Study 329 continuation phase: Safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression.
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This is an analysis of the unpublished continuation phase of Study 329, the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the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Restoring Invisible and Abandoned Trials (RIAT) initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.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.ANOVA testing (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.
School of Medical Sciences, Bangor University, Wales, UK.
Joanna
J
Le Noury
Department of Psychiatry, Emory University, Atlanta, GA, USA.
John M
JM
Nardo
School of Medical Sciences, Bangor University, Wales, UK.
David
D
Healy
Critical and Ethical Mental Health Research Group, Robinson Research Institute, University of Adelaide, North Adelaide, SA, Australia.
Jon
J
Jureidini
Critical and Ethical Mental Health Research Group, Robinson Research Institute, University of Adelaide, North Adelaide, SA, Australia.
Melissa
M
Raven
Critical and Ethical Mental Health Research Group, Robinson Research Institute, University of Adelaide, North Adelaide, SA, Australia.
Catalin
C
Tufanaru
Department of Psychiatry, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Elia
E
Abi-Jaoude
D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007099:Imipramine / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D017374:Paroxetine / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D012008:Recurrence
D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; D007099:Imipramine
Paroxetine; SSRIs; depression; imipramine; relapse; taper phase
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11437014
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3303100