Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescenceBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4320 (Published 16 September 2015) Cite this as: BMJ 2015;351:h4320
- Joanna Le Noury, research psychologist1,
- John M Nardo, retired clinical assistant professor2,
- David Healy, professor1,
- Jon Jureidini, clinical professor3,
- Melissa Raven, postdoctoral fellow3,
- Catalin Tufanaru, research associate4,
- Elia Abi-Jaoude, staff psychiatrist5
- 1School of Medical Sciences, Bangor University, Bangor, Wales, UK
- 2Emory University, Atlanta, Georgia, USA
- 3Critical and Ethical Mental Health Research Group, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
- 4Joanna Briggs Institute, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia
- 5Department of Psychiatry, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Correspondence to: J Jureidini
- Accepted 3 August 2015
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.
We thank Carys Hogan for database work and Tom Jefferson and Leemon McHenry for comments on earlier drafts.
The SmithKline Beecham study was registered as No 29060/329. The protocol was SmithKline Beecham study 29060/329, final clinical report (acute phase), appendix a, Protocol, from p 531.13 The study was funded by SmithKline Beecham. The data analysis protocol for RIAT reanalysis was submitted to GSK on 28 October 2013 and approved by GSK on 4 December 2013.
Contributors: Conception/design of the work: DH, JJ, JMN. Acquisition of data: JJ (negotiation with GSK); CT and EA-J (RIATAR); JMN (efficacy data using GSK online remote system); JLN (harms data using GSK online remote system). Data analysis: JMN (efficacy); JLN and DH (harms). Data interpretation: all authors. Drafting the work and revising it critically for important intellectual content, final approval of the version to be published: all authors. All authors agree to be accountable for all aspects of the work. JJ is guarantor. The first four authors made equal contribution to the paper.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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, and is on the advisory board of the Foundation for Excellence in Mental Health Care. DH and JLN are founder members of RxISK. 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. Some of the authors are in discussions with an academic publisher regarding adapting the case of Study 329 as a book for educational purposes.
Ethical approval: The protocol and statement of informed consent were approved by an institutional review board before each centre’s initiation, in compliance with 21 United States Code of Federal Regulations (CFR) Part 56. Written informed consent was obtained from each patient before entry into the study, in compliance with 21 CFR Part 50. Case report forms were provided for each patient’s data to be recorded (Final Clinical Report page 000030). The sample informed consent is provided in the appendix to the protocol, appendix C, pp 000590-4. No further information is available regarding the particular institutional review board that approved the study.
Transparency: JJ affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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