Biological markers of sex-based differences in major depressive disorder and in antidepressant response.

Major depressive disorder (MDD) presents different clinical features in women and men, with women being more affected and responding differently to antidepressant treatment. Specific molecular mechanisms underlying these differences are not well studied and this narrative review aims at providing an overview of the neurobiological features underlying sex-differences in biological systems involved in MDD pathophysiology and response to antidepressant treatment, focusing on human studies. The majority of the reviewed studies were performed through candidate gene approaches, focusing on biological systems involved in MDD pathophysiology, including the stress response, inflammatory and immune, monoaminergic, neurotrophic, gamma-aminobutyric acid and glutamatergic, and oxytocin systems. The influence of the endocrine system and sex-specific hormone effects are also discussed. Genome, epigenome and transcriptome-wide approaches are less frequently performed and most of these studies do not focus on sex-specific alterations, revealing a paucity of omics studies directed to unravel sex-based differences in MDD. Few studies about sex-related differences in antidepressant treatment response have been conducted, mostly involving the inflammatory system, with less evidence on the monoaminergic system and sparse evidence in omics approaches. Our review covers the importance of accounting for sex-differences in research, optimizing patient stratification for a more precise diagnostic and individualized treatment for women and men.

Transcriptional biomarkers of response to pharmacological treatments in severe mental disorders: A systematic review.

Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.

Recommendations for pharmacotranscriptomic profiling of drug response in CNS disorders.

Pharmacotranscriptomics is a still very new field of research that has just begun to flourish and promises to enable target discovery, inform biomarker and evaluate drug efficacy beyond pharmacogenomics. The aim of this review is to provide a critical overview of the biological foundations of transcriptomics, methodological approaches to transcriptomic studies, and their advantages and limitations. We present the different RNA species (rRNAs, tRNAs, mtRNAs, snRNAs, scRNAs, mRNAs, ncRNAs, LINE and SINE transcripts, circular RNAs, piRNAs, miRNAs, snoRNAs) and their potential for pharmacotranscriptomic studies as markers to predict treatment response in neurological and psychiatric disorders. We also review the accessible sources of RNA in patients peripheral blood cells (including platelets), plasma, microvesicles, exosomes, apoptotic bodies, and how those affect the integrity and relative abundances of RNAs and reflect the situation in the Central Nervous System (CNS). Finally, we discuss the suitability and indications of different techniques, such as microarrays and RNA-sequencing (RNA-Seq) techniques to understand gene expression differences or to reveal variation in expression levels of coding and non-coding genes. We conclude with some recommendations for future directions, e.g., gaps of knowledge and particular RNAs/tissues that have been overlooked.

Clinical validation of a combinatorial PharmAcogeNomic approach in major Depressive disorder: an Observational prospective RAndomized, participant and rater-blinded, controlled trial (PANDORA trial).

BACKGROUND: Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only approximately one third of patients respond to the first treatment because of the ineffectiveness or side effects of antidepressants. Precision medicine in psychiatry might offer clinicians the possibility to tailor treatment according to the best possible evidence of efficacy and tolerability for each subject. In this context, our study aims to carry out a clinical validation of a combinatorial pharmacogenomics (PGx) test in an Italian MDD patient cohort with advocacy license independence. METHODS: Our study is a prospective participant- and rater-blinded, randomized, controlled clinical observational trial enrolling 300 MDD patients who are referred to psychiatric services to receive a new antidepressant due to the failure of their current treatment and/or the onset of adverse effects. Eligible participants are randomized to the TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, DNA is collected with a buccal brush. The primary outcome is the reduction in depressive symptomatology. The secondary outcomes involve a range of scales that assess MDD symptoms and social functioning outcomes. The assessment is performed at four timepoints: baseline and 4, 8, and 12 weeks. DISCUSSION: This project represents the first randomized controlled clinical trial to investigate whether a non-commercial PGx test improves outcomes in an MDD naturalistic cohort. Moreover, the identification of new genetic variants associated with non-response or side effects will improve the efficacy of the test, leading to further cost-saving. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04615234. Registered on November 4, 2020.

Molecular Biomarkers of Electroconvulsive Therapy Effects and Clinical Response: Understanding the Present to Shape the Future.

Electroconvulsive therapy (ECT) represents an effective intervention for treatment-resistant depression (TRD). One priority of this research field is the clarification of ECT response mechanisms and the identification of biomarkers predicting its outcomes. We propose an overview of the molecular studies on ECT, concerning its course and outcome prediction, including also animal studies on electroconvulsive seizures (ECS), an experimental analogue of ECT. Most of these investigations underlie biological systems related to major depressive disorder (MDD), such as the neurotrophic and inflammatory/immune ones, indicating effects of ECT on these processes. Studies about neurotrophins, like the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF), have shown evidence concerning ECT neurotrophic effects. The inflammatory/immune system has also been studied, suggesting an acute stress reaction following an ECT session. However, at the end of the treatment, ECT produces a reduction in inflammatory-associated biomarkers such as cortisol, TNF-alpha and interleukin 6. Other biological systems, including the monoaminergic and the endocrine, have been sparsely investigated. Despite some promising results, limitations exist. Most of the studies are concentrated on one or few markers and many studies are relatively old, with small sample sizes and methodological biases. Expression studies on gene transcripts and microRNAs are rare and genetic studies are sparse. To date, no conclusive evidence regarding ECT molecular markers has been reached; however, the future may be just around the corner.

Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.

Inflammation-related microRNAs are involved in stressful life events exposure and in trauma-focused psychotherapy in treatment-resistant depressed patients.

