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Review
. 2010 Oct 12;341:c4737.
doi: 10.1136/bmj.c4737.

Reboxetine for Acute Treatment of Major Depression: Systematic Review and Meta-Analysis of Published and Unpublished Placebo and Selective Serotonin Reuptake Inhibitor Controlled Trials

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Free PMC article
Review

Reboxetine for Acute Treatment of Major Depression: Systematic Review and Meta-Analysis of Published and Unpublished Placebo and Selective Serotonin Reuptake Inhibitor Controlled Trials

Dirk Eyding et al. BMJ. .
Free PMC article

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Design: Systematic review and meta-analysis including unpublished data.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trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin).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 Publication bias was measured by comparing results of published and unpublished trials.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 Data on 74% (3033/4098) of these patients were unpublished.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 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.

Conflict of interest statement

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.

Figures

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Fig 1 Flowchart of study selection. *Excluding long term acute treatment trial
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Fig 2 Forest plot showing meta-analyses of remission and response rates for trials that compared reboxetine with placebo. Empty boxes show published studies and filled boxes show unpublished studies. Study 091 is not included in the pooled analysis of response of reboxetine versus placebo because of high heterogeneity (see text for details). CI, confidence interval; n, number of patients with event; N, number of patients in treatment group
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Fig 3 Forest plot showing meta-analyses of remission and response rates for trials that compared reboxetine with selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine, and citalopram). Empty boxes show published studies and filled boxes show unpublished studies. Empty diamonds show subtotals (individual SSRIs) and filled diamonds show overall totals (all SSRIs). CI, confidence interval; n, number of patients with event; N, number of patients in treatment group
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Fig 4 Forest plot showing meta-analyses of rates of patients with at least one adverse event and rates of withdrawals owing to adverse events for trials that compared reboxetine with placebo. Empty boxes show published studies and filled boxes show unpublished studies. CI, confidence interval; n, number of patients with event; N, number of patients in treatment group
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Fig 5 Forest plot showing meta-analyses of rates of patients with at least one adverse event and rates of withdrawals owing to adverse events for trials that compared reboxetine with selective serotonin reuptake inhibitors (SSRIs; fluoxetine and paroxetine). Empty boxes show published studies and filled boxes show unpublished studies. Empty diamonds show subtotals (individual SSRIs) and filled diamonds show overall totals (all SSRIs). CI, confidence interval; n, number of patients with event; N, number of patients in treatment group
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Fig 6 Forest plot showing meta-analyses of published, unpublished, and all trials. Publication bias (right column) is presented as the ratio of odds ratios of published results versus overall results. The extent of publication bias is expressed as percentage change between the analysis of published trials only and the analysis of all trials (that is, publication bias=100×(ORpublished data/ORtotal data–1)). *Fluoxetine controlled studies only

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References

    1. Hajos M, Fleishaker JC, Filipiak-Reisner JK, Brown MT, Wong EH. The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile. CNS Drug Rev 2004;10:23-44. - PMC - PubMed
    1. Page ME. The promises and pitfalls of reboxetine. CNS Drug Rev 2003;9:327-42. - PMC - PubMed
    1. Pharmacia Limited. Summary of product characteristics: Edronax 4 mg tablets. 2009. www.medicines.org.uk/EMC/medicine/8386/SPC/Edronax+4mg+Tablets/#INDICATIONS.
    1. Preskorn SH. Reboxetine: a norepinephrine selective reuptake pump inhibitor. J Psychiatr Pract 2004;10:57-63. - PubMed
    1. Schwabe U, Paffrath D. [Drug prescription report] [German]. Springer, 2009.
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