SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder.

Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted.

Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile. METHODS: EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico. RESULTS: Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200 nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity. CONCLUSION: We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD.

Relation of hippocampal volume and SGK1 gene expression to treatment remission in major depression is moderated by childhood maltreatment: A CAN-BIND-1 report.

Preclinical research implicates stress-induced upregulation of the enzyme, serum- and glucocorticoid-regulated kinase 1 (SGK1), in reduced hippocampal volume. In the current study, we tested the hypothesis that greater SGK1 mRNA expression in humans would be associated with lower hippocampal volume, but only among those with a history of prolonged stress exposure, operationalized as childhood maltreatment (physical, sexual, and/or emotional abuse). Further, we examined whether baseline levels of SGK1 and hippocampal volume, or changes in these markers over the course of antidepressant treatment, would predict treatment outcomes in adults with major depression [MDD]. We assessed SGK1 mRNA expression from peripheral blood, and left and right hippocampal volume at baseline, as well as change in these markers over the first 8 weeks of a 16-week open-label trial of escitalopram as part of the Canadian Biomarker Integration Network in Depression program (MDD [n = 161] and healthy comparison participants [n = 91]). Childhood maltreatment was assessed via contextual interview with standardized ratings. In the full sample at baseline, greater SGK1 expression was associated with lower hippocampal volume, but only among those with more severe childhood maltreatment. In individuals with MDD, decreases in SGK1 expression predicted lower remission rates at week 16, again only among those with more severe maltreatment. Decreases in hippocampal volume predicted lower week 16 remission for those with low childhood maltreatment. These results suggest that both glucocorticoid-related neurobiological mechanisms of the stress response and history of childhood stress exposure may be critical to understanding differential treatment outcomes in MDD. ClinicalTrials.gov: NCT01655706 Canadian Biomarker Integration Network for Depression Study.

Transcriptional signatures of early-life stress and antidepressant treatment efficacy.

Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response.

DNA Methylation Signatures of Functional Somatic Syndromes: Systematic Review.

OBJECTIVE: Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as fatigue and pain, raises the important question of their underlying pathophysiology. Psychosocial stress represents a significant factor in the development of FSS and can induce long-term modifications at the epigenetic level. The aim of this review was to systematically review, for the first time, whether individuals with FSS are characterized by specific alterations in DNA methylation. METHODS: MEDLINE and PsycINFO were searched from the first available date to September 2022. The inclusion criteria were as follows: a) adults fulfilling the research diagnostic criteria for chronic fatigue syndrome, fibromyalgia syndrome, and/or irritable bowel syndrome; b) healthy control group; and c) candidate-gene or genome-wide study of DNA methylation. RESULTS: Sixteen studies ( N = 957) were included. In candidate-gene studies, specific sites within NR3C1 were identified, which were hypomethylated in individuals with chronic fatigue syndrome compared with healthy controls. In genome-wide studies in chronic fatigue syndrome, a hypomethylated site located to LY86 and hypermethylated sites within HLA-DQB1 were found. In genome-wide studies in fibromyalgia syndrome, differential methylation in sites related to HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , and LY6G5C was found. CONCLUSIONS: Individuals with chronic fatigue syndrome and fibromyalgia syndrome seem to be characterized by altered DNA methylation of genes regulating cellular signaling and immune functioning. In chronic fatigue syndrome, there is preliminary evidence for these to be implicated in key pathophysiological alterations, such as hypocortisolism and low-grade inflammation, and to contribute to the debilitating symptoms these individuals experience. PREREGISTRATION: PROSPERO identifier: CRD42022364720.

SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants.

