Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode

Abstract

To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.

Translational identification of transcriptional signatures of major depression and antidepressant response

“…We identified 15 candidates (5 overexpressed and 10 underexpressed in S-C vs. NS-C comparison; Supplementary Table S6A). We identified Cenpo, Mpp1 and Tbc1d10c which were genes also dysregulated in our previous human transcriptome data (Belzeaux et al, 2012; already validated from the classical threshold method selection) and identified three additional candidates: Fused in sarcoma (Fus), Immunoglobulin mu binding protein 2 (Ighmbp2), and Nucleotide binding protein 1 (Nubp1) for validation (Supplementary Table S6A, bold genes). Secondly, we extracted genes whose expression variations were negatively correlated between blood and the brain, and were different between S-C and NS-C mice groups.…”

“…For example, CMAS, encoding cytidine monophosphate N-acetylneuraminic acid synthetase, regulates brain sialylation, which is important for the development of brain structure and function (Yoo et al, 2015). CMAS was among the short list of blood-based biomarkers from the Redei et al (2014) studies, as well as among the candidate gene list from a transcriptome analysis on a naturalistic cohort of MDE patients responding to antidepressant treatment (Belzeaux et al, 2012). CMAS is also part of the most dysregulated transcripts in the UCMS procedure between stressed mice responding to fluoxetine and stressed mice that were either untreated or not responding to fluoxetine (Supplementary Table S5).…”

“…A search into the microarray data for probes showing stable expression in the stressed, non-stressed and Flx-treated animals but also blood, DG and ACC, revealed Rab5a as a moderately expressed reference gene. For human expression, we used CRYL1 as a reference gene for highly/moderately expressed genes and SV2A for weakly expressed genes (Belzeaux et al, 2012;Supplementary Table S2). Raw Ct values were obtained with manual baseline settings on the RQ Manager software (Applied Biosystems), and then the relative expression level of each mRNA was quantified by using the 2 −∆∆Ct method (Livak and Schmittgen, 2001).…”

“…on human blood samples (Belzeaux et al, 2012;Supplementary Table S5, underlines genes). Using this method, we selected the Acyl-CoA synthetase long-chain family member 1 (Acsl1), Cytidine monophosphate N-acetylneuraminic acid synthetase (Cmas), and Membrane palmitoylated protein 1 (Mpp1) as candidate genes underexpressed after stress and restored to basal level after fluoxetine treatment in responder mice ( Figure 3A and Supplementary Table S5, bold genes).…”

“…From the dysregulated in both blood and ACC (18 genes), and blood and DG (nine genes), we found five and three genes (Supplementary Table S4A, underlined genes), respectively, that were also dysregulated in a previous transcriptome analysis we conducted from blood samples from MDE patients and healthy controls (Belzeaux et al, 2012). We selected among them, TBC1 domain family member 10C (Tbcad10c) and Centromere protein O (Cenpo) genes (for convergence between blood and DG) as well as the Rho guanine nucleotide exchange factor 1 (Arhgef1) and Poly(A) binding protein 1 (Pabpn1) genes (for convergence between blood and ACC) as candidate biomarkers ( Figure 3A and Supplementary Table S4A, bold genes).…”