VHA’s top clinical priority is preventing veteran suicide and LMS is a recommended best practice to achieve this aim. While LMS counselling is an acceptable suicide prevention practice among veterans, it is not being delivered to all veterans who may benefit. To reach at-risk veterans, LMS must be implemented in primary care (PC) and primary care mental health integration (PCMHI), where veterans first engage in VA services. However, PC providers have concerns about LMS counselling, in part because few guidelines outline how to conduct LMS counseling among adults. To facilitate LMS counselling in PC settings, we will leverage the expertise of the VISN1 MIRECC and Mental Health Clinical Trials Network to develop a brief motivational interviewing (MI) manual. MI is an evidence-based, directive, patient-centered clinical approach for eliciting behavior change that may give providers a method and principles to respectfully engage in sensitive LMS conversations. Formative research with multiple stakeholders is needed to guide manual development. This project proposes to conduct a qualitative study to examine the perspectives of PC and PCMHI providers and key stakeholders (including clinic leadership, suicide prevention coordinators, and other members of the clinics’ multidisciplinary team) about LMS counselling at three sites within VISN1. Results will directly inform the development of a brief, provider-administered, MI manual for LMS counselling. Leveraging the Replicating Effective Programs framework, we aim to: 1) conduct qualitative interviews to identify PC and PCMHI providers’ comfort with, current practice of, and barriers to conducting both LMS counselling and MI; 2) conduct qualitative interviews with stakeholders to understand the needs, opinions, and perceived barriers to LMS counselling within PC and PCMHI; and 3) develop a brief MI manual for LMS counselling in preparation for a future feasibility and acceptability pilot trial in PC.

Research: Veterans of the U.S. military die by suicide at a rate of two to six times that of their civilian counterparts. Suicidal ideation (SI) and suicide attempts (SA), cardinal precursors to death by suicide, occur at significantly greater frequency than death and cause immense individual and societal burden, yet relatively little is known about their pathophysiology. This is especially so in posttraumatic stress disorder (PTSD), a signature injury of the wars in Iraq and Afghanistan. High rates of comorbidity and inflated prevalence of both suicidality and PTSD in Veterans, highlights the urgency of advancing understanding of the shared and distinguishing neural mechanisms between these. Evidence of trauma- and stress-related synaptic loss and large-scale alterations in intrinsic connectivity networks in brain regions implicated in mood, cognition, and behavior exists in both SI/SA and PTSD literature. However, a major obstacle in field is the scarcity of neurobiologically-based studies of SI/SA in PTSD cohorts. Preliminary data supports the notion that the location and pattern of synaptic alterations may interact with individual and environmental characteristics to affect clinical presentation and symptom severity. Specifically, Veterans with PTSD endorsing SI appear to have a neural signature of synaptic alterations distinct from PTSD symptom severity, depression, and age. Extending this work, state-of-the-art multimodal neuroimaging and behavioral assessment sessions will be conducted in 96 Veterans across 3 study groups (n=32/group): PTSD only; PTSD+SI; PTSD+SA. Robust, complimentary evidence of a unique pattern and location of synaptic alterations will be demonstrated using (a) whole-brain vertex-wise structural magnetic resonance imaging (MRI) to measure cortical thickness, (b) resting-state functional connectivity MRI (rs-fcMRI) to measure global brain connectivity (GBC), and (c) diffusion MRI to measure diffusion GBC (dGBC), a measure of microstructural architecture and connectivity. Veterans will be matched on age, sex, PTSD symptom severity, and history of traumatic brain injury. This study may identify biomarkers of treatment targets in two of the operational priority areas for the VA ? suicide and PTSD, inform novel drug development of efficacious pharmacologic interventions, and ultimately advance the field making way to alleviate suffering of millions of individuals ? Veteran and civilian alike - struggling with suicidality. Candidate: Dr. Averill has demonstrated an unwavering commitment to improving Veterans? mental health care, with emphasis on PTSD and suicide prevention for well over a decade. Short-term goals include receipt of the CDA-2 to both advance her expertise through rigorous training objectives (focused on the neurobiology of SI/SA, multimodal neuroimaging, and statistics) and to provide data for future funding as she establishes a niche program of research in the National Center for PTSD-Clinical Neurosciences Division (NCPTSD-CND). Long-term goals include becoming a thought leader in the areas of suicide prevention and PTSD in Veterans through empirical investigations aimed at informing novel drug development and improved prevention, diagnostics, identification of biomarkers of risk and resilience in SI/SA, and treatment options. Environment: The infrastructure, quality of mentors, supplementary funding support, technology, and Veteran-focused research environment available at the National Center for PTSD-Clinical Neurosciences Division and Yale are unparalleled. This offers unique opportunity to support Dr. Averill in her transition to independence though exceptional targeted training/mentorship and to conduct a low cost/high yield study with great potential to advance the field, lead to improved outcomes for Veterans, and set a foundation for a successful VA-centric career.

