Abstract

A better understanding of the biological factors underlying antidepressant treatment in patients with major depressive disorder (MDD) is needed. We perform gene expression analyses and explore sources of variability in peripheral blood related to antidepressant treatment and treatment response in patients suffering from recurrent MDD at baseline and after 8 weeks of treatment. The study includes 281 patients, which were randomized to 8 weeks of treatment with vortioxetine (N = 184) or placebo (N = 97). To our knowledge, this is the largest dataset including both gene expression in blood and placebo-controlled treatment response measured by a clinical scale in a randomized clinical trial. We identified three novel genes whose RNA expression levels at baseline and week 8 are significantly (FDR < 0.05) associated with treatment response after 8 weeks of treatment. Among these genes were SOCS3 (FDR = 0.0039) and PROK2 (FDR = 0.0028), which have previously both been linked to depression. Downregulation of these genes was associated with poorer treatment response. We did not identify any genes that were differentially expressed between placebo and vortioxetine groups at week 8 or between baseline and week 8 of treatment. Nor did we replicate any genes identified in previous peripheral blood gene expression studies examining treatment response. Analysis of genome-wide expression variability showed that type of treatment and treatment response explains very little of the variance, a median of <0.0001% and 0.05% in gene expression across all genes, respectively. Given the relatively large size of the study, the limited findings suggest that peripheral blood gene expression might not be the best approach to explore the biological factors underlying antidepressant treatment.

Highlights

  • Major depressive disorder (MDD) is a commonly occurring mental disorder [1, 2]

  • Core symptoms of MDD listed by the Diagnostic and Statistical Manual IV (DSM-IV) include, sleep disturbance, dysphoria, anhedonia, and cognitive disabilities [3]

  • Second-generation antidepressants are generally beneficial in the treatment of MDD, 37% of patients do not respond during 6–12 weeks of treatment and 53% of patients do not achieve remission [7]

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Summary

Introduction

Major depressive disorder (MDD) is a commonly occurring mental disorder [1, 2]. Core symptoms of MDD listed by the Diagnostic and Statistical Manual IV (DSM-IV) include, sleep disturbance, dysphoria, anhedonia, and cognitive disabilities [3]. The most prescribed antidepressant medications for the treatment of MDD are second-generation antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors, which compared to firstgeneration antidepressants are safer and better tolerated [7]. Individual response to a specific treatment can vary widely, and today limited evidence can guide the choice of one medication over another based on greater effectiveness and efficacy [7, 8]. The selection of a first-line medication for a given patient is primarily the clinician’s subjective opinion. To better understand treatment response and to guide the choice of antidepressant medication for each individual patient, we need to learn more about the biological factors underlying antidepressant treatment response and the mechanism of action of antidepressants

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