Jack G. Modell

Bupropion XL in adults with attention-deficit/hyperactivity disorder : A randomized, placebo-controlled study

BACKGROUND Data remain limited on treatment strategies for adults with attention-deficit/hyperactivity disorder (ADHD). This study evaluated the efficacy and safety of an extended-release, once-daily formulation of bupropion (XL) in the treatment of adults with ADHD. METHODS This multisite, placebo-controlled, 8-week prospective trial evaluated 162 adult patients diagnosed with ADHD (combined and inattentive types). Subjects were treated with up to 450 mg/day of bupropion XL. The primary efficacy endpoint was the proportion of ADHD responders (defined as at least a 30% reduction in the investigator-rated ADHD Rating Scale score) at week 8 (last observation carried forward [LOCF]). RESULTS Bupropion XL responders (53%) exceeded placebo responders (31%) (p =.004 at week 8) with a significantly greater proportion of bupropion XL responders as early as week 2 (p = .01). Treatment effect size calculated for the ADHD Rating Scale total score was .6. Bupropion XL appeared to provide sustained benefit throughout the day compared with placebo (morning p =.033, afternoon p =.004, evening p = .024). Bupropion XL was safe and well tolerated, with no serious or unexpected adverse events and a low rate of drug-related study discontinuation (5%). CONCLUSIONS The results from this multisite study indicate that bupropion XL is an effective and well-tolerated nonstimulant treatment for adult ADHD.

Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL.

BACKGROUND Seasonal affective disorder (SAD) can cause significant distress and impairment. No antidepressant studies have previously attempted to prevent the onset of autumn-winter depression. METHODS Three prospective, randomized, placebo-controlled prevention trials were conducted on 1042 SAD patients, enrolled in autumn and treated while still well, across the northern US and Canada. Patients received either bupropion XL 150-300 mg or placebo daily by mouth from enrollment until spring and were then followed off medications for 8 additional weeks. Primary efficacy variables were end-of-treatment depression-free rates and survival distributions of depressive recurrence. RESULTS Despite a reported average of 13 previous seasonal depressive episodes, almost 60% of patients had never previously been treated for depression. Major depression recurrence rates during the three studies for bupropion XL and placebo groups were 19% versus 30% (p = 0.026), 13% versus 21% (p = 0.049), and 16% versus 31%; yielding a relative risk reduction across the three studies of 44% for patients taking bupropion XL. Survival analyses for depression onset also favored bupropion XL over placebo (p = .081, .057, and <.001). CONCLUSIONS It is possible to prevent recurrence of seasonal major depressive episodes by beginning bupropion treatment early in the season while patients are still well.

Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR.

Bupropion, a noradrenaline/dopamine reuptake inhibitor, and venlafaxine, a serotonin/noradrenaline reuptake inhibitor, are both established antidepressants with proven efficacy in randomized controlled clinical trials. The objective of this double-blind, randomized, placebo- and active-controlled, eight-week, flexible-dose study was to evaluate the efficacy and tolerability of the once-daily extended-release formulations of these two antidepressants compared with placebo. Patients with major depressive disorder were randomized to once-daily treatment with bupropion XR 150 mg (n = 204), the extended-release formulation of venlafaxine (venlafaxine XR) 75 mg (n = 198) or placebo (n = 189) during weeks 1 to 4, with the option to double the dose at week 5 if response was inadequate. In this study, bupropion XR did not demonstrate statistically significant evidence of greater improvement from baseline compared with placebo on week 8 Montgomery Asberg Depression Rating scale scores (primary endpoint) or on secondary endpoints including CGI, HAM-A and responder and remitter analyses. Descriptive statistics for venlafaxine XR indicated separation versus placebo on MADRS total scores at week 8 and other intermediate time points, and on other endpoints including CGI, HAM-A and responder and remitter analyses. Both active treatments elicited improvement on the Sheehan Disability Scale and its subscales and were generally well tolerated at the doses studied. Rates of nausea, dry mouth, dizziness, hyperhidrosis, insomnia, constipation, tremor, anorexia and male sexual dysfunction were elevated in the venlafaxine XR group, consistent with its mixed serotonergic/noradrenergic mechanism. Rates of dry mouth, insomnia and hyperhidrosis were elevated in the bupropion XR group, consistent with its catecholaminergic mechanism.

Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR

Abstract The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of ≥18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: −16.0 for bupropion XR (P = 0.006 vs placebo), −17.1 for venlafaxine XR (P < 0.001 vs placebo) and −13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.

Double-blind, placebo-controlled evaluation of extended-release bupropion in elderly patients with major depressive disorder

Major depressive disorder in the elderly is associated with increased morbidity and reduced quality of life. This 10 week, placebo-controlled study investigated the efficacy and tolerability of extended-release bupropion (150—300 mg once daily) in depressed patients aged 65 years or older. The statistical assumptions necessary for the validity of the protocol-specified analysis of covariance were not met for the analysis of the primary outcome variable (Montgomery-Asberg Depression Rating Scale total score at Week 10, last observation carried forward). Alternative statistical methods used for the analysis of this variable demonstrated statistical significance. Statistically significant improvements were observed on the majority of secondary end points when compared with placebo, including the health outcome measures for motivation and energy, and life satisfaction and contentment. Adverse events were generally mild to moderate and similar between treatment groups. This study demonstrated that the extended-release bupropion is an effective, well-tolerated treatment for major depression in the elderly.

Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials

GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18–64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1–2 mg/d), or active control (Study 1: venlafaxine XR 150–225 mg/d; Study 2: paroxetine 20–30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.