as much as 1.5 times in young (age 18–24) adults (data close to statistical significance). However, they decrease the suicidal thoughts and behavior for persons aged 31 to 64 years by 23% (statistically significant). Most importantly, considering the high risk of suicide among older people, antidepressants decrease suicidal thoughts and behavior 2.5-fold for persons 65 or more years old.[55]

The suicidal ideation/behavior in clinical trials is rare. For the above analysis, the FDA had to combine the results of 295 recent trials of 11 different antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, bupropion and 9 other antidepressants were not statistically different from placebo. Only fluoxetine caused a significant decrease in suicidal ideation/behavior.[55]

The suicidal behavior is even less likely when bupropion is prescribed for quitting smoking. According to Cochrane Database review, there have been 4 suicides per 1,000,000 prescriptions and 1 case of suicidal behavior/ideation per 10,000 prescriptions of bupropion for smoking cessation in the UK. The review concludes that, "Although some suicides and deaths while taking bupropion have been reported, thus far there is insufficient evidence to suggest they were caused by bupropion."[56]

Abuse liability

According to the US government classification of psychiatric medications, bupropion is non-abusable[57] or has low abuse potential.[58] However, in animal studies bupropion maintained intravenous self-administration by squirrel monkeys[59] and rats,[60] which may indicate abuse potential. On the other hand, important differences of bupropion metabolism in rats and humans make any extrapolation of rats' results to humans invalid (see Pharmacokinetics).

Two studies on drug abusers indicated that subjective effects of bupropion are markedly different from those of amphetamine.[61][62] Healthy volunteers trained to discriminate amphetamine and placebo, recognized bupropion (400 mg) as amphetamine in 20% of cases as compared to 10% for placebo and 75% for methylphenidate (20 mg). They also reported feeling alert, vigorous, elated and energetic, reflecting general stimulating properties of bupropion. However, in contrast to amphetamine and methylphenidate, there was no feeling of "liking the drug" and desire to take it again.[63] A comparison of bupropion SR (150 mg) and caffeine (178 mg) indicated that caffeine may have higher abuse liability since caffeine resulted in greater frequency of reports of pleasant feelings and "high" than bupropion.[64]

There have been only three reports of bupropion abuse in the literature. All three cases were teenagers crushing and insufflating (snorting) bupropion, one of them ending up with seizures.[65] An article on abuse of medications in prisons mostly concerned with the recreational use of quetiapine (Seroquel) mentions bupropion as one of the psychotropic medications commonly abused by inmates. Other such medications are gabapentin (Neurontin), tricyclic antidepressants and trihexyphenidyl.[66]

Side effects

For Bupropion SR (300 mg/day) common side effects with the greatest difference from placebo are dry mouth (17% vs 7% for placebo), nausea (13% vs 8% for placebo), insomnia (11% vs 6% for placebo), tremor (6% vs 1% for placebo), excessive sweating (6% vs 2% for placebo) and tinnitus (6% vs 2% for placebo). The two side effects which most often resulted in interruption of the treatment in the same trial were rash (2.4%) and nausea (0.8%). The development of mild to moderate skin rashes is associated with sensitivity to dye components within the pill coating. This can often be alleviated by simply prescribing a different color pill. [54]

Seizure is the most controversial side effect of bupropion, which caused its earlier mentioned withdrawal from the market. The risk of seizure is highly dose-dependent: 0.1% at 100–300 mg of bupropion, 0.4% at 300–450 mg, and 2% at 600 mg. For comparison, the incidence of the first unprovoked seizure in the general population is 0.07–0.09%; the risk of seizure for other antidepressants is as follows: imipramine 0.1–0.6% depending on dosage, amitriptiline 0–0.06% depending on dosage, clomipramine 0.5%, maprotiline 0.4%, fluoxetine and fluvoxamine 0.2%.[67] Experiments on mice indicate that increased susceptibility to seizure is a general side effect of antidepressants inhibiting norepinephrine transporter, such as imipramine, desipramine and reboxetine, given chronically.[68] On the other hand, depression was reported to increase occurrence of seizures 2–7 fold as compared to the general population. In this light, the above statistics could indicate that low to moderate doses of antidepressants, including bupropion, may actually have an anti-convulsive action.[69] Nevertheless, patients using bupropion should still be screened for pre-disposing factors that could contribute to and/or indicate a low seizure threshold. A prescriber may also review all other medications/substances the patient is using and make dosing decisions based on the results.