Reducing Veteran suicide has been one of the Department of Veterans Affairs (VA) top priorities for the past decade. Efforts to address Veteran suicide have typically included downstream approaches focused on suicide risk management for those who have previously been identified to be at elevated risk. The Joint Commission, however, released a Sentinel Event Alert1 highlighting findings that a substantial number of those who died by suicide had not presented to mental health clinics or psychiatric units. Research suggests that many individuals, including Veterans who die by suicide had been seen by their primary care provider or in other medical settings within the year of their death2-4. Based on this, the Office of Mental Health and Suicide Prevention (OMHSP) tasked an interdisciplinary workgroup to develop an evidence-based, population-level approach to identifying suicide risk in Veterans who present in a wide range of healthcare settings. From this work, the largest implementation of a system-wide suicide risk screening and evaluation initiative within a U.S. healthcare system was developed - the VA Suicide Risk Identification Strategy (VA Risk ID). VA Risk ID is comprised of three stages: The first stage utilizes the Patient Health Questionnaire-95, item 9 as a primary screen to maximize sensitivity; the second stage uses the Columbia Suicide Severity Rating Scale Screener6 as a secondary screen to maximize specificity, and the third stage uses the VA Comprehensive Suicide Risk Evaluation (CSRE) to gather information related to clinical impressions of acute and chronic suicide risk, which are used to develop a risk mitigation plan. The goal of the proposed project is to employ a Sequential Multiple Assignment Randomized Trial (SMART) design to improve the implementation of VA Risk ID’s three-stage screening and evaluation process to fidelity (in correct sequence, by the appropriate provider, and within the designated time frame) for Veterans receiving annual screenings for depression and PTSD. Within the SMART, two evidence-based implementation interventions will be compared to Implementation as Usual (IAU): Audit and Feedback (A/F) and Audit and Feedback plus External Facilitation (A/F+EF). IAU is available to all sites and includes proactive technical assistance, tools, training and a quality assurance dashboard. A/F will provide sites with frequent, non-punitive reports that include information on: individual site performance and comparisons with national average (based on VA Risk ID clinical performance measures), specific areas of improvement and suggested actions. A/F+EF groups will receive A/F reports and external facilitation, which includes strategies such as, stakeholder engagement, identification of barriers and facilitators and problem-solving. This project will occur over three phases: run-in phase, intervention phase I and intervention phase II. The unit of intervention is the site and randomization will occur at the site level. A sequence of decisions regarding which interventions sites will receive during intervention phases I and II are built into the study design. Decisions will be based on site performance. Specifically, only sites who do not meet the program office’s benchmark for adequate performance (i.e., completion of secondary screening and CSRE for 80% or more of eligible patients) will be randomized to receive the implementation interventions, beginning with the less intensive intervention (i.e., A/F) for 10 months. Sites that still do not meet the performance benchmark after receiving A/F, will be re- randomized at the end of Phase I to continue receiving either A/F or a more intensive intervention consisting of A/F + external facilitation (A/F + EF) for another 10 months. The primary aim seeks to understand whether the addition of A/F during the initial phase will significantly improve performance measure scores compared to IAU alone; a secondary aim will examine whether A/F+EF significantly improves performance scores compared to A/F alone. Exploratory aims will consider contextual factors which may influence response to implementation interventions as well as clinical outcomes related to VA Risk ID.

