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.

Clinical efficacy of trauma-focused psychotherapies in treatment-resistant depression (TRD) in-patients: A randomized, controlled pilot-study.

In major depressive disorder (MDD) patients, life stress events represent a risk factor for a severe, early-onset, treatment-resistant and chronic endophenotype. Treatment-resistant depression (TRD) patients who have experienced traumatic events could benefit from evidence-based trauma-focused psychotherapies. Because this topic has never been investigated, the aim of this pilot trial was to evaluate whether trauma-focused cognitive-behavioural therapy (TF-CBT) and/or eye movement desensitization and reprocessing (EMDR) can help achieve depressive symptom remission in TRD patients. We carried out a single-blind randomized controlled trial with TRD patients and we compared EMDR (N = 12) with TF-CBT (N = 10). Patients received 3 individual sessions per week over a period of 8 weeks. The symptomatological assessments were performed at 4 timepoints: baseline (T0), 4 (T4), 8 (T8) and 12 (T12) weeks. After 24 weeks, a clinical interview was carried out by phone. All TRD patients showed a significant improvement in depressive symptomatology; however, post hoc comparisons showed a significant difference between the two treatment groups, with lower depressive symptom scores in the EMDR than in the TF-CBT group at the follow-up (T12). This effect was partly maintained at 24 weeks. This pilot study suggests that evidence-based trauma-focused psychotherapies, particularly EMDR, can represent effective interventions to treat TRD patients.