J. Andrew Johnston

Pharmacokinetics of Bupropion and its Metabolites in Cigarette Smokers versus Nonsmokers

Bupropion is an antidepressant agent that is also effective as an aid to quit cigarette smoking. A single 150‐mg tablet of sustained‐release bupropion hydrochloride was administered to two groups of volunteers, cigarette smokers and nonsmokers, who were matched for race, gender, body frame, age, and weight. Pharmacokinetic parameters were calculated for bupropion, and three major metabolites (hydroxybupropion and the aminoalcohol isomers, threohydrobupropion and erythrohydrobupropion, expressed as a composite total). Mean (±SD) values of area under the concentration‐time curve from time 0 extrapolated to infinity (AUC0–∞), maximum concentration (Cmax), time to reach Cmax (tmax), and half‐life (t1/2) of bupropion in smokers and nonsmokers, respectively, were 1,164 ± 220 ng · hr/mL and 1,161 ± 292 ng · hr/mL; 144 ± 28 ng/mL and 143 ± 39 ng/mL; 3.00 ± 0.50 hours and 2.88 ± 0.49 hours; and 19 ± 5 hours and 18 ± 3 hours. No clinically significant differences between smokers and nonsmokers or between male and female volunteers were observed for the pharmacokinetics of bupropion or its metabolites. The absence of pharmacokinetic differences indicates that dosage adjustments are not necessary when bupropion is prescribed to male and female cigarette smokers.

Evaluation of Sexual Functioning in Depressed Outpatients: A Double-blind Comparison of Sustained-release Bupropion and Sertraline Treatment

Sexual dysfunction is a frequently reported side effect of many antidepressants, including serotonin reuptake inhibitors. Bupropion, an antidepressant of the aminoketone class, is relatively free of adverse sexual effects. In a randomized, double-blind, multicenter trial, sustained-release bupropion (bupropion SR) and sertraline, a selective serotonin reuptake inhibitor, were found to be similarly efficacious in the treatment of outpatients with moderate to severe depression. This report describes the results of a double-blind comparison of the sexual side effect profiles of bupropion SR and sertraline. Two hundred forty-eight patients who had received a diagnosis of moderate to severe major depression were randomly assigned to receive treatment with bupropion SR (100-300 mg/day) or sertraline (50-200 mg/day) for 16 weeks. Eligible patients were required to be in a stable relationship and to have normal sexual functioning. Sexual functioning was assessed by the investigator at each clinic visit using investigator-rated structured interviews. A significantly greater percentage of sertraline-treated patients (63% and 41% of men and women, respectively) developed sexual dysfunction compared with bupropion SR-treated patients (15% and 7%, respectively). Sexual dysfunction was noted as early as day 7 in sertraline-treated patients at a dose of 50 mg/day and persisted until the end of the 16-week treatment phase. Four patients, all of whom were treated with sertraline, discontinued from the study prematurely because of sexual dysfunction. Given the similar efficacy of the two drugs in treating depression, bupropion SR may be a more appropriate antidepressant choice than sertraline in patients for whom sexual dysfunction is a concern.

Safety profile of sustained-release bupropion in depression: Results of three clinical trials

