R01MH132137

Role of Synaptic Density in Mediating the Relation Between Social Disconnection and Late-Life Suicide Risk - Project Summary:

Social disconnection (SDC) and suicide deaths are major public health concerns for the aging population. SDC is one of the strongest risk factors of suicidal ideation, attempts, and deaths in older adults, and is a modifiable target for suicide prevention efforts in this population.

While accumulating evidence has established an association between SDC and late-life suicide risk, the neural mechanisms that underlie this association remain unknown. Consequently, our understanding of how to optimally intervene to mitigate the adverse effects of SDC on suicide risk in older adults is limited.

To address this gap, we propose to conduct the first in vivo molecular imaging study of a potential neural mechanism – corticolimbic synaptic density – that may mediate the link between SDC and late-life suicide risk. Given a higher prevalence of suicide death in older men than women, we will also examine whether sex moderates this association.

Converging evidence from human magnetic resonance imaging and postmortem studies and preclinical work suggests brain alterations in SDC and suicidality, with robust evidence implicating lower corticolimbic synaptic density. In animal models of SDC, socialization appears to reverse some of these synaptic losses. These studies have also observed sex differences in synaptic changes in interventions designed to reverse SDC-related synaptic losses.

Thus, it is critical to conduct in vivo human studies to evaluate molecular mechanisms that may confer risk for suicide in older adults with SDC in order to identify who is at greatest risk and how to mitigate burden of suicide to older adults, their families, and the community at large.

In vivo quantification of synaptic density in humans is possible with the radioligand 11C-UCB-J, which quantifies the density of synaptic vesicle glycoprotein 2A (SV2A), a ubiquitously expressed marker of synaptic density, using positron emission tomography (PET) imaging.

Our preliminary data from a diverse sample of older adults confirm preclinical findings of lower corticolimbic synaptic density in SDC and suggest sex-specific differences. In the proposed study, we will recruit a transdiagnostic cohort of older adults presenting with the full range of SDC and evaluate whether lower corticolimbic synaptic density mediates the relation between SDC and longitudinal trajectories of late-life suicide risk in a sex-specific manner.

We will employ a novel, data-driven approach to model predominant trajectories of late-life suicide risk, which will include measures of suicide depressive and death ideation, symptoms, loss of personal and self-worth, executive control, and perceived meaning in life.

Results of the proposed study will provide the first human in vivo data on the role of synaptic density alterations as a putative neural mechanism linking SDC to late-life suicide risk. They will also inform the development and testing of targeted interventions to enhance synaptogenesis (e.g., medications such as ketamine or psychosocial interventions such as peer support), as well as public policies to promote social connection among older adults who may suffer from illness or other issues that lead to SDC.

Yale Univ

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. WE FULFILL THIS MISSION BY SUPPORTING AND CONDUCTING RESEARCH ON MENTAL ILLNESSES, HEALTH SERVICES, AND THE UNDERLYING BASIC SCIENCE OF THE BRAIN AND BEHAVIOR; SUPPORTING THE TRAINING OF SCIENTISTS TO CARRY OUT BASIC AND CLINICAL MENTAL HEALTH RESEARCH; AND COMMUNICATING WITH SCIENTISTS, PATIENTS, PROVIDERS, AND THE PUBLIC ABOUT MENTAL HEALTH RESEARCH ADVANCES AND PRIORITIES. IN MAY 2024, NIMH RELEASED ITS STRATEGIC PLAN FOR RESEARCH. THE STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH.THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTES RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

New Haven, Connecticut 065102715 United States

Single Zip Code

Social disconnection and Suicide Risk in Late Life (R01 Clinical Trial Optional) (RFA-MH-22-135)

Amendment Since initial award the total obligations have increased 99% from $1,808,910 to $3,607,770.