Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trialsBMJ 2010; 341 doi: http://dx.doi.org/10.1136/bmj.c4737 (Published 12 October 2010) Cite this as: BMJ 2010;341:c4737
- Dirk Eyding, project manager1,
- Monika Lelgemann, senior researcher2,
- Ulrich Grouven, statistician34,
- Martin Härter, head of department of medical psychology5,
- Mandy Kromp, statistician3,
- Thomas Kaiser, head of department of drug assessment3,
- Michaela F Kerekes, data manager3,
- Martin Gerken, researcher6,
- Beate Wieseler, deputy head of department of drug assessment3
- 1German Cancer Society, Berlin, Germany (former affiliation: Institute for Quality and Efficiency in Health Care)
- 2Medical Advisory Service of Social Health Insurance, Essen, Germany
- 3Institute for Quality and Efficiency in Health Care, Cologne, Germany
- 4Hanover Medical School, Hanover, Germany
- 5University Clinic Eppendorf, Hamburg, Germany
- 6Health Technology Assessment Centre, University of Bremen, Bremen, Germany
- Correspondence to: B Wieseler, Institute for Quality and Efficiency in Health Care, Dillenburger Strasse 27, 51105 Cologne, Germany
- Accepted 16 August 2010
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Design Systematic review and meta-analysis including unpublished data.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trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin).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 (I2=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; I2=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 1.06 to 3.05; P=0.031). 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.
Conclusions Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.
We thank Katharina Quitmann, Yvonne-Beatrice Schüler, and Volker Vervölgyi for general support, and Natalie McGauran for editorial support. We also thank Elke Hausner for developing the search strategy and performing the literature search. All persons listed above are employed by the Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, Germany.
Contributors: DE coordinated and BW supervised the review. DE, ML, UG, MH, TK, MG, and BW designed the protocol. UG and MK planned and did the statistical analyses. DE, ML, and MG selected studies. MFK did the data extraction. All authors (except MFK) assessed studies. DE wrote the first draft of the paper. All authors contributed to data interpretation and to critical revision of the paper, and have seen and approved the final version. BW is the guarantor.
Funding: This work was supported by IQWiG. The original health technology assessment report was commissioned by the German Federal Joint Committee. MG, MH, and ML acted as consultants for the preparation of the original health technology assessment report. For this they were reimbursed by IQWiG.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any company for the submitted work; DE was employed by H Lundbeck A/S, Copenhagen, between January 2006 and April 2007; MH received remuneration from Boehringer Ingelheim and Lilly Pharma for three talks on depression guidelines in 2008; and UG, MK, TK, MFK, and BW are employees of IQWiG. DE is a former employee of IQWiG. In order to produce unbiased health technology assessment reports, the institute depends on access to all of the relevant data on the topic under investigation. The authors therefore support the mandatory worldwide establishment of trial registries and study results databases. ML and MH were involved in the development of the German Disease Management Guideline on Depression.
Ethical approval: Not required.
Data sharing: The full (German) version of the health technology assessment report (including the search strategy) and the clinical study reports on reboxetine are available on the IQWiG website (www.iqwig.de).
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