Efficacy and tolerability of SNRIs in depression.

Efficacy and tolerability of SNRIs in depression.

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

Elias Eriksson has been on advisory boards and received speaker's honoraria from Lundbeck, Lilly, Servier and JanssenCilag.Received speakers' fees from Servier.

Background
Over 7% of the population in many countries are currently medicating with modern antidepressants, i.e. selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenalin reuptake inhibitors (SNRIs). However, many influential researchers and debaters have recently gained considerable attention when presenting the theory that these drugs are in fact devoid of any specific 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 modern antidepressants has to a large extent been based on post hoc analyses (analyses performed after the experiment was concluded, looking for patterns that were not specified beforehand) of drug company-sponsored placebo-controlled trials. According to the critics, such analyses hence reveal that the possible superiority of the SNRIs/SSRIs over placebo is too small to be clinically meaningful. Also, it has been argued that post-hoc analyses provide support for the conclusion that these drugs enhance rather than reduce suicidal ideation.

The analyses underlying these conclusions have however been marred by considerable methodological shortcomings, including being based on trial-level rather than patient-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 SNRIs and 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.

So far, this project has resulted in two publications: one showing the consistent superiority of SSRIs over placebo when using the single item depressed mood from the HDRS 17-scale as an effect parameter, instead of the scale as a whole (Hieronymus et al, Mol Psych 21: 523-530, 2016) and one demonstrating how inclusion of suboptimal doses in meta-analyses (analyses that combine the results of multiple studies) may have led to an underrating of the effect size of the SSRIs (Hieronymus et al, Transl Psych e834, 2016). We now want to expand this project to comprise also an SNRI, duloxetine.

Aims
The aim of this project is to explore the following aspects of the clinical profile of duloxetine in adult depression: i) the effect on different symptoms, ii) then time course for the effect on different symptoms, iii) the possible relationship between side effects and response, iv) the possible association between baseline symptom profile and response, v) the possible influence of gender and age on response, vi) the possible dose-dependency of the response and vii) possible differences versus SSRIs with respect to effect on individual items.

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