Study 329 continuation phase: safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression

Joanna Le Noury, John M. Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: This is an analysis of the unpublished continuation phase of Study 329, the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the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 objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.

Methods: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43%) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVAtesting (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics.

Results: Of patients entering the continuation phase, 15 of 49 for paroxetine (31%), 12 of 39 for imipramine (31%) and 12 of 31 for placebo (39%) completed as responders. Across the study, 25 patients on paroxetine relapsed (41% of those showing an initial response), 15 on imipramine (26%), and 10 on placebo (21%). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events.

Conclusions: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.

LanguageEnglish
Pages143-161
Number of pages19
JournalInternational Journal of Risk and Safety in Medicine
Volume28
Issue number3
DOIs
Publication statusPublished - 2016
Externally publishedYes

Bibliographical note

Copyright the IOS Press and the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Paroxetine
  • SSRIs
  • imipramine
  • depression
  • relapse
  • taper phase

Cite this

Le Noury, Joanna ; Nardo, John M. ; Healy, David ; Jureidini, Jon ; Raven, Melissa ; Tufanaru, Catalin ; Abi-Jaoude, Elia. / Study 329 continuation phase : safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression. In: International Journal of Risk and Safety in Medicine. 2016 ; Vol. 28, No. 3. pp. 143-161.
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title = "Study 329 continuation phase: safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression",
abstract = "Objective: This is an analysis of the unpublished continuation phase of Study 329, 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 objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.Methods: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43{\%}) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVAtesting (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics.Results: Of patients entering the continuation phase, 15 of 49 for paroxetine (31{\%}), 12 of 39 for imipramine (31{\%}) and 12 of 31 for placebo (39{\%}) completed as responders. Across the study, 25 patients on paroxetine relapsed (41{\%} of those showing an initial response), 15 on imipramine (26{\%}), and 10 on placebo (21{\%}). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events.Conclusions: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.",
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Study 329 continuation phase : safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression. / Le Noury, Joanna; Nardo, John M.; Healy, David; Jureidini, Jon; Raven, Melissa; Tufanaru, Catalin; Abi-Jaoude, Elia.

In: International Journal of Risk and Safety in Medicine, Vol. 28, No. 3, 2016, p. 143-161.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Study 329 continuation phase

T2 - International Journal of Risk and Safety in Medicine

AU - Le Noury, Joanna

AU - Nardo, John M.

AU - Healy, David

AU - Jureidini, Jon

AU - Raven, Melissa

AU - Tufanaru, Catalin

AU - Abi-Jaoude, Elia

N1 - Copyright the IOS Press and the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2016

Y1 - 2016

N2 - Objective: This is an analysis of the unpublished continuation phase of Study 329, 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 objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.Methods: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43%) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVAtesting (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics.Results: Of patients entering the continuation phase, 15 of 49 for paroxetine (31%), 12 of 39 for imipramine (31%) and 12 of 31 for placebo (39%) completed as responders. Across the study, 25 patients on paroxetine relapsed (41% of those showing an initial response), 15 on imipramine (26%), and 10 on placebo (21%). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events.Conclusions: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.

AB - Objective: This is an analysis of the unpublished continuation phase of Study 329, 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 objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.Methods: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients (43%) entered the six-month continuation phase (paroxetine n = 49; imipramine n = 39; placebo n = 31), in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse (based on Hamilton Depression Scale scores) across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVAtesting (generalized linear model) using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics.Results: Of patients entering the continuation phase, 15 of 49 for paroxetine (31%), 12 of 39 for imipramine (31%) and 12 of 31 for placebo (39%) completed as responders. Across the study, 25 patients on paroxetine relapsed (41% of those showing an initial response), 15 on imipramine (26%), and 10 on placebo (21%). In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events.Conclusions: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.

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KW - SSRIs

KW - imipramine

KW - depression

KW - relapse

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