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Randomized Controlled Trial
. 2015 Sep 16;351:h4320.
doi: 10.1136/bmj.h4320.

Restoring Study 329: Efficacy and Harms of Paroxetine and Imipramine in Treatment of Major Depression in Adolescence

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Free PMC article
Randomized Controlled Trial

Restoring Study 329: Efficacy and Harms of Paroxetine and Imipramine in Treatment of Major Depression in Adolescence

Joanna Le Noury et al. BMJ. .
Free PMC article

Abstract

Objectives: To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.

Design: Double blind randomised placebo controlled trial.

Setting: 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998.

Participants: 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality.

Interventions: Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo.

Main outcome measures: The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified.

Results: The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.

Conclusions: Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: DH has been and is an expert witness for plaintiffs in legal cases involving GlaxoSmithKline’s drug paroxetine. He is also a witness for plaintiffs in actions involving other antidepressants with the same mechanism of action as paroxetine. JJ has been paid by Baum, Hedlund, Aristei and Goldman, Los Angeles, CA, to provide expert analysis and opinion about documents obtained from GlaxoSmithKline in a class action over Study 329, and from Forest in relation to paediatric citalopram randomised controlled trials.

Figures

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Fig 1 Group allocations and discontinuations in trial of paroxetine and imipramine in treatment of major depression in adolescence
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Fig 2 Differences in HAM-D scores in study of efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence (table 2 shows numerical values). Points are least squares means (95% CI). LOCF=last observation carried forward, MI=multiple imputation
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Fig 3 Differences in HAM-D % responders in study of efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence (table 2 shows numerical values). LOCF=last observation carried forward, MI=multiple imputation
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Fig 4 Timing of suicidal and self injurious events in Study 329, Keller and colleagues, and RIAT analysis

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References

    1. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865. - PMC - PubMed
    1. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40:762-72. - PubMed
    1. McHenry L, Jureidini J. Industry-sponsored ghostwriting in clinical trial reporting: a case study. Account Res 2008;15:152-67. - PubMed
    1. Jureidini J, McHenry L, Mansfield P. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Saf Med 2008;20:73-81.
    1. Jureidini J, McHenry L. Conflicted medical journals and the failure of trust. Account Res 2011;18:45-54. - PubMed

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