Alok Krishen

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.

BACKGROUND Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. METHODS We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. FINDINGS 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1·28 (95% CI -2·40 to -0·15) and -0·08 (-1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were -1·07 (-2·21 to 0·08) and 0·13 (-1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1·59 (95% CI -0·42 to 3·59) and 1·78 (-0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (-0·81 to 3·25) and 1·42 (-0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. INTERPRETATION The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. FUNDING Pfizer and GlaxoSmithKline.

Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study.

Many persons who attempt to quit smoking have made previous unsuccessful attempts to quit with pharmacologic aids. An understanding of the impact of these previous attempts to quit is vital for selecting medications that may be more successful in a future attempt to quit. In particular, the effect of repeated use of bupropion SR (Zyban; INN, amfebutamone) on abstinence rates has not been studied previously.

Resolution of Sleepiness and Fatigue in Major Depressive Disorder: A Comparison of Bupropion and the Selective Serotonin Reuptake Inhibitors

BACKGROUND The purpose of this study was to examine whether the treatment of major depressive disorder (MDD) with the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion results in a greater resolution of sleepiness and fatigue than with the selective serotonin reuptake inhibitors (SSRIs). METHODS Six double-blind, randomized clinical trials comparing bupropion (n = 662) with an SSRI (n = 655) for the treatment of MDD were pooled. Hypersomnia scores were defined as the sum of scores of the Hamilton Depression Rating Scale (HDRS) items #22, 23, and 24. Fatigue scores were defined as the score of HDRS item #13. RESULTS There was a greater improvement in hypersomnia scores among bupropion-treated than SSRI-treated (p < .0001) or placebo-treated patients (p = .0008). There was also a greater improvement in fatigue scores among bupropion-treated (p < .0001) and SSRI-treated (p = .0005) than placebo-treated patients as well as a greater improvement in fatigue scores among bupropion-treated than SSRI-treated patients (p = .0078). Fewer bupropion-remitters than SSRI-remitters experienced residual hypersomnia (20.5% vs. 32.1%; p = .0014) or residual fatigue (19.5% vs. 30.2%; p = .0020). CONCLUSION Treatment of MDD with the NDRI bupropion resulted in a greater resolution of sleepiness and fatigue than SSRIs treatment. Although preliminary, these results warrant prospectively designed studies examining potential differences between bupropion and the SSRIs on these specific depressive symptoms.

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.

Using prior information to allocate significance levels for multiple endpoints

We maximize power in a replicated clinical trial involving multiple endpoints by adjusting the individual significance levels for each hypothesis, using preliminary data to obtain the optimal adjustments. The levels are constrained to control the familywise error rate. Power is defined as the expected number of significances, where expectations are taken with respect to the posterior distributions of the non-centrality parameters under non-informative priors. Sample size requirements for the replicate study are given. Intuitive principles such as downweighting insignificant variables from a preliminary study and giving primary endpoints more emphasis are justifiable within the conceptual framework.

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.

Cognitive performance on the Alzheimer's disease assessment scale : effect of education

The cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-Cog) is used to monitor disease progression and treatment efficacy in clinical trials of Alzheimers disease (AD). Using data from a 12-week drug trial, we retrospectively studied the effect of education on ADAS-Cog performance in a group of 444 patients with AD. The effect of education was statistically significant on baseline ADAS-Cog total scores. This effect remained statistically significant after controlling for age, gender, and dementia severity. Education effects were also statistically significant at week 12 for ADAS-Cog total and 10 of 11 subitem scores in 138 AD patients in the placebo arm of the trial. Post hoc analysis showed that non-high school graduates performed worse than those with greater educational levels across a broad range of cognitive domains. Our results, in conjunction with reports linking lower educational level with a higher risk for AD, suggest that educational level of patients be given consideration in the design and interpretation of cognitive tests in AD drug trials.

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.

NSAIDs and cognition in Alzheimer's disease

To the Editor: Recent studies have suggested a neuroprotective influence for nonsteroidal anti-inflammatory drugs (NSAIDs). [1-4] The Rotterdam Study, [1] the Canadian Study of Health and Aging, [2] and a co-twin control study [3] found that anti-inflammatory treatments were associated with a reduced risk of Alzheimers disease (AD). The Honolulu Heart Program study found that concurrent aspirin use was associated with superior cognitive scores in nondemented subjects. [4] We studied 444 AD subjects selected for a multicenter clinical trial to test the hypothesis that concurrent NSAID …