Identifying Neurobiological Targets for Suicide Prevention in Mood Disorder

Suicide is a major public health concern, and mood disorders (M.D.s) such as major depression and bipolar disorder significantly elevate the risk of suicidal thoughts and behaviors (STBs). Thus, there is an urgent need for identifying objective and modifiable targets for suicide prevention in individuals with M.D.s. The proposed AFSP Early Career Research Grant aims to identify brain-based features that are predictive of future suicidal behavior in individuals with M.D.s—features that can be targeted with new intervention and prevention strategies.

Existing cross-sectional studies reveal functional connectivity disturbances in the ventral prefrontal cortex (vPFC) and its connection sites in suicidal behavior. However, the notably scarce longitudinal studies and the small sample sizes have limited our understanding of whether these features also pertain to future suicide risk and how clinical and behavioral factors interact with imaging markers to amplify suicide risk. Additionally, evidence suggests synaptic connection alterations in the vPFC in suicidal pathology, however much of that evidence has come from post-mortem studies.

Therefore, to address these limitations, this project proposes two aims. The first aim is a longitudinal study to identify a functional connectivity model that can predict future suicidal behavior in M.D.s. The study examines functional connectivity measures in a Danish cohort (n=1000) for whom information on future suicidal behavior is available using the unique National Health Registers. The model is subsequently validated using an independent sample (n=200) from Yale University with longitudinal data on suicidal behavior.  We will explore demographic, clinical, behavioral and psychosocial factors that interact with the brain imaging markers to amplify suicide risk. The second aim represents a shift from post-mortem investigations of synaptic density in suicidal behavior.  It utilizes the recently developed [11C]UCB-J radioligand for one of the first examinations of synaptic density in suicidal behavior in living individuals with M.D.s and examine its link to functional connectivity features.

The study encompasses 1200 individuals with M.D.s across Denmark and US, and combines multimodal neuroimaging with clinical, behavioral, and psychosocial data for an in-depth study of the neurobiological pathways to future suicidal behavior. This project builds on the candidate’s international experience in the study of STBs, brain molecular and functional connectivity markers, and Danish Register data outcomes. The project's mentor, Dr. Blumberg, has long-performed STB research and has a research program dedicated to study and prevention of STBs.

This study has the potential to uncover novel targets for suicide risk reduction. The identification of replicable connectivity features predictive of future suicidal attempts could point to targets that could be modifiable with neuromodulation techniques. Additionally, exploring the role of synaptic connection alterations in suicidal behavior offers potential mechanisms for reducing suicide risk. This study represents a cornerstone for establishing an international research program dedicated to the study and prevention of STBs, and the findings could contribute to drug discovery and policy change for suicide prevention. It is planned that future studies will build on this one to investigate individuals with other psychiatric conditions to identify transdiagnostic aspects of risk and generalizable targets for suicide prevention.