This series of studies was undertaken to assess the safety profile of sustained-release (SR) bupropion in the treatment of depressed outpatients. Adults with a diagnosis of major depression were evaluated in 1 of 3 multicenter, randomized, double-masked, parallel-group, placebo-controlled trials conducted in private-practice psychiatric outpatient clinics. Following a 1-week, single-masked, placebo lead-in period, patients received bupropion SR for 8 weeks (study 1: 150 or 300 mg/d; study 2: 100, 200, 300, or 400 mg/d; study 3: 50 to 150 or 100 to 300 mg/d). Safety assessments included monitoring adverse events, patient discontinuation rates, changes in weight, vital signs, and clinical laboratory test results. Across studies, the most frequently reported adverse events were headache, dry mouth, and nausea. The incidence of adverse events was similar (< or =5% difference) between the bupropion SR and placebo groups, with the exception of dry mouth (bupropion SR, 16%; placebo, 7%). Dry mouth, nausea, and insomnia occurred significantly more often in bupropion SR-treated patients than in patients who received placebo (P<0.05). Nearly all (94% to 99%) adverse events reported in these studies were mild or moderate. Less than 10% of patients in either group discontinued treatment prematurely because of adverse events, and no deaths or serious drug-related adverse events were reported. Sexual dysfunction was reported as an adverse event by <1% of patients in either group. Bupropion SR was associated with dose-related weight loss in all 3 studies. No consistent patterns of change were observed in vital signs or in the results of clinical laboratory tests. Data from these 3 clinical trials demonstrate the favorable safety profile of bupropion SR in the treatment of depressed outpatients.

Comparison of Bupropion and Trazodone for the Treatment of Major Depression

Bupropion and trazodone were compared in a two-center, double-blind clinical trial of outpatients with moderate to severe major depression. After a 1-week placebo lead-in, 124 patients were randomly assigned to receive either bupropion (N = 63) or trazodone (N = 61) for 6 weeks; data from 111 patients were used in the efficacy analysis. Dosing ranged from 225 to 450 mg/day for bupropion and 150 to 400 mg/day for trazodone. The overall efficacy for each of the two drugs was similar; although improvement in the trazodone treatment group was significantly greater on day 7 because of the effects on sleep. At the end of treatment, 58% of the bupropion-treated patients and 46% of the trazodone-treated patients were considered much or very much improved. Weight measurements at the time of discontinuation indicated a 2.5-lb mean weight loss for the bupropion treatment group and a 1.2-lb mean weight gain for the trazodone treatment group. The adverse experience profiles for bupropion and trazodone were consistent with their known pharmacologic profiles (i.e., activating versus sedating). Anorexia and anxiety were reported significantly more often for the bupropion treatment group, whereas somnolence, appetite increase, and edema were reported significantly more often for the trazodone treatment group.

A double-blind comparison between bupropion XL and venlafaxine XR : Sexual functioning, antidepressant efficacy, and tolerability

Abstract: In this double-blind, multicenter study, bupropion XL, a norepinephrine-dopamine reuptake inhibitor, and venlafaxine XR, a serotonin-norepinephrine reuptake inhibitor, were compared with regard to sexual functioning, efficacy, and tolerability. A total of 348 sexually active adult outpatients with depression were randomized to receive bupropion XL (titrated to a target dose of 300-450 mg/d) or venlafaxine XR (titrated to a target dose of 150-225 mg/d) for 12 weeks. Total scores on the primary dependent variable, the Changes in Sexual Functioning Questionnaire (self-report), increased for subjects receiving bupropion XL and decreased for those treated with venlafaxine XR; the mean change scores differed significantly between groups from week 2 onward. Among subjects with normal pretreatment sexual functioning, Changes in Sexual Functioning Questionnaire total scores remained essentially unchanged for the bupropion XL group but were decreased significantly for the venlafaxine XR group; mean change scores also differed between groups from week 2 onward. Although the therapies resulted in similar change on the 17-item Hamilton Depression Rating Scale, remission rates were significantly higher among those treated with bupropion XL (46%) versus venlafaxine XR (33%) (odds ratio, 1.93; 95% confidence interval, 1.07-3.46). Aside from adverse effects of venlafaxine XR on sexual function, both treatments were reasonably well tolerated. In conclusion, in this patient population (ie, relatively young, sexually active outpatients), bupropion XL was at least as effective as venlafaxine XR and had a significantly more favorable sexual side effect profile.