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Multi-omic modeling of antidepressant response implicates dynamic immune and inflammatory changes in individuals who respond to treatment.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, and is commonly treated with antidepressant drugs (AD). Although effective, many patients fail to respond to AD treatment, and accordingly identifying factors that can predict AD response would greatly improve treatment outcomes. In this study, we developed a machine learning tool to integrate multi-omic datasets (gene expression, DNA methylation, and genotyping) to identify biomarker profiles associated with AD response in a cohort of individuals with MDD. MATERIALS AND METHODS: Individuals with MDD (N = 111) were treated for 8 weeks with antidepressants and were separated into responders and non-responders based on the Montgomery-Åsberg Depression Rating Scale (MADRS). Using peripheral blood samples, we performed RNA-sequencing, assessed DNA methylation using the Illumina EPIC array, and performed genotyping using the Illumina PsychArray. To address this rich multi-omic dataset with high dimensional features, we developed integrative Geneset-Embedded non-negative Matrix factorization (iGEM), a non-negative matrix factorization (NMF) based model, supplemented with auxiliary information regarding gene sets and gene-methylation relationships. In particular, we factorize the subjects by features (i.e., gene expression or DNA methylation) into subjects-by-factors and factors-by-features. We define the factors as the meta-phenotypes as they represent integrated composite scores of the molecular measurements for each subject. RESULTS: Using our model, we identified a number of meta-phenotypes which were related to AD response. By integrating geneset information into the model, we were able to relate these meta-phenotypes to biological processes, including a meta-phenotype related to immune and inflammatory functions as well as other genes related to depression or AD response. The meta-phenotype identified several genes including immune interleukin 1 receptor like 1 (IL1RL1) and interleukin 5 receptor (IL5) subunit alpha (IL5RA), AKT/PIK3 pathway related phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), and sphingomyelin phosphodiesterase 3 (SMPD3), which has been identified as a target of AD treatment. CONCLUSIONS: The derived meta-phenotypes and associated biological functions represent both biomarkers to predict response, as well as potential new treatment targets. Our method is applicable to other diseases with multi-omic data, and the software is open source and available on Github (https://github.com/li-lab-mcgill/iGEM).

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes.

Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.

Oxytocin receptor expression and epigenetic regulation in the anterior cingulate cortex of individuals with a history of severe childhood abuse.

Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples. We, therefore, aimed to characterize the relationship between early-life adversity and oxytocin receptor (OXTR) expression in the brain, using post-mortem human samples, as well as a rodent model of naturally occurring variation in early-life environment. Focusing on the dorsal anterior cingulate cortex, we compared OXTR expression and epigenetic regulation between MDD suicides with (N = 26) and without history of childhood abuse (N = 24), as well as psychiatrically healthy controls (N = 23). We also compared Oxtr expression in the cingulate cortex of adult rats raised by dams displaying high (N = 13) and low levels (N = 12) of licking and grooming (LG) behavior. Overall, our results indicate that childhood abuse associates with an upregulation of OXTR expression, and that similarly, this relationship is also observed in the cingulate cortex of adult rats raised by low-LG dams. Additionally, we found an effect of rs53576 genotype on expression, showing that carriers of the A variant also show upregulated OXTR expression. The effects of early-life adversity and rs53576 genotype on OXTR expression are, however, not explained by differences in DNA methylation within and around the MT region of the OXTR gene.

Circular RNA circCCNT2 is upregulated in the anterior cingulate cortex of individuals with bipolar disorder.

Gene expression dysregulation in the brain has been associated with bipolar disorder, but little is known about the role of non-coding RNAs. Circular RNAs are a novel class of long noncoding RNAs that have recently been shown to be important in brain development and function. However, their potential role in psychiatric disorders, including bipolar disorder, has not been well investigated. In this study, we profiled circular RNAs in the brain tissue of individuals with bipolar disorder. Total RNA sequencing was initially performed in samples from the anterior cingulate cortex of a cohort comprised of individuals with bipolar disorder (N = 13) and neurotypical controls (N = 13) and circular RNAs were identified and analyzed using "circtools". Significant circular RNAs were validated by RT-qPCR and replicated in the anterior cingulate cortex in an independent cohort (24 bipolar disorder cases and 27 controls). In addition, we conducted in vitro studies using B-lymphoblastoid cells collected from bipolar cases (N = 19) and healthy controls (N = 12) to investigate how circular RNAs respond following lithium treatment. In the discovery RNA sequencing analysis, 26 circular RNAs were significantly differentially expressed between bipolar disorder cases and controls (FDR < 0.1). Of these, circCCNT2 was RT-qPCR validated showing significant upregulation in bipolar disorder (p = 0.03). This upregulation in bipolar disorder was replicated in an independent post-mortem human anterior cingulate cortex cohort and in B-lymphoblastoid cell culture. Furthermore, circCCNT2 expression was reduced in response to lithium treatment in vitro. Together, our study is the first to associate circCCNT2 to bipolar disorder and lithium treatment.

