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Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (N = 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (CERCAM, DARS-AS1, FAM228B, HBEGF) whose change over time was independently associated with a response status. For all except HBEGF, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in DARS-AS1 and HBEGF also differentiated later responders from nonresponders. Additionally, HBEGF was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.

International audience; Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate

Although circular RNAs (circRNAs) are abundantly expressed in the mammalian brain and preferentially-derived from synaptic genes, their relevance for brain function and psychiatric disorders and their interactions with neuronal protein-coding gene expression still remain poorly understood. Here we show that alterations in the levels of circHomer1, a neuronal-enriched circRNA altered in psychiatric disease that has been shown to influence OFC-mediated cognitive flexibility, are inversely associated with the relative expression of the long linear HOMER1B mRNA isoform in both the orbitofrontal cortex (OFC) and stem cell-derived neuronal cultures of subjects with psychiatric disorders. Using in vivo mature circHomer1-specific knockdown (KD) in adult mouse OFC, we further demonstrate that downregulation of circHomer1 results in increased synaptic expression of Homer1b mRNA. Furthermore, we utilize circRNA antisense purification to show that circHomer1 directly binds to Homer1b mRNA. We then demonstrate that in vivo Homer1b-specific KD increases synaptic circHomer1 levels within the OFC and improves OFC-mediated behavioral flexibility. Importantly, we show that double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we demonstrate that circHomer1 is an experience-dependent circRNA that is significantly altered during chance reversal learning and that variability in its baseline expression within the OFC is significantly inversely correlated to behavioral performance during chance reversal learning. Taken together our data provide novel mechanistic insights into the importance of circRNAs in brain function and disease.

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response., It is not fully understood why some patients respond or do not respond to antidepressant treatment. Here the authors show that in the blood of individuals with depression, GPR56 expression increases in responders to antidepressant treatment, but not in non-responders.

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b-specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease.

Major depressive disorder (MDD) is a serious and common psychiatric disorder that affects millions of people worldwide. The most common treatment methods for MDD are antidepressant drugs, many of which act by regulating monoamines by inhibiting pre-synaptic reuptake and/or by modulating monoamine receptors. Despite advances in antidepressants and other treatment options, therapy is often based on subjective decisions made by the physician. Moreover, it requires time to determine treatment outcome and to define whether the prescribed treatment is effective. Biomarkers may help identify individuals with MDD who are more likely to respond to specific antidepressant treatment and may thus provide more objectivity in treatment decision making. MicroRNA as biomarkers of antidepressant response has engendered substantial enthusiasm. In this review, we give a detailed overview of biomarkers, particularly the major studies that have investigated microRNA in relationship to antidepressant treatment response.

Background Antidepressant treatment is associated with a high rate of poor response, and thus, biomarker development is warranted. Methods We aimed to synthesize studies investigating gene expression, small RNAs, and epigenomic biomarkers of antidepressant response. We conducted a narrative review of the literature. Results Firstly, we detailed the challenges involved, in terms of biological tissues, relevant study time frames, and mandatory statistical tools. Secondly we synthesized results obtained in gene expression studies, focusing mainly on genome-wide studies, particularly small non-coding RNA, including micro-RNA and other small RNA species. In addition, we reviewed the potential biomarkers of antidepressant response arising from studies investigating DNA methylation variation and histone modifications. Limitations We did not conduct a meta-analysis due to the heterogeneity of the study. Conclusion Although promising, the field of gene expression and epigenomic biomarkers of antidepressant response is still in its infancy, and needs further development to define useful biomarkers in clinical practice.

Major depressive disorder is a chronic and debilitating illness. It is most commonly treated with antidepressant drugs, however, as the majority of patients do not respond on their first trial or following several adequate trials, there is great interest in identifying biological factors that may help select the most appropriate treatment for each patient and in understanding biological processes that mediate treatment response. Epigenetic factors, such as non-coding RNAs (ncRNAs), hold potential as biomarkers of antidepressant response. In this chapter, we review key methodological considerations when investigating ncRNA biomarkers, including biological samples and technologies which have been used in these studies. Secondly, we summarize findings from studies investigating ncRNAs in antidepressant treatment response. Finally, we discuss some of the future directions which will be necessary for the development of clinically relevant epigenetic tools.

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems., Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.

Major depressive disorder (MDD) is a common psychiatric disorder affecting millions of people worldwide, yet its etiology remains elusive. The last decades have seen great advances in our understanding of the genome structure and functional organization. Noncoding RNAs (ncRNAs) are RNAs that do not code for proteins but have important regulatory roles. The investigation of ncRNAs as regulators of gene expression has been a topic of growing interest in health research, including in studies investigating etiological and therapeutic factors in major depression. Several different species of ncRNAs have been identified in association to and have shown to be dysregulated in depressed individuals or in animal models of depression. This review will detail the complex relation between ncRNAs and major depression and the studies that propose mechanisms and pathways that specific ncRNAs may be involved in major depression.

Major depressive disorder (MDD) is a common psychiatric disorder affecting millions of people worldwide, yet its etiology remains elusive. The last decades have seen great advances in our understanding of the genome structure and functional organization. Noncoding RNAs (ncRNAs) are RNAs that do not code for proteins but have important regulatory roles. The investigation of ncRNAs as regulators of gene expression has been a topic of growing interest in health research, including in studies investigating etiological and therapeutic factors in major depression. Several different species of ncRNAs have been identified in association to and have shown to be dysregulated in depressed individuals or in animal models of depression. This review will detail the complex relation between ncRNAs and major depression and the studies that propose mechanisms and pathways that specific ncRNAs may be involved in major depression.