Effects of gender on relapse prevention in smokers treated with bupropion SR

BACKGROUND Recent data suggest that women smokers respond differently than men to cessation pharmacotherapies, particularly nicotine replacement therapy (NRT). Lower abstinence and higher relapse rates are often reported for women treated with NRT. Gender effects for those treated with non-nicotinic, bupropion-hydrochloride sustained release for relapse prevention have not been studied. METHODS Data from a multicenter relapse-prevention (RP) trial of bupropion (November 1995-June 1998) were analyzed for gender differences. Men and women smokers (N=784) were treated with open-label bupropion for 7 weeks. Those abstinent at Week 7 (n=432) were enrolled in the double-blind relapse-prevention phase and randomized to placebo or continued bupropion for 45 additional weeks. RESULTS Differences in point-prevalence abstinence rates between men (61.8%) and women (55.6%) in open-label bupropion (Week 7) were not significant. In the RP-phase Week 52, continuous abstinence rates for men and women were 37.8% and 36.4% (bupropion) and 36.6% and 29.9% (placebo), respectively; point-prevalence abstinence rates for men and women were 54.1% and 55.9% (bupropion) and 42.9% and 41.3% (placebo), respectively. Abstinence rates and time to relapse were superior for both men and women who received longer treatment. Gender differences within treatment groups were not significant. Median time to relapse was equal for men and women within each treatment group: Week 32 for bupropion and Week 20 for placebo. CONCLUSIONS Our data suggest that bupropion is a promising pharmacotherapy for preventing relapse, particularly for women.

Targeting smokers at increased risk for relapse: treating women and those with a history of depression

Some studies have shown that female smokers and smokers with a history of depression have an increased risk of relapse following smoking cessation treatment. This study examined the efficacy of bupropion sustained-release (SR) and the nicotine patch for smoking cessation in subgroups of smokers at possible risk for relapse. Data for this study were from a previously published randomized, double-blind, placebo-controlled clinical trial in which 893 smokers were randomized to four treatment conditions: placebo tablet + placebo patch, placebo tablet + 21 mg/24-hr nicotine patch, 300mg bupropion SR + placebo patch, and 300mg bupropion SR + 21 mg/24-hr nicotine patch. Study medication continued for 8 weeks after the quit day; brief individual cessation counseling was provided during weekly clinic visits. In comparison to the placebo tablet, bupropion SR approximately tripled 1-year non-smoking rates among women and previously depressed individuals. In contrast, the nicotine patch did not significantly improve cessation rates for any group. We conclude that bupropion SR is a first-line treatment for smoking that has the potential to benefit all smokers, especially women and the previously depressed.

Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo

OBJECTIVE The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release (SR), the nicotine patch, and the combination of these 2 treatments in patients who initially failed treatment. METHODS This was a post hoc analysis of a multicenter, double-blind, randomized, placebo-controlled clinical trial in 893 smokers. Patients were randomly assigned to 9 weeks of treatment with placebo (n = 160), bupropion SR (n = 244), nicotine patch (n = 244), or a combination of nicotine patch and bupropion SR (n = 245). The study was originally designed with a follow-up period of 52 weeks. In this analysis, short-term success was defined as smoking cessation after 14 or 21 days of therapy and long-term success was defined as smoking cessation after >21 days of therapy. Patients who did not achieve short-term success were evaluated for long-term success at week 9 (end of treatment), 6 months, and 1 year after the start of the study. RESULTS The mean age of the smokers was 44 years. The majority (93%) of patients were white, and 52% were female. The study subjects smoked an average of 27 cigarettes per day. Among the 467 patients who initially failed treatment in the first 3 weeks, treatment with bupropion SR alone and in combination with the nicotine patch produced significant increases in successful smoking cessation rates from weeks 4 to 9 (19% bupropion SR or combination, 7% nicotine patch, 7% placebo), at month 6 (11% bupropion SR, 13% combination, 2% nicotine patch, 3% placebo), and at month 12 (10% bupropion SR, 7% combination, 2% nicotine patch, 1% placebo) (P < 0.05 for bupropion SR and combination vs nicotine patch or placebo). CONCLUSION Among patients who initially failed treatment, continued therapy with bupropion SR, either alone or in combination with the nicotine patch, resulted in significantly higher short- and long-term smoking cessation rates than treatment with the nicotine patch alone or placebo.

