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Proposal 1273

Title of the Proposed Research

Post-hoc analysis of placebo-controlled trials in children and adolescents with depression

Lead Researcher

Elias Eriksson

Affiliation

University of Gothenburg

Funding Source

Supported by the Swedish Medical Council, Hållsten's Foundation, Söderberg's Foundation and the Swedish Brain Foundation. No funding from commercial organisations.

Potential Conflicts of Interest

Elias Eriksson has previously been on advisory boards for Lilly, Lundbeck and Pfizer, and has also received speaker honoraria from these companies. In addition, he has previously received research grants from Lundbeck.

Data Sharing Agreement Date

1 September 2015

Lay Summary

Background

Whereas >7% of the population in many countries are medicating with selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression and other conditions, many influential researchers and debaters have recently gained considerable attention when presenting the theory that these drugs are in fact devoid of any specific pharmacological antidepressant effect. Needless to say, the lack of consensus on this important matter is highly unsatisfactory, especially given the gravity of the disorders in question.

The questioning of the SSRIs has to a large extent been based on post hoc analyses of drug company-sponsored placebo-controlled trials. According to the critics, such analyses hence reveal that the possible superiority of the SSRIs over placebo is too small to be clinically meaningful, and possibly caused by side-effects breaking the blind so that the psychological placebo effect is enhanced in those given active treatment. Also, it has been argued that post-hoc analyses provide support for the conclusion that SSRIs enhance rather than reduce suicidal ideation.

The analyses underlying these conclusions have however been marred by considerable methodological shortcomings, including dealing with trial-level rather than subject-level data and/or focusing on a subjective selection of trials. We have hence started an extensive project aiming to solve the controversies regarding the SSRIs which is based on the fact that we have access to patient-level data from all company-sponsored placebo-controlled trials in adult depression regarding three of the four major first-generation SSRIs: paroxetine, sertraline and citalopram.

While the use of SSRIs for adult depression is controversial, their use in depressed children and adolescents is even more so. For this reason, we now aim to repeat all analyses we conduct on trials of adults also on trials in the young.

Aims

By conducting post hoc analyses of patient-level data from all drug company sponsored trials regarding paroxetine, citalopram and sertraline we hope to shed new light on the pros of cons of using SSRIs for the treatment of depression in the young. For example, we will assess i) the result of replacing the sum of the rating of all symptoms on a rating scale as effect parameter, ii) the possible relationship between side-effects and response, iii) the influence of drug treatment on the suicidality item at different time points and iv) the possible association between baseline symptom profile and response.

Design

Post hoc analyses will be conducted on the data received from GSK, as well as on corresponding data received from other companies (Lundbeck, Pfizer). These will largely follow a statistical plan decided upon a priori, but permitting certain deviations prompted by the results obtained.

Dissemination of results

The results will be published in an international scientific journal.

Study Data Provided

Study GSK-BRL-029060/329: Acute Phase: A Multi-center, Double-blind, Placebo-Controlled Study of Paroxetine and Imipramine in Adolescents with Unipolar Major Depression - Acute Phase
Study GSK-BRL-029060/377: A Double-blind, Multicentre Placebo-Controlled Study of Paroxetine in Adolescents with Unipolar Major Depression.
Study GSK-BRL-029060/701: A multi-center, double blind, placebo-controlled flexible dose study to evaluate the efficacy and safety of Paroxetine in children with major depression.
Study GSK-29060/329_1: A Multi-center, Double-blind, Placebo-Controlled Study of Paroxetine and Imipramine in Adolescents with Unipolar Major Depression - Continuation Phase.

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.