Characterizing Inflammatory Profiles and Suicidal Behavior in Adolescents

This project aims to characterize immunological tone and responsivity in adolescents with varying risk for suicide behavior, and evaluate the stability of immune dysfunction associated with suicide behavior and risk. Inflammatory response markers and suicide behaviors will be assessed longitudinally in a sample (n=180, 60 per group) of adolescents (ages 12-18) who: 1) have suicide behavior, 2) have risk of depression and/or suicidality, or 3) are healthy controls, in order to determine the immune pathology underlying suicidal behavior and risk. Although evidence that the immune system is dysfunctional in depression and suicide has been known for many years, a robust characterization of this dysfunction has yet to be completed, particularly within the high-risk and developmentally unique population of adolescents.  Our pilot work suggests markedly low levels of IL-4 in adolescents and young adults with recent suicide behavior as compared to healthy individuals, which is suggestive of increased susceptibility to an autoimmune process.  For the proposed study, we will expand upon this work to provide characterization of immune regulation through quantification of T cells (which play a strong role in regulating immunological tolerance and reactivity), evaluation of pro- and anti-inflammatory response through lab-based stimulation, and quantification of autoantibodies. We specifically hypothesize that adolescents with suicide behavior have immune hyper-reactivity, as reflected in dysfunctional cells mediating both innate and adaptive immune response. Suicide behavior will be measured with the Concise Health Risk Tracking assessment, which allows for multiple aspects of suicidality to be characterized. The results of this study will inform the potential for IL-4 and other markers of inflammatory response to serve as risk markers for suicide, finally providing key biomarkers that can support and inform clinical practice. We have identified targets of clinical utility for both suicide risk identification and novel therapeutic development. Specifically, a state of immune hyper-reactivity that predisposes to suicidal behavior can be corrected by the use of immunomodulatory agents. Blood tests screening for presence of autoantibodies may be implemented as diagnostic tests to predict future suicide risk. Monoclonal antibodies have gained recent attention for their use in other central nervous system disorders (such as multiple sclerosis and migraine) and have been shown to be effective for some patients with depression. However, the utility of anti-inflammatory treatments for depression has been limited by a lack of biomarkers to guide their use. Thus, presence of autoantibodies may identify a sub-group of adolescents and young adults with suicidality who are candidates for treatment with monoclonal antibodies.  A number of classically defined immunological diseases have worked to map these pathways and we are in the earliest stages of understanding how dysfunctional inflammatory response is related to suicidality. The proposed research provides a critical first step to better refine the mechanisms and timing associated with immune dysregulation in adolescents with suicide behavior, with clear pathways toward actionable treatments and preventative measures that will mitigate this maladaptive response.