Deriving psychiatric symptom-based biomarkers from multivariate relationships between psychophysiological and biochemical measures

Identification of biomarkers for psychiatric disorders remains very challenging due to substantial symptom heterogeneity and diagnostic comorbidity, limiting the ability to map symptoms to underlying neurobiology. Dimensional symptom clusters, such as anhedonia, hyperarousal, etc., are complex and arise due to interactions of a multitude of complex biological relationships. The primary aim of the current investigation was to use multi-set canonical correlation analysis (mCCA) to derive biomarkers (biochemical, physiological) linked to dimensional symptoms across the anxiety and depressive spectrum. Active-duty service members (N = 2,592) completed standardized depression, anxiety and posttraumatic stress questionnaires and several psychophysiological and biochemical assays. Using this approach, we identified two phenotype associations between distinct physiological and biological phenotypes. One was characterized by symptoms of dysphoric arousal (anhedonia, anxiety, hypervigilance) which was associated with low blood pressure and startle reactivity. This finding is in line with previous studies suggesting blunted physiological reactivity is associated with subpopulations endorsing anxiety with comorbid depressive features. A second phenotype of anxious fatigue (high anxiety and reexperiencing/avoidance symptoms coupled with fatigue) was associated with elevated blood levels of norepinephrine and the inflammatory marker C-reactive protein in conjunction with high blood pressure. This second phenotype may describe populations in which inflammation and high sympathetic outflow might contribute to anxious fatigue. Overall, these findings support the growing consensus that distinct neuropsychiatric symptom patterns are associated with differential physiological and blood-based biological profiles and highlight the potential of mCCA to reveal important psychiatric symptom biomarkers from several psychophysiological and biochemical measures.