Association between the expression of lncRNA BASP-AS1 and volume of right hippocampal tail moderated by episode duration in major depressive disorder: a CAN-BIND 1 report.

The pathophysiology of major depressive disorder (MDD) encompasses an array of changes at molecular and neurobiological levels. As chronic stress promotes neurotoxicity there are alterations in the expression of genes and gene-regulatory molecules. The hippocampus is particularly sensitive to the effects of stress and its posterior volumes can deliver clinically valuable information about the outcomes of antidepressant treatment. In the present work, we analyzed individuals with MDD (N = 201) and healthy controls (HC = 104), as part of the CAN-BIND-1 study. We used magnetic resonance imaging (MRI) to measure hippocampal volumes, evaluated gene expression with RNA sequencing, and assessed DNA methylation with the (Infinium MethylationEpic Beadchip), in order to investigate the association between hippocampal volume and both RNA expression and DNA methylation. We identified 60 RNAs which were differentially expressed between groups. Of these, 21 displayed differential methylation, and seven displayed a correlation between methylation and expression. We found a negative association between expression of Brain Abundant Membrane Attached Signal Protein 1 antisense 1 RNA (BASP1-AS1) and right hippocampal tail volume in the MDD group (ß = -0.218, p = 0.021). There was a moderating effect of the duration of the current episode on the association between the expression of BASP1-AS1 and right hippocampal tail volume in the MDD group (ß = -0.48, 95% C.I. [-0.80, -0.16]. t = -2.95 p = 0.004). In conclusion, we found that overexpression of BASP1-AS1 was correlated with DNA methylation, and was negatively associated with right tail hippocampal volume in MDD.

Treatment-emergent and trajectory-based peripheral gene expression markers of antidepressant response.

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.

Neuron-derived extracellular vesicles enriched from plasma show altered size and miRNA cargo as a function of antidepressant drug response.

Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEV) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N = 20) and did not respond (N = 20) to escitalopram treatment, as well as controls (N = 20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEV by immunoprecipitation with L1CAM. EVs and NDEVs were characterized, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed that they were smaller than other EVs isolated from plasma (p < 0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p < 0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p < 0.05), and NDEV size increased with ADT response (p < 0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p, and miR-486-5p together (p < 0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p < 0.05). Together, this study indicates that changes in peripherally isolated NDEV can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

miR-323a regulates ERBB4 and is involved in depression.

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 < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.

The Role of Epigenetic Dysregulation in Suicidal Behaviors.

Suicidal behaviors have been associated with both heritable genetic variables and environmental risk factors. Epigenetic processes, such as DNA methylation, have important roles in mediating the effects of the environment on behavior. Dysregulation of these processes has been observed in many psychiatric disorders, and evidence suggests that they may also be involved in suicidal behaviors. Herein, we have summarized candidate gene and epigenome-wide studies which have investigated DNA methylation in relation to suicidal behaviors, as well as discussed some of the limitations of the field to date.

Machine Learning Analysis of Blood microRNA Data in Major Depression: A Case-Control Study for Biomarker Discovery.

BACKGROUND: There is a lack of reliable biomarkers for major depressive disorder (MDD) in clinical practice. However, several studies have shown an association between alterations in microRNA levels and MDD, albeit none of them has taken advantage of machine learning (ML). METHOD: Supervised and unsupervised ML were applied to blood microRNA expression profiles from a MDD case-control dataset (n = 168) to distinguish between (1) case vs control status, (2) MDD severity levels defined based on the Montgomery-Asberg Depression Rating Scale, and (3) antidepressant responders vs nonresponders. RESULTS: MDD cases were distinguishable from healthy controls with an area-under-the receiver-operating characteristic curve (AUC) of 0.97 on testing data. High- vs low-severity cases were distinguishable with an AUC of 0.63. Unsupervised clustering of patients, before supervised ML analysis of each cluster for MDD severity, improved the performance of the classifiers (AUC of 0.70 for cluster 1 and 0.76 for cluster 2). Antidepressant responders could not be successfully separated from nonresponders, even after patient stratification by unsupervised clustering. However, permutation testing of the top microRNA, identified by the ML model trained to distinguish responders vs nonresponders in each of the 2 clusters, showed an association with antidepressant response. Each of these microRNA markers was only significant when comparing responders vs nonresponders of the corresponding cluster, but not using the heterogeneous unclustered patient set. CONCLUSIONS: Supervised and unsupervised ML analysis of microRNA may lead to robust biomarkers for monitoring clinical evolution and for more timely assessment of treatment in MDD patients.

