Considering the burden of depression and the lack of efficacy of available treatments, there is a need for biomarkers to predict tailored or personalized treatments. However, identifying reliable biomarkers for depression has been challenging, likely owing to the vast symptom heterogeneity and high rates of comorbidity that exists. Examining biomarkers that map onto dimensions of depression as well as shared symptoms/constructs that cut across disorders could be most effective for informing personalized treatment approaches. With a sample of 539 young adults, we conducted a principal component analysis (PCA) followed by hierarchical cluster analysis to develop transdiagnostic clusters of depression and anxiety symptoms. We collected blood to assess whether neuroendocrine (cortisol) and inflammatory profiles (C-reactive protein (CRP), Interleukin (IL)-6, and tumor necrosis factor (TNF) – α) could be used to differentiate symptom clusters. Six distinct clusters were identified that differed significantly on symptom dimensions including somatic anxiety, general anxiety, anhedonia, and neurovegetative depression. Moreover, the neurovegetative depression cluster displayed significantly elevated CRP levels compared to other clusters. In fact, inflammation was not strongly associated with overall depression scores or severity, but rather related to specific features of depression marked by eating, appetite, and tiredness. This study emphasizes the importance of characterizing the biological underpinnings of symptom dimensions and subtypes to better understand the etiology of complex mental health disorders such as depression.

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Depression is thought to arise from a combination of stressful experiences and genetic susceptibility as it has been shown that genes regulating the hypothalamus pituitary adrenal (HPA)-axis, not only modulate physiological stress reactivity, but have likewise been associated with depressive phenotypes. To explore genetic susceptibility, we examined the relation between a validated multilocus genetic profile score (MGPS), comprising genes that regulate HPA axis activity, with mental health outcomes and peripheral biomarkers levels in the context of stressful life experiences. We observed interactions between the MGPS score with traumatic experiences revealing that when individuals were exposed to high levels of trauma, those with lower MGPS, displayed higher stress, depressive, and anxiety symptoms. This study calls attention to the importance of environmental factors when examining genetic susceptibility to mental illnesses.Ultimately, these data suggest that experiences of trauma could potentially "set boundaries" on the impact of genes, overriding genetic predisposition to depression.

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