There is a pressing need to detect biological signatures, or biomarkers, for psychiatric diseases that will improve our understanding of their architecture of risk and methods of diagnosis and treatment, as their public health burden continues to grow alarmingly. This is especially true for suicide and suicidal behavior, the most serious sequelae of psychiatric diseases and the 3rd leading cause of death among adolescents and young adults. While suicidal behavior occurs in the context of psychiatric disorders, relatively few subjects with psychiatric disorders attempt suicide. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is postulated as one of the pathways between stress, psychiatric diseases, and suicidal behavior. In this R21 pilot study, we propose to examine hair cortisol concentrations (HCC) in psychiatric inpatients, 13-25 years of age, admitted for suicide attempt (n=35) and compare them to psychiatric inpatients with suicidal ideation but no previous history of attempts (n=35) and healthy controls (n=35). HCC is a marker of chronic activation of the HPA axis as it provides a retrospective assessment of cortisol levels over the past few months and thus will provide an assessment of cortisol levels prior to suicide attempt. This temporal assessment is not possible using standard methods of HPA axis measurement. This R21 study is the first to use this innovative method in the context of suicidal behavior. HPA axis dysregulation also affects the inflammatory response. We propose a model for the biological pathways to suicidal behavior where we will examine the pathways from gene expression in the HPA axis and inflammatory pathways in peripheral blood to HCC, glucocorticoid receptor (GR) sensitivity, systemic levels of inflammation (Interleukin-6, C-reactive protein), clinical correlats of suicidal behavior, and suicidal behavior. This study is also the first to examine peripheral gene expression and the relationship between the HPA axis and inflammatory pathways in relation to suicidal behavior. We hypothesize that suicide attempters will have decreased GR expression, increased HCC, decreased GR sensitivity, increased expression of inflammatory genes, and increased inflammation as compared to the other two groups. These biological measures will be associated with increased sleep disturbances, impulsive aggression, emotion dysregulation, and reduced distress tolerance. Biological and clinical measures will together predict suicidal behavior. This study is in line with NIMH's Research Domain Criteria (RDoC) where we are measuring the sustained threat construct of the negative valence systems in subjects who are on the spectrum of suicidal behavior from normal to ideation and attempt. This R21 study is the first exploratory stage of a future project that will examine the clinical efficac of HCC and test our proposed model for the biological pathways of suicidal behavior in larger samples. Achieving these goals will bring innovative methods to clinical practice to detect individuals at high risk and will result in the development of new treatment approaches, which will both lead to a significant reduction in psychiatric morbidity and mortality resulting from suicidal behavior in youth.