Integrating Immune Dysregulation and Reward Circuitry in Veterans with Mood Disorders and Suicide"

Depression is among the most disabling mental health conditions and associated with profound functional impairment resulting in tremendous economic burden for the Department of Veterans Affairs (VA). Critically, depression is one of the leading causes of suicide, which is known to be much higher for Veterans compared to non-Veterans. There are major gaps in knowledge regarding the fundamental pathophysiology of depression that limit novel diagnostic and treatment approaches contributing to its health burden. Abnormal functioning in the peripheral immune system has been linked consistently to risk for depression and suicide based on prior empirical studies and theoretical models. Likewise, abnormalities within the brain reward system are established risk factors for depression and suicide. However, the molecular underpinnings of peripheral immune dysregulation – and their relationship to brain reward circuit abnormalities – is not well understood in depression or suicide. Our prior human studies showed that circulating immune factors, such as cytokines, fail to fully capture relevant immune dysregulation in depression, and that a clear “pro-inflammatory” profile of elevated cytokines and chemokines was observed only following ex-vivo stimulation of peripheral blood mononuclear cells (PBMCs) with liposaccharide (LPS). We also found that abnormally elevated peripheral immune response was associated with lower neural response within the brain reward system, which in turn was linked to higher levels of anhedonia and increased risk of suicide. In the proposed multi-PI study two clinician investigators (Szeszko/Murrough) will build on our prior work by examining immune profiles derived from LPS ex-vivo stimulation of peripheral immune cells (i.e., PBMCs) using advanced methods for proteomic analyses. We will interrogate a brain reward circuit utilizing state-of-the-art neuroimaging methods and integrate them with next-generation immune cell-specific proteomic approaches in 70 Veterans with major depressive disorder (MDD), including 35 with and 35 without a prior suicide attempt history, and 60 unaffected Veterans. Pro-inflammatory profiles derived from ex-vivo LPS stimulation of PBMCs will be examined in relationship to in-vivo neural activity within the ventral striatum/nucleus accumbens (VS/NAc) using functional magnetic resonance imaging during an incentive flanker task. Pro-inflammatory profiles will also be examined in relation to in-vivo free water measures derived from neurite orientation dispersion and density imaging as an index of inflammation within the accumbofrontal white matter tract, which connects the VS/NAc with the orbital frontal cortex to form a reward circuit. Veterans will be followed longitudinally and receive 6-month and 1-year assessments of suicidal behavior to determine whether baseline measures can be used to predict future suicidal risk. We will test the following specific aims: (1) to characterize the peripheral immune profile of Veterans with MDD; (2) to determine the relationship between peripheral immune profiles and reward circuitry in Veterans with MDD and (3) (exploratory) to investigate the association between peripheral immune profiles, reward circuitry, and suicidal risk in Veterans with MDD. This translational study addresses the critical need to identify mechanisms of immune hyper-reactivity relevant for depression and suicidal risk as well as pathways linking pro-inflammatory profiles with reward function to identify targets for treatment development. The clinical implications of this study are underscored by the identification of pro-inflammatory profiles that could provide novels ways of identifying Veterans who may not demonstrate adequate treatment response to traditional pharmacotherapy due to the potential role of inflammation and advancing the utility of using blood biomarkers to identify Veterans with depression at risk of suicide. Project Number: 1I01CX002787-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: PHILIP SZESZKO (+1 co-PI) | Institution: JAMES J PETERS VA MEDICAL CENTER, BRONX, NY | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 MHBC-F (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11052103