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

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

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

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

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.

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