GPR56/ADGRG1 is associated with response to antidepressant treatment.

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.

Neural and molecular correlates of psychological pain during major depression, and its link with suicidal ideas.

OBJECTIVES: Psychological pain increases the risk of suicidal ideas and acts, and represents a potential therapeutic target. However, the mechanisms of mental pain remain unclear. Here, we assessed the peripheral transcriptomic and central neural correlates of mental pain during a depressive episode. METHODS: 172 adult un-medicated depressed patients were recruited. Leucocytes were extracted for RNA quantification at baseline (T0) and after 8 weeks (T8) of an antidepressant treatment. Ninety-nine genes of the cortisol, immune, opioid, serotonergic, and kynurenine systems were a priori selected, and 41 were sufficiently expressed to be analyzed. At both T0 and T8, mean level of mental pain over the last 15 days was measured with a visual analog scale. A subset of 38 patients was additionally scanned with Magnetic Resonance Imaging at T0. Resting-state sequences of 4 networks (default-mode, basal ganglia, central executive, salience) were examined. RESULTS: Mean psychological pain scores significantly decreased between T0 and T8. At conservative p-corrected levels, T0 mental pain was significantly correlated with 11 brain clusters encompassing the prefrontal, parietal, and temporal cortices, the striatum, and the cerebellum. There was no direct association between peripheral gene expression and mean mental pain at any time points or in terms of temporal changes. However, expressions of 5HTR2B at p-corrected levels, and 5HTR3A, TPH1, and OPRL1 were correlated with the activity of several identified brain clusters at T0. Finally, while suicidal ideas and mental pain were correlated, the neural and molecular correlates of suicidal ideas were not the same. CONCLUSION: Our study suggests that the serotonergic and nociceptin systems are associated with the activity of a cortico-subcortical brain network underlying the perception of mental pain during depression. Mental pain may be a necessary but insufficient condition for the emergence of suicidal ideation during depression.

Validation study of microRNAs previously associated with antidepressant response in older adults treated for late-life depression with venlafaxine.

BACKGROUND: MicroRNAs (miRNAs) are small 22 nucleotides long, non-coding RNAs that are potential biomarkers for antidepressant treatment response. We aimed to replicate previous associations of miRNAs with antidepressant treatment response in a sample of older adults diagnosed with late-life depression. METHODS: Our sample included 184 older adults diagnosed with moderately severe depression that received open-label venlafaxine (up to 300 mg/day) for approximately 12 weeks. We quantified miRNA expression levels at baseline and week 12 for miRNAs miR-1202, miR-135a-5p, miR-16-5p, miR-146a-5p, miR-146b-5p, miR-425-3p, and miR-24-3p to explore their association with remission status, response trajectories, and time-to-remission. RESULTS: At T0 and T12, there were no differences in miRNA expression levels between remitters and non-remitters. However, remitters showed a trend toward higher baseline miR-135a-5p (Median = 11.3 [9.9, 15.7], p = .083). Prior to correction, baseline miR-135a-5p expression levels showed an association with remission status (OR = 1.8 [1.0, 3.3], p = .037). Individuals with higher baseline miR-135a-5p showed better response trajectories (F = 4.5, FDR-corrected p = 4.4 × 10-4), particularly at weeks 10 and 12 (p < .05). In addition, individuals with higher miR-135a-5p expression reached remission faster than those with lower expression (HR = 0.6 [0.4, 0.9], FDR-corrected p = .055). LIMITATIONS: Although the sample size was relatively modest, our findings are consistent with the literature suggesting that higher miR-135a-5p levels may be associated with better antidepressant treatment response. CONCLUSIONS: However, the miRNA signature of antidepressant response in older adults may be different as compared to younger adults.