Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials

Abstract

Objectives To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine. Design Systematic review and meta-analysis including unpublished data. Data sources Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin). Eligibility criteria Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression. Outcome measures Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes). Data extraction and data synthesis The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials. Results We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I 2 =67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I 2 =42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI

Most systematic reviews of adverse effects did not include unpublished data

“…This is despite empirical data suggesting that conclusions of systematic reviews can change when unpublished data are used. A classic example is the review of reboxetine, where publication bias has been clearly demonstrated (29,30) Although some systematic reviewers in this cohort contacted manufacturers, the decline in reviewers contacting manufacturers is of great concern and requires research into the reasons. This may ironically be a result of the recent publicity on the difficulties experienced by reviewers when attempting to obtain unpublished data from manufacturers (31) and the very long delays before a response is received (32), or with such small numbers may not be an overall trend.…”

Disclosure of Clinical Trial Results When Product Development Is Abandoned

“…Pharmaceutical company sponsors o en do not submit the results of negative drug trials for publication (11)(12)(13) and may downplay adverse events (14,15). Selective reporting of clinical trial results can yield awed estimates of drug e ectiveness and provide an erroneous impression of the risk-bene t ratio of treatments, leading physicians to make inappropriate prescribing decisions (16).…”

The role of the funnel plot in detecting publication and related biases in meta-analysis

“…2 Publication bias in medical research continues to be a problem today, as shown by a recent meta-analysis which compared the effectiveness of reboxetine with selective serotonin reuptake inhibitors (SSRI) or placebo for treating major depression. 8 The investigators found that 74% of data were not published and 'published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm'. 8 Previous findings of reboxetine's effectiveness were reversed.…”

“…8 The investigators found that 74% of data were not published and 'published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm'. 8 Previous findings of reboxetine's effectiveness were reversed.…”

“…2,3,[5][6][7][8] In an early example (1986), Simes compared the benefit of treating advanced ovarian cancer using an alkylating agent with combination chemotherapy. He conducted a meta-analysis of published trials only and a meta-analysis of all registered trials.…”