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation

A population pharmacokinetic and pharmacodynamic analysis evaluated the relationships of dose, plasma concentrations of bupropion and metabolites, and patient covariates with the safety and efficacy of bupropion sustained release (SR) for smoking cessation. A total of 519 outpatient chronic cigarette smokers were randomized to one of three bupropion SR doses: 100, 150, or 300 mg/day or placebo. The bupropion plasma concentration time data were fit and subject-specific bayesian estimates of clearance were obtained. Logistic regression analyses evaluated the role of dose, concentrations, and covariates in predicting efficacy and safety endpoints. For the evaluation of efficacy, patients were classified as quitters or non-quitters on the basis of a 4-week quit variable (defined as complete abstinence for weeks 4-7 of the study). For the evaluation of safety, patients were classified into two categories for each adverse event evaluated, corresponding to whether the patient ever experienced the adverse event during the course of the study or never experienced the event, regardless of whether the event was treatment-emergent. The efficacy of bupropion SR in facilitating smoking cessation was found to be related to dose and a mean metabolite concentration, and quitting in general was found to be related to the number of cigarettes smoked per day at baseline. Smoking cessation was 1.42, 1.69, and 2.84 times more likely in patients receiving 100, 150, and 300 mg/day of bupropion SR, respectively, as compared to placebo (p = 0.0001). As the baseline number of cigarettes smoked per day increased, the likelihood of quitting decreased regardless of the treatment condition. Insomnia and dry mouth were positively associated with mean metabolite concentrations, and dry mouth was inversely related to patient weight. Anxiety was inversely related to predicted steady-state concentration (Cpss), suggesting a positive effect on this withdrawal symptom. Bupropion SR exhibits a statistically significant dose/plasma level-response relationship for smoking cessation. Dry mouth and insomnia, related to concentrations, may be managed with dose reduction, with the realization that smoking cessation may be impaired.

A multicenter evaluation of the efficacy and safety of 150 and 300 mg/d sustained-release bupropion tablets versus placebo in depressed outpatients

This multicenter, randomized, double-masked, placebo-controlled, parallel-group study compared the antidepressant efficacy and safety of bupropion sustained-release (SR) tablets (150 mg QD or 150 mg BID) with placebo in outpatients with moderate-to-severe depression. The study consisted of a 1-week placebo phase followed by 8 weeks of active treatment with bupropion SR 150 mg/d (150 mg QD, n = 121) or 300 mg/d (150 mg BID, n = 120) or placebo (n = 121). Efficacy was measured by changes in scores on the 17-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions for Severity of Illness (CGI-S) and Clinical Global Impressions for Improvement of Illness (CGI-I) scales. Safety was monitored by regular assessment of vital signs and adverse events as well as by pretreatment and posttreatment physical and clinical laboratory examinations. By day 56, both bupropion SR treatments were more effective in relieving the symptoms of depression than was placebo. Compared with those receiving placebo, patients in the bupropion SR 150- and 300-mg/d groups had significantly reduced symptoms by treatment day 56, as measured on the 17-item HAM-D, CGI-S, and CGI-I scales (P < 0.05). Bupropion SR was well tolerated, with no serious adverse events reported by bupropion-treated patients; 95% of all reported adverse events were of mild or moderate intensity. No clinically significant changes in vital signs, laboratory test results, or physical findings were observed. A greater mean weight loss was observed at the end of treatment in both the bupropion SR 150-mg (0.5 kg) and bupropion SR 300-mg (1.0 kg) group compared with placebo (0.2 kg). We found that bupropion SR 150 mg administered either once or twice daily was more effective than placebo in treating depression and that once-daily dosing appears to be at least as effective as twice-daily dosing. Should this prove true, depressed patients may be able to benefit from the convenience and improved tolerability associated with once-daily dosing.