Even the strongest of individual risk factors are poor predictors of suicide attempts. Many risk factors rely on subjective or self- reported measures and underreporting contributes to poor prediction accuracy. In the midst of the ongoing Veteran suicide crisis, we clearly need new, objective predictors of risk that can be implemented across the VA system. Previous findings indicate that behavioral and neuroimaging correlates of decision- making and cognitive control are promising, objective markers of suicidal risk. Though intriguing, these findings are from research conducted primarily in depressed civilians. It is unknown if these potential markers of suicide risk will generalize to a transdiagnostic sample of Veterans. The primary research objective of this CDA- 2 is to evaluate whether structural neuroimaging, and functional neuroimaging during decision- making and cognitive control tasks can be used to identify brain- behavior correlates of suicidal thoughts and behaviors in Veterans. Suicidal thoughts and behaviors are associated with short- sighted, maladaptive, decision- making that is accompanied by differences in striatal- prefrontal reward circuitry. However, studies that have compared decision- making task performance between individuals who have made more organized, lethal attempts at self- harm vs. those making less serious attempts have identified differences in their behavior that may supply more nuanced information about suicidal severity. Interestingly, the decision- making of serious attempters is actually less impulsive. In fact, decision making in serious attempters is less impulsive even relative to healthy controls. This implies that a greater capacity for cognitive control may facilitate, rather than protect against, harm in suicidal individuals. These potential objective markers of suicidal thoughts and behaviors and suicidal risk severity are promising and demand further evaluation. The proposed behavioral and neuroimaging methodologies (diffusion imaging, morphometry analyses, univariate and functional connectivity neuroimaging) included in this proposal have been successfully applied by the candidate, a cognitive neuroscientist, in previous published work. The candidate's exploratory research objective is to apply machine learning algorithms to a blended dataset of participants? electronic health data and neurocognitive markers in a preliminary predictive modeling project. This exploratory objective will provide foundational data for future Merit- funded work focused on the development of clinically implementable suicide risk prediction tools. Though the proposed neurocognitive research has the potential to improve the effectiveness of suicide screening and treatment, the candidate acknowledges that all too often, insights from neuroscience fail to improve clinical care because few neuroscientists have the clinical perspective needed to translate mechanistic knowledge into clinical innovations. The protected time funded by this CDA award will allow the candidate to participate in activities imparting a unique combination of skills and perspectives that will allow the candidate to bridge basic and clinical science in the service of reducing Veteran suicide. The CDA training plan builds competencies in three areas: 1) methodologies and practical skills for suicide research, 2) psychiatric assessment and clinical perspective, and 3) training in bioinformatics and machine learning methodologies. The candidate is well- established within the VA system holding a Health Science Specialist position since 2015. The candidate's mentorship team is comprised primarily of VA clinician- scientists actively working with suicidal or high- risk populations and are well- qualified to mentor the candidate toward the career goal of becoming a leader in translational Veteran suicide research.

The proposed randomized control trial will examine the efficacy of a brief behavioral treatment for reducing suicidal ideation and for increasing reasons for living in older Veterans at risk for suicide. Two common issues in older adults, functional disability and executive dysfunction, increase suicide risk and will be examined as moderators and mediators of treatment outcomes. The proposed study will examine Problem Solving Therapy (PST) using a protocol that teaches skills to address emotional and practical barriers to effective problem solving. The VA usual care practice of collaborative safety planning will be the control condition, herein referred to as enhanced usual care (EUC). For participant safety, Veterans enrolled in PST will also receive EUC. The study design is random assignment to the treatment, PST plus EUC, or the control condition, EUC only. Both the treatment and the control are evidence-based interventions delivered in six sessions. The study will occur at VA Palo Alto (primary site) and VA Syracuse/VA Canandaigua (secondary site). The assessments and treatments will be conducted entirely by phone. Longitudinal assessment of suicidal ideation and reasons for living will occur at eleven timepoints: baseline, after each of the six weekly treatment sessions, posttreatment (7 weeks), at 1-, 3-, and 6-month follow-up. The recruitment goal is 150 Veterans over a five-year period with 75 participants randomized to each treatment. Veterans must be 60 years or older, report suicide ideation, and meet diagnostic criteria for a depressive disorder, anxiety disorder, and/or posttraumatic stress disorder