Three cases of liver toxicity of bupropion have been reported in the literature.[70] This is extremely rare considering the widespread use of the drug.

The prescribing information notes that hypertension, sometimes severe, was observed in some patients, both with and without pre-existing hypertension, treated with bupropion. At the same time, the frequency of this side effect was under 1% and not significantly higher than for placebo.[54] In a group of cardiac patients with depression, high doses of bupropion (400–500 mg/day) caused a rise of supine blood pressure but no effect on pulse rate.[71] No statistically significant changes in blood pressure or heart rate occurred in patients both with and without heart conditions at a lower dose (300 mg/day) .[72] In a study of bupropion for ADHD, a rise of systolic blood pressure by 6 mm Hg and heartbeat rate by 7 bits per minute (both statistically significant) was observed.[73] A study of smokers hospitalized for heart disease found a 1.5-fold increase (close to being statistically significant) in the subsequent cardiovascular events in bupropion group as compared to the placebo group but no difference in blood pressure.[74] Although cardiovascular side effects of bupropion appear to be mild, it can not be recommended for patients with heart disease since the safety comparison with SSRI antidepressants (such as sertraline and fluoxetine which may have a preventative effect after a myocardial infarction[75]) is not in its favor.

A single case of clitoral priapism (clitorism) has been reported in the literature.[76]

In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion's approval by MHRA as a part of the Yellow Card Scheme which monitored side effects. Approximately 540,000 people were treated by bupropion for smoking cessation during that period. 60 reports of "suspected (emphasis by MHRA) adverse reactions to Zyban which had a fatal outcome" were received. The agency concluded that "in the majority of cases the individual’s underlying condition may provide an alternative explanation."[77] This is consistent with a large (9300 patients) safety study, which indicated that mortality of smokers taking bupropion is not higher than natural mortality of smokers of the same age.[78]

Interactions

As bupropion is metabolized to hydroxybupropion by CYP2B6, drug interactions with CYP2B6 inhibitors (paroxetine, sertraline, fluoxetine metabolite norfluoxetine, diazepam, clopidogrel, orphenadrine and others) are possible. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers (carbamazepine, clotrimazole, rifampicin, ritonavir, St John's Wort and others).[79]

Hydroxybupropion (but not bupropion) inhibits CYP2D6 and is a substrate of that enzyme. Significant increase of the concentration of some drugs metabolized by CYP2D6 (venlafaxine, desipramine and dextromethorphan, but not fluoxetine or paroxetine) when taken with bupropion has been observed.[79][80]

Bupropion lowers the seizure threshold; therefore, extreme care should be taken when prescribing bupropion with other medications lowering the seizure threshold (antipsychotics, theophylline, steroids, some tricyclic antidepressants (see: Side effects).[54] Combination with nicotine replacement therapies can elevate blood pressure; at the same time, it is not more effective than nicotine patch or bupropion alone (see:Indications—Smoking cessation), so it should not be recommended.

The prescribing information recommends to minimize the use of alcohol, since in rare cases bupropion reduced alcohol tolerance, and also because the excessive use of alcohol may lower the seizure threshold.[54] A small study conducted by GSK indicated that bupropion (100 mg) may counteract the subjective effects of small doses of alcohol (16–32 mL, slightly less than 1–2 US standard drinks). The volunteers reported feeling more sober and clear headed, and less sedated. Bupropion also partially neutralized the detrimental effect of alcohol on auditory vigilance. In addition, the combination of bupropion (100 mg) and 2 drinks of alcohol increased the heart rate by 6 beats/min (statistically significant).[81]

