Time Course of Changes in Peripheral Blood Gene Expression During Medication Treatment for Major Depressive Disorder

Abstract

Changes in gene expression (GE) during antidepressant treatment may increase understanding of the action of antidepressant medications and serve as biomarkers of efficacy. GE changes in peripheral blood are desirable because they can be assessed easily on multiple occasions during treatment. We report here on GE changes in 68 individuals who were treated for 8 weeks with either escitalopram alone, or escitalopram followed by bupropion. GE changes were assessed after 1, 2, and 8 weeks of treatment, with significant changes observed in 156, 121, and 585 peripheral blood gene transcripts, respectively. Thirty-one transcript changes were shared between the 1- and 8-week time points (seven upregulated, 24 downregulated). Differences were detected between the escitalopram- and bupropion-treated subjects, although there was no significant association between GE changes and clinical outcome. A subset of 18 genes overlapped with those previously identified as differentially expressed in subjects with MDD compared with healthy control subjects. There was statistically significant overlap between genes differentially expressed in the current and previous studies, with 10 genes overlapping in at least two previous studies. There was no enrichment for genes overexpressed in nervous system cell types, but there was a trend toward enrichment for genes in the WNT/β-catenin pathway in the anterior thalamus; three genes in this pathway showed differential expression in the present and in three previous studies. Our dataset and other similar studies will provide an important source of information about potential biomarkers of recovery and for potential dysregulation of GE in MDD.

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

“…Here we present the largest study to date using next-generation sequencing to assess gene expression changes in SSRI treatment and treatment response in peripheral blood in patients from a randomized clinical trial suffering from MDD. While similar studies have been done before, they were focusing on different treatments [10][11][12][13][14][15][16], technologies [10][11][12][13][14][15], and did not have a placebo group [10][11][12][13][14][15][16]. Despite the bigger size of our study, we did not identify any significant genes after multiple test correction in comparison between the two time points or treatment and placebo.…”

“…Due to the limited access to neuronal tissue, transcriptomic studies have focused on gene expression changes in peripheral blood, which have shown to be a useful proxy for the measure of changes in gene expression in the central nervous system [9]. Few studies have investigated gene expression in peripheral blood related to treatment response [10][11][12][13][14][15] and antidepressant treatment [13,16]. However, the studies were not placebo controlled and they are smaller in sample size (N < 136) and limited in number of significant genes after adjustment for multiple testing.…”

Transcriptomic Studies of Antidepressant Action in Rodent Models of Depression: A First Meta-Analysis

“…Eight upregulated genes (Cfh, Ddr1, Gsn, Homer1, Igfbp6, Knstrn, Sel1l3, and Sema3a) and nine downregulated genes (Doc2b, Fat4, Itga4, Itsn1, Pcdh19, Rasgrf1, Scn3b, Tnxb, and Zfp316) are common to the signatures we obtained with both methods (Tables 6 and 7). frontal cortex (10) amygdala (9) nucleus accumbens (9) striatum (6) anterior cingulate cortex (5) hypothalamus (5) peripheral tissues (6) other brain regions (10) cerebrum (3) cortex ( 5)…”

“…For the moment, despite efforts in this direction, there is no reliable biomarker that can predict the therapeutic response in a patient suffering from an MDE, and there is no absolute predictor to guide the choice of the therapeutic approach [ 9 ]. For this, we believe it is necessary to know exactly what the effects of AD drugs are, in particular the changes in the gene expression program that they induce over time [ 10 ], in the parts of our body directly involved in the processing of emotions and mood.…”

Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs

“…In addition, there is reproducibility with findings generated by independent large scale genetic studies that came out after our analyses were completed, and were thus not included in our CFG approach. A number of their top findings were present in our candidate gene expression biomarkers for mood list that had survived our initial whole-genome, unbiased, within-subject discovery step, before any CFG literature prioritization: 15 out of their 36 top genes for bipolar disorder (Stahl et.al., their Table 1) [31], 187 out of 553 genes for depression (Coleman et.al, their Table S4) [32], 128 out of 268 genes for depression (Howard et al, their Table S9) [33], 487 out of 1291 genes for depression (Chan et al, their Tables S2, S3, S14, S17) [34], 491 out of 819 genes involved in antidepressant response [35], and 79 out of 223 genes for depression (Levey et al 2020 Medrxiv.org, their Supplementary Tables 1 and 3) (see Supplementary Information-Pathways, Predictions and Reproducibility file). This independent reproducibility of findings between our studies and the genetic studies, which are done in independent cohorts from ours, with independent methodologies, is reassuring, and provides strong convergent evidence for the validity and relevance of our approach and of their genetic approaches.…”