Transcriptomic Prediction of Early-Life Stress on Antidepressant Treatment Outcomes and Sex Differences

Abstract

Early-life stress (ELS) is estimated to affect more than one billion children worldwide every year. ELS includes abuse and neglect, as well as poverty, environmental destruction, and war. ELS poses a major risk for an individual’s future development of depression and other neuropsychiatric disorders, and this early experience may decrease the efficacy of antidepressant drug treatment. Importantly, women are twice as likely to be diagnosed with major depressive disorder compared to men, although less is known about the variation in the efficacy of antidepressant treatment by sex and gender. Understanding the link between ELS and antidepressant outcomes is therefore crucial for improving therapeutic interventions. Here I investigated the predictive role of ELS in altering the efficacy of different classes of antidepressants, focusing on the brain’s nucleus accumbens and sex differences. To emphasize sex differences in ELS, I review in detail the current literature on the role of sex in moderating genome-wide transcriptional patterns in the brain. Further, I conducted translational studies in which I leveraged and performed computational analyses of cross-species genome-wide data from humans and mice treated with different classes of antidepressants. I describe the experiments I conducted of in vivo pharmacological approaches to understand how molecular changes in the brain following ELS may causally alter antidepressant response. Combining computational analyses and experimentation, I found that gene expression patterns in the nucleus accumbens—a brain center of reward and mood—correspond with transcriptional patterns of antidepressant treatment failure. Additionally, transcriptional patterns predicting treatment failure were strongest among female subjects. By profiling global gene expression changes in the brain that contribute to antidepressant treatment outcomes, this research aims to inform translational, clinical decision-making and enhance possible sex-specific efficacy of therapeutic interventions for individuals with depression and a history of ELS.