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Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

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 th...

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Autores principales: Le Noury, Joanna, Nardo, John M, Healy, David, Jureidini, Jon, Raven, Melissa, Tufanaru, Catalin, Abi-Jaoude, Elia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group Ltd. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572084/
https://www.ncbi.nlm.nih.gov/pubmed/26376805
http://dx.doi.org/10.1136/bmj.h4320
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author Le Noury, Joanna
Nardo, John M
Healy, David
Jureidini, Jon
Raven, Melissa
Tufanaru, Catalin
Abi-Jaoude, Elia
author_facet Le Noury, Joanna
Nardo, John M
Healy, David
Jureidini, Jon
Raven, Melissa
Tufanaru, Catalin
Abi-Jaoude, Elia
author_sort Le Noury, Joanna
collection PubMed
description 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.
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spelling pubmed-45720842015-09-27 Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence Le Noury, Joanna Nardo, John M Healy, David Jureidini, Jon Raven, Melissa Tufanaru, Catalin Abi-Jaoude, Elia BMJ Research 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. BMJ Publishing Group Ltd. 2015-09-16 /pmc/articles/PMC4572084/ /pubmed/26376805 http://dx.doi.org/10.1136/bmj.h4320 Text en © Le Noury et al 2015 http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Le Noury, Joanna
Nardo, John M
Healy, David
Jureidini, Jon
Raven, Melissa
Tufanaru, Catalin
Abi-Jaoude, Elia
Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
title Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
title_full Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
title_fullStr Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
title_full_unstemmed Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
title_short Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
title_sort restoring study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572084/
https://www.ncbi.nlm.nih.gov/pubmed/26376805
http://dx.doi.org/10.1136/bmj.h4320
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