Dosage

  • Depression: the target dosage is 300 mg daily, starting with 150 mg in the first few days. If indicated and directed by physician, the dosage may be increased to a maximum of 450 mg daily.
  • Tobacco withdrawal: 150 mg initially, may be increased to 300 mg if indicated and directed by physician. In patients also receiving insulin, sympathomimetic anorectical drugs, or antimalaria agents, the daily dose of bupropion should not exceed 150 mg.
  • Due to high variability of bupropion's pharmacokinetics (see Pharmacokinetics) the recommended starting dose of 150 mg in some patients may be equivalent to 450–500 mg for an average patient. Based on this, some researchers advocated monitoring of the blood level of bupropion and hydroxybupropion.[82] As this is impossible in a routine clinical practice, a lower starting dose of 75 mg should be considered. This dose can be increased gradually based on individual tolerability up to the maximum dose of 450 mg. According to GSK, a 150-mg Bupropion SR tablet can be divided in two and still retain its sustain-release characteristics.[83]

Dose forms

Brand and generic pills are available in three forms: immediate release, sustained release (SR), and extended release (XL, ER).

Availability in the UK

Zyban is available via prescription, only if you are able to get a letter from a smoking cessation clinic to your GP confirming that you are a heavy smoker on whom nicotine replacement therapies have been tried and are useless.

Brand Name Dosage Color
Wellbutrin 75 mg yellow-gold
Wellbutrin 100 mg red
Wellbutrin SR 100 mg blue
Wellbutrin SR 150 mg purple
Wellbutrin SR 200 mg pink
Wellbutrin XL 150 mg white
Wellbutrin XL 300 mg white
Zyban SR 150 mg purple
Budeprion SR 100 mg light yellow
Budeprion XL 300 mg light yellow
Zylexx SR 75 mg white

Overdosage

GlaxoSmithKline has reported that overdoses of up to 30 g or more of Wellbutrin (bupropion) had resulted in seizure in about one third of all cases. Hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias were reported as other serious reactions of overdoses of bupropion alone. Multiple overdoses including bupropion had resulted in fever, rhabdomyolysis, stupor, hypotension, coma, muscle rigidity, and respiratory failure.[54]

Additional information

Trade names

May cause false-positive for amphetamine

Two cases of false-positive urine amphetamine tests in persons taking bupropion have been reported. It is likely that bupropion metabolites erythro-hydrobupropion and threo-hydrobupropion, which have phenethylamine structure resembling amphetamine, were responsible for this reaction. More specific tests conducted afterwards were negative.[84][85]

Bipolar disorder

Recently, addition of bupropion to a mood-stabilizer in patients with bipolar depressions was shown to have the same effectiveness as placebo.[86]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ The INN originally assigned in 1974 by the World Health Organization was "amfebutamone". In 2000, the INN was reassigned as bupropion. See World Health Organization (2000). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 83" (PDF). WHO Drug Information. 14 (2).
  3. ^ Stahl S, Pradko J, Haight B, Modell J, Rockett C, Learned-Coughlin S (2004). "A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor". Prim Care Companion J Clin Psychiatry. 6 (4): 159–166. PMID 15361919.{{cite journal}}: CS1 maint: multiple names: authors list (link) PMC 514842
  4. ^ Slemmer J E, Martin R M, Damaj M I (2000). "Bupropion is a Nicotinic Antagonist". J Pharmacol Exp Ther. 295 (1): 321–327.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  6. ^ After sertraline, escitalopram and fluoxetine. The bupropion prescriptions were calculated as a total of prescriptions for Wellbutrin XR, Budeprion XR, Bupropion XR and Bupropion ER using data from the charts for generic and brand name drugs."Top 200 generic drugs by units in 2006. Top 200 brand-name drugs by units". Drug Topics, Mar 5, 2007. Retrieved 2007-04-08.
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  13. ^ For another review, see: Kanaly KA, Berman JR (2002). "Sexual side effects of SSRI medications: potential treatment strategies for SSRI-induced female sexual dysfunction". Curr Women's Health Rep. 2 (6): 409–16. PMID 12429073.
  14. ^ For a short review, see: Zimmerman M, Posternak MA, Attiullah N, Friedman M, Boland RJ, Baymiller S, Berlowitz SL, Rahman S, Uy KK, Singer S, Chelminski I, Thongy, T (2005). "Dr. Zimmerman and colleagues reply to MJ Menaster". J Clin Psychiatry. 66 (10): 1336–9.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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External links

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