Neural Components of Stress Response and Suicide Behavior: Preventive Impact of Ketamine

About This Grant

PROJECT SUMMARY / ABSTRACT Suicide rates in the US have risen approximately 34% since the Surgeon General’s call to make suicide prevention a national priority in the U.S over 20 years ago. Without a science-driven paradigm shift in our understanding of suicide, there is little prospect of a breakthrough in suicide prevention. A better explanatory model of suicidal behavior could offer new methods to recognize those at heightened risk for suicide; identify novel, modifiable treatment targets for suicide prevention; and assess the impact of such intervention in at-risk patients. We have proposed a stress-diathesis model of suicidal behavior wherein suicidal behavior is the result of interactions between an immediate stressor (generally, an external life event), clinical stressors (such as untreated depression), and a diathesis—a collection of traits underlying the predisposition to suicidal behavior that includes response styles to stress. However, little is known about how naturalistic stress interacts with risk factors to facilitate transition from suicidal ideation to behavior in high-risk depressed patients. This Conte Center grant will address this knowledge gap by examining neurotransmitter and circuitry elements underlying responses to naturalistic stressors, focusing on the glutamatergic system and cognitive factors, as well as the impact of ketamine (randomized to low vs. standard dose) on responses to daily life stress. Studying a large group of higher-risk depressed suicide attempters relative to depressed non-attempters and healthy volunteers, we will use novel and converging approaches across projects to increase our understanding of suicide pathogenesis, thereby identifying potential biomarkers and treatable targets for suicide risk. Project 1 will use ecological momentary assessment to measure suicidal ideation and mood symptoms in the context of daily stress and quantify change in these variables following ketamine administration. In the same sample, Project 2 will use multimodal MRI to characterize the downstream effects of altered glutamate and functional neurocircuitry on mood- and cognition-related risk factors for suicide, specifically, memory alterations, deficits in emotion regulation, and glutamatergic pain processing. This sample will also undergo PET imaging in Project 3 to examine synaptic density and mGluR5 binding, and assess their role in stress responses. Project 4 will use spatial and single nuclei cell type specific transcriptomics in postmortem brain tissue to examine suicide and impact of recent life stressors, homologous to Projects 1-3. Project 5, a mouse study, will examine helplessness, stress responses, and memory at the circuit and molecular components and the impact of ketamine. Project 6 will harness the rich, multimodal dataset of Projects 1-5 to model high dimensional and complex data in profiling suicidal behavior. We aim to delineate a model of suicide risk linking molecular and neurobiological mechanisms to clinical factors and real-world responses to stress, with the long-term goal of enhancing stress resilience as a suicide prevention approach.