Towards Precision Medicine for Stress Disorders: Diagnostic Biomarkers and Targeted Drugs ( Molecular Psychiatry, under review)

The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analogue scale for life stress in psychiatric patients, a high risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design, we were successful in identifying gene expression biomarkers that were predictive of high stress states, and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. First, we used a powerful longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low stress and high stress states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach, comprehensively integrating previous published human and animal model evidence in the field, and directly citing it. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with high scores on a clinical stress rating scale. Fourth, we tested if the candidate biomarkers from the first three steps are able to predict high stress state, and future psychiatric hospitalizations with stress, in another independent cohort of psychiatric subjects. We tested the biomarkers in all subjects in the independent test cohort, as well as in a more personalized fashion by gender and psychiatric diagnosis, showing increased accuracy with the personalized approach. A. Independent Discovery Cohort (n=36) (91 visits) B. Independent Validation Cohort with Clinically Severe Stress(n=48) (75 visits)