A large-scale genome-wide gene expression analysis in peripheral blood identifies very few differentially expressed genes related to antidepressant treatment and response in patients with major depressive disorder

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.

Trial registration: ClinicalTrials.gov NCT01422213.

Figures

Fig. 1. Examination of genes correlated to treatment response.

Plots of log2-transformed TMM-normalized gene expression as a function of percentage improvement in MADRAS total score at week 8 from baseline for PROK2 (A) and SOCS3 (B). Percentage improvement is plotted to account for the MADRS score at baseline, since change in MADRS score depends on the MADRS score at baseline. Boxplots of log2-transformed TMM-normalized gene expression difference between responders and non-responders for each timepoint (baseline and week 8) and each treatment type (placebo and vortioxetine) for PROK2 (C) and SOCS3 (D). PBL = samples from placebo-treated patients at baseline; PW8 = samples from placebo-treated patients at week 8; TBL = samples from vortioxetine-treated patients at baseline; TW8 = samples from vortioxetine-treated patients at week 8. Response is defined as >50% decrease in the MADRS total score from baseline. E Bar plot of variance partitioned on the covariates in the experimental design for the nine genes, with an FDR < 0.05, related to treatment response.

Fig. 2. Examination of the distribution of variance across all genes.

A Violin plot of the distribution of variance across all genes for the covariates in the experimental design. Inside the violin plots are boxplots. B Bar plot of variance partitioned on the covariates in the experimental design for the genes highlighted in plot A. The variance of the covariates for each gene sum to 1. C Violin plot of the distribution of variance across all genes for the covariates in the experimental design and explorative variables.