Background: About 30% of major depressive disorder (MDD) patients are classified as resistant to treatment (treatment-resistant depression, TRD). Among the factors associated with unfavourable treatment outcomes, stressful life events play a relevant role, and trauma-focused psychotherapy has been successfully proposed for the treatment of patients with a history of such events. Stressful experiences are related to enhanced inflammation and, recently, microRNAs (miRNAs) have emerged as potential mediators of the association between these experiences and psychiatric disorders. To date, no study has explored the effects of stressful life events on miRNAs in MDD patients. Objective: The objective of the present study was to assess possible miRNA blood expression alterations in TRD patients induced by the exposure to stressful life events and to investigate the effects of trauma-focused psychotherapy on the expression profiles of the same miRNAs, as well as their possible predictivity in relation to therapy outcome. Method: The basal levels (T0) of seven candidate miRNAs (miR-15a/miR-29a/miR-125b/miR-126/miR-146a/miR-195/let-7f) were measured in the whole blood of 41 TRD patients. A subgroup of patients (n = 21) underwent trauma-focused psychotherapy; for all of them, miRNA levels were also longitudinally assessed (T4: after 4 weeks of treatment; T8: end of treatment; T12: follow-up visit), contextually to clinical evaluations. Results: miR-146a levels negatively correlated with recent stressful life event scores (p = .001), whereas the levels of miR-15a, miR-29a, miR-126, miR-195, and let-7f changed during the psychotherapy (best p = 1.98*10-9). miR-29a was also identified as a response predictor, with lower baseline levels predicting non-response (p = .019) or worse improvement in mood symptoms (p = .032). Conclusions: The study results could contribute to clarify the underlying molecular mechanisms and to identify novel biomarkers of stressful experiences and response to targeted treatments.

Antecedentes: Alrededor del 30% de los pacientes con un Trastorno Depresivo Mayor (TDM) son clasificados como resistentes a tratamiento (Depresión Resistente a Tratamiento, TRD por su sigla en inglés). Entre los factores asociados a resultados de tratamiento desfavorables, los eventos vitales estresantes juegan un rol relevante, y la psicoterapia con foco en el trauma ha sido propuesta con éxito para el tratamiento de los pacientes con historia de tales eventos. Las experiencias estresantes están relacionadas a un aumento de la inflamación y, recientemente, microARNs (miARNs), han surgido como potenciales mediadores de la asociación entre estas experiencias y trastornos psiquiátricos. A la fecha, ningún estudio ha explorado los efectos de los eventos vitales estresantes sobre los miARNs en pacientes con TDM.Objetivo: El objetivo del presente estudio fue evaluar posibles alteraciones en la expresión de miARN en sangre en pacientes con TRD inducidas por la exposición a eventos vitales estresantes e investigar los efectos de la psicoterapia con foco en el trauma sobre los perfiles de expresión de los mismos miARNs, así como su posible predictividad en relación al resultado de la terapia.Método: Los niveles basales (T0) de 7 miARN candidatos (miR-15a/miR-29a/miR-125b/miR-126/miR-146a/miR-195/let-7f) fueron medidos en la sangre completa de 41 pacientes con TRD. Un subgrupo de pacientes (n = 21) se sometió a psicoterapia con foco en el trauma; para todos ellos, los niveles de miARN fueron también evaluados longitudinalmente (T4: después de 4 semanas de tratamiento; T8: fin del tratamiento; T12: visita de seguimiento), contextualmente a evaluaciones clínicas.Resultados: Los niveles de miR-146a se correlacionaron negativamente con los puntajes de eventos vitales estresantes recientes (p = .001), mientras que los niveles de miR-15a, miR-29a, miR-126, miR-195, y let-7f cambiaron durante la psicoterapia (mejor p = p = 1.98*10−9). miR-29a también fue identificado como un predictor de respuesta, con menores niveles basales prediciendo falta de respuesta (p = .019) o menor mejoría en los síntomas anímicos (p = .032).Conclusiones: Los resultados del estudio contribuyen a clarificar los mecanismos moleculares subyacentes y a identificar nuevos biomarcadores de experiencias estresantes y respuesta a tratamientos dirigidos.

Biological correlates of early life stressful events in major depressive disorder.

Major depressive disorder (MDD) is the most common psychiatric disorder and responds for important psychosocial consequences. Stressful life events, especially early life stress (ELS), contribute to an increased probability to develop MDD, leading in particular to severe and chronic manifestation and unfavorable treatment outcome. The association between ELS and MDD seems to have biological bases, consisting in dysregulations occurring at different levels. The aim of this narrative review is to propose an overview of the literature ranging from genetic, epigenetic, expression and protein to neuroimaging correlates underlying this relationship. A search on Pubmed of studies assessing biological correlates of ELS in MDD development, focusing on human studies conducted in both peripheral and brain tissues, was performed. Evidence indicated that the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic, dopaminergic, neurotrophin and oxytocin systems might play a role in the mediation between ELS and MDD. The most consistent results were found for genetic and epigenetic studies and indicated a joint involvement of the systems mentioned. Expression studies are less numerous and point to an involvement of stress-related systems. Concerning protein studies, the main mediators are markers related to the inflammatory and immune systems. Neuroimaging studies aiming at evaluating brain alterations connecting ELS and MDD in relation to biomarkers indicated the hippocampus, the amygdala and the frontal cortex as important anatomical mediators. These findings can build the bases for future research and clinical interventions; indeed, the clarification of biological mechanisms mediating the relationship between ELS and MDD can lead to new and individualized preventive and therapeutic possibilities.

Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments.

Despite the extensive research conducted in recent decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternative ones to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field.

Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.