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Proposal 1103

Title of the Proposed Research

A study on the possible association between antidepressant response to SSRIs and proneness for side effects

Lead Researcher

Elias Eriksson, MD, PhD

Affiliation

University of Gothenburg
Gothenburg, Sweden

Funding Source

Sponsors are the Swedish Medical Research Council, Bertil Hållsten's Foundation and Torsten & Ragnar Söderberg's Foundation. There is no commercial sponsor.

Potential Conflicts of Interest

Lead Researcher: Elias Eriksson has been on advisory boards and received speaker's honoraria from Lundbeck, Lilly, Servier and JanssenCilag.

Since the SSRIs are no longer patent protected, the commercial implications of this project are close to zero. GSK and other companies are (and have been) requested to provide us with data files, but do not provide any other support, and have no commercial interest in the outcome

Data Sharing Agreement Date

10 Mar 2015

Lay Summary

BACKGRUND, RATIONAL AND AIM

Selective serotonin reuptake inhibitors (SSRIs) are first line of treatment for depression. In many countries, between 5-10% of the adult population are treated with these compounds.

Recently, however, the SSRIs have been questioned, some suggesting that they are devoid of specific antidepressant effects. According to these critics, the reason that patients with depression in placebo-controlled trials are more improved than those on placebo may be due to the fact that the presence of side effects make those on active treatment realize that they are not given placebo which may enhance the placebo effect. SSRIs outperforming placebo may hence, according to these writers, not be due to their effects on brain neurotransmission but a psychological result of their side effects.

If antidepressants exert a genuine, pharmacological antidepressant effect or not is a matter of considerable importance. In case the current questioning of these drugs is justified, and their apparent antidepressant effect is merely secondary to their side effects, their current wide spread use should be reconsidered. On the other hand, if the questioning is unfounded, it is important that this becomes clarified, so that doctors do not refrain from prescribing these drugs to patients needing them.

PROJECT PLAN

In an on-going project, we are making attempts to shed further light on why some SSRI trials fail to reveal a difference between active drug and placebo. For this purpose, pharmaceutical companies have provided us with patient-level data from controlled trials regarding the SSRIs paroxetine, sertraline, citalopram and escitalopram.

So far, our analyses have been focussed i) on how the outcome of SSRI trials are influenced by the shortcomings marring the most commonly used instrument for symptom assessment, i e the HDRS), and ii) the possible relationship between symptom profile at inclusion and response. In the subproject for which we now request data we will address the possibility association between side effects and response.

GSK has already kindly provided us with patient-level efficacy data from all the selected studies, as well as certain other relevant variables. What we now request, in order to perform the planned study, is i) patient level-based side effect data and ii) information on body weight (enabling us to adjust for differences in drug exposure).

These side-effect data will be used to examine to what extent spontaneously reported side effects are positively associated with response, both when assessed using the traditional primary effect parameter, i.e. the sum of the rating for all items on the instrument used for symptom assessment (which will usually be the Hamilton Depression rating scale) or various items or subscales extracted from this scale. Aspects such as age, gender, dose, body weight, length of treatment and premature discontinuation (i.e. drop-out) will also be taken into consideration.

Study Data Provided

Study 29060/785: A double-blind, placebo-controlled, fixed-dosage study comparing the efficacy and tolerability of paroxetine CR and citalopram to placebo in the treatment of Major Depressive Disorder with anxiety
Study 29060/115: A multicenter, randomized, double-blind, placebo-controlled comparison of paroxetine and fluoxetine in the treatment of major depressive disorder.
Study 29060/448: A Double-Blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Immediate Release Paroxetine and Modified Release Paroxetine in the Treatment of Major Depression
Study 29060/449: A Double-Blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Immediate Release Paroxetine and Modified Release Paroxetine in the Treatment of Major Depression
Study 29060/810: A double-blind, placebo-controlled, 3-arm, fixed-dose study of 12.5 mg/day and 25mg/day Paroxetine CR in the treatment of Major Depression.
Study 29060/874: Assessment of Paxil CR, 12.5 and 25 mg/day in treating elderly patients with major depression
Study 29060/01/001: A Phase II, Placebo-Controlled, Double-Blind Study of Paroxetine in Depressed Outpatients
Study 29060/02/001: A Double-Blind, Placebo-Controlled Study of Paroxetine in Depressed Outpatients
Study 29060/03/001: A Double-Blind, Imipramine- and Placebo-Controlled Study of Paroxetine in Depressed Outpatients
Study 29060/009: A Multicenter, Double-blind, Placebo-controlled Fixed-dose Evaluation of Four Doses of Paroxetine
Study 29060/128: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Comparison of Paroxetine and Fluoxetine in the Treatment of Major Depressive Disorder
Study 29060/251: A Double-Blind, Randomized Trial of Paroxetine Versus Placebo In Patients With Depression Accompanied by Anxiety
Study 29060/006: A study to assess the effectiveness and tolerance of paroxetine by double-blind comparison with placebo
Study 29060/276: A double-blind study to investigate the efficacy, safety and tolerability of Paroxetine in the treatment of depression in comparison with placebo
Study 29060/012: A Placebo-controlled, single-dose, five-period crossover evaluation of the pharmacokinetic properties of paroxetine when administered by the oral route
Study 29060/487: A Double-Blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Immediate Release Paroxetine and Controlled Release Paroxetine in the Treatment of Major Depression in Elderly Patients
Study 29060/625: A double-blind, placebo-controlled multi-centre study to evaluate the efficacy and tolerability of Paroxetine in the treatment of post-stroke depression.

Statistical Analysis Plan

This will be added after the research is published.

Publication Citation