Barbara Nussbaumer

Average effect estimates remain similar as evidence evolves from single trials to high-quality bodies of evidence: a meta-epidemiologic study

OBJECTIVES The objective of our study was to use a diverse sample of medical interventions to assess empirically whether first trials rendered substantially different treatment effect estimates than reliable, high-quality bodies of evidence. STUDY DESIGN AND SETTING We used a meta-epidemiologic study design using 100 randomly selected bodies of evidence from Cochrane reports that had been graded as high quality of evidence. To determine the concordance of effect estimates between first and subsequent trials, we applied both quantitative and qualitative approaches. For quantitative assessment, we used Lins concordance correlation and calculated z-scores; to determine the magnitude of differences of treatment effects, we calculated standardized mean differences (SMDs) and ratios of relative risks. We determined qualitative concordance based on a two-tiered approach incorporating changes in statistical significance and magnitude of effect. RESULTS First trials both overestimated and underestimated the true treatment effects in no discernible pattern. Nevertheless, depending on the definition of concordance, effect estimates of first trials were concordant with pooled subsequent studies in at least 33% but up to 50% of comparisons. The pooled magnitude of change as bodies of evidence advanced from single trials to high-quality bodies of evidence was 0.16 SMD [95% confidence interval (CI): 0.12, 0.21]. In 80% of comparisons, the difference in effect estimates was smaller than 0.5 SMDs. In first trials with large treatment effects (>0.5 SMD), however, estimates of effect substantially changed as new evidence accrued (mean change 0.68 SMD; 95% CI: 0.50, 0.86). CONCLUSION Results of first trials often change, but the magnitude of change, on average, is small. Exceptions are first trials that present large treatment effects, which often dissipate as new evidence accrues.

Efficacy and Harms of Second-generation Antidepressants for the Prevention of Seasonal Affective Disorder: a Systematic Review

Introduction Seasonal Affective Disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occur during autumn or winter and remit in spring. Second-generation antidepressants (SGAs) are established interventions to treat acute episodes of SAD. However, little is known about the efficacy and potential harms of these interventions for preventing SAD. Objectives To assess the efficacy and safety of SGAs to prevent SAD and improve patient–centered outcomes in adults with a history of SAD. Methods We searched the Cochrane Depression, Anxiety and Neuorosis Review Groups specialised register, EMBASE, MEDLINE, PsycINFO and the Cochrane Central Register of Controlled Trials. In addition, we searched pharmaceutical industry trials registers via the Internet to identify unpublished trial data. We also conducted grey literature searches and handsearches of pertinent reference lists. Two authors reviewed the evidence, abstracted data, and assessed risk of bias. We pooled data for meta-analysis when participant groups were similar and the studies assessed the same treatments with the same comparator. Results We did not find eligible studies for most comparisons. We included three RCTs comparing bupropion XL with placebo. Statistically significantly fewer patients treated with bupropion experienced the onset of a major depressive episode during winter months. The overall risk of adverse events was similar between treatment groups. However, bupropionn-treated patients had significantly higher risk for headache, insomnia, and nausea. Conclusion The evidence base on SGA treatment to prevent SAD is limited. Future studies are needed to provide a sufficient evidence base for clinical decisionmaking.

Comparative Benefits and Harms of Second-generation Antidepressants in the Pharmacologic Treatment of Depression in Older Adults: Systematic Revview and Network Meta-analysis

Introduction Second-generation antidepressants dominate the medical management of major depressive disorder (MDD). Some have questioned whether these medications are equally effective in older adults. Objectives To compare the benefits and harms of bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, venlafaxine, vilazodone, and vortioxetine for the treatment of MDD in older adults and to assess whether efficacy differed in older adults compared with the adults of all ages. Methods To identify relevant studies, we searched MEDLINE, EMBASE, the Cochrane Library, PsycINFO, and CINAHL through December, 2014. Two persons independently reviewed the literature, abstracted data, and rated the risk of bias. We conducted mixed treatment comparisons to derive indirect estimates of the comparative efficacy among all second-generation antidepressants and we conducted meta-regression by assessing whether efficacy differed in trials that enrolled older adults compared with trials that enrolled adults of any age. The outcome was treatment response as measured by ≥50% improvement from baseline on the HAM-D. Results Evidence on older adults compared with adults of any age is sparse. In older adults, evidence indicates that efficacy does not differ substantially among second-generation antidepressants; however, there may be some differences in adverse events. Our meta-regression found a trend toward lesser efficacy of SGAs in older adults than adults of any age. Conclusions Our findings suggests that SGAs may be less effective in older populations. There is a great need for research focusing directly on the efficacy and safety of SGAs in older adults.

EPA-1042 – Immediate vs. extended release second-generation antidepressants in the treatment of major depressive disorder – a systematic review

Introduction Major depressive disorder (MDD) has harmful effects on an individuals personal life. In the European Union, in any given year, about 7% of all adults suffer from it. Primary choice of medical management is pharmacotherapy - second generation antidepressants (SGA). Some SGA are available as both immediate-release (IR), and extended-release formulations. Advantages of extended-release formulations may be the potentially improved adherence, and tolerability. Objectives The objective of this systematic review was to assess the comparative efficacy, risk of harms, and adherence of IR- and extendedrelease antidepressants for the treatment of MDD. Aims To systematically review the evidence on differences between IR and extended-release formulations to provide an objective basis for clinical decision-making. Methods Abstracts were retrieved from PubMed, EMBASE, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to October 2012 as well as from hand search. We dually reviewed abstracts and full-texts and assessed quality ratings. We conducted network meta-analyses using Bayesian methods, due to the lack of head-to-head trials. Response on the Hamilton Depression Rating Scale (HAM-D) was our outcome measure. Results We located seven head-to-head trials and 94 placebo and active controlled trials for network meta-analysis. Overall, our analyses show that IR and extended-release formulations of bupropion, trazodone, venlafaxine and paroxetine have similar efficacy. However, evidence suggests that there might be a difference between formulations based on adverse events and adherence. Conclusion Current evidence couldn’t prove a significant difference in the efficacy of IR- and extended-release formulations.