to be eligible. Veterans will be excluded and referred for other services if they have psychotic symptoms, bipolar disorder, severe OCD, or elevated symptoms indicative of borderline personality disorder; an alcohol/substance use disorder; severe or unstable medical conditions; recent head injury (past year) or history of a head injury with loss of consciousness for 24 or more hours; terminal illness; positive cognitive screen indicative of possible dementia; or if they are unable to participate in the study or follow-up sessions. Recruitment will occur through multiple strategies at VA, Vet centers, and in the community to ensure the feasibility of recruiting a total of 75 Veterans at each site. To meet this recruitment goal, the primary and secondary site will each enroll 2 to 3 Veterans per month. Fidelity ratings of audiotaped treatment sessions will be made by independent raters on 20% of sessions. Mixed effects modeling will be used to estimate the effect of treatment versus the control for the outcomes of suicidal ideation and reasons for living. Models will covary for demographics, medical and psychiatric comorbidity, and psychotropic use. For the primary aim, models will determine whether PST plus EUC is associated with a larger treatment effect compared with EUC only for suicidal ideation and reasons for living. Secondary aims will determine if baseline functional disability and executive dysfunction moderate treatment outcomes, and whether a change in these two variables from baseline to posttreatment are significantly associated with (mediate) change in suicidal ideation and reasons for living. The tertiary aims will use qualitative methods to assess Veteran satisfaction with the treatment and control including the types of problems with which treatment helped them, and suggestions for improving it for future Veterans. The current VA/DoD Clinical Practice Guidelines (CPGs) for suicide do not list treatment options specifically for older Veterans despite the majority of VHA patients being 55 years or older. Thus, evidence-based outcomes from the proposed work have potential to inform the CPG recommendations for using PST with Safety Planning and/or Safety Planning alone with older Veterans. Dissemination of the treatment could be supported by expanding existing VA training infrastructure in problem solving based interventions.

This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine neurobiological mechanistic studies in animals with human imaging and biomarker analysis to understand the manner in which TBI influences impulsivity and suicidal behavior. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI is a risk factor for suicidality. Moreover, increased impulsivity is one of the most prevalent symptoms following TBI, and is itself a risk factor for suicide, depression and drug abuse. Thus, understanding the underlying mechanisms responsible for high impulsivity following TBI is key to understanding the link between TBI and suicide. Serotonin is important for rational decision-making and loss of serotonin neurons leads to increased impulsivity. Previously, we demonstrated that mild TBI (mTBI) in an animal model caused long-lasting suppression of the acoustic startle response (ASR), pathological inflammation and degeneration of neurons in the nucleus reticularis pontis caudalis (PnC), a brain region essential for ASR. Anatomically, serotonergic neurons in the pontine raphe nucleus are located in the immediate vicinity of the PnC, and it is not unreasonable to expect inflammation and neurodegeneration in the raphe nucleus following mTBI, as in the PnC. Our preliminary data support this idea. We also present preliminary results that mTBI increases motor and cognitive impulsivity following lateral fluid percussion injury in rats. The proposed studies will build on these preliminary results and investigate the hypothesis that inflammation and degeneration of the serotonergic raphe nuclei lead to increased impulsivity after TBI. This hypothesis will be tested in three aims. Aim 1 will determine whether mild TBI (mTBI) alone and in combination with social isolation stress enhances impulsivity. The lateral fluid percussion injury model will be used to generate mTBI in rats. Two aspects of impulsivity will be assessed: motor impulsivity and cognitive impulsivity using a Go/No-Go and a delay discounting procedure, respectively. It is predicted that impulsivity will be increased at 1 month and continue to worsen at 3 months after TBI. Aim 2 will determine whether mTBI causes inflammation and degeneration of serotonergic raphe neurons. The prediction is that mTBI will cause an early inflammatory response in the raphe nuclei, followed by loss of serotonergic neurons starting at 1 month after mTBI with greater degeneration at 3 months. Aim 3 will determine if blocking inflammation immediately or 1 week after mTBI or enhancing serotonin levels at the time of behavioral testing will prevent/reverse the TBI-induced impulsivity. It is predicted that blocking inflammation with an inhibitor of NFB will prevent inflammation from occurring after mTBI and thereby prevent degeneration of serotonergic neurons, and impulsivity. Additionally, selective serotonin reuptake inhibitors are expected to enhance synaptic serotonin and thereby reverse the enhanced impulsivity due to TBI. The proposed studies will test the novel hypothesis that loss of brainstem serotonin neurons is a key mechanism by which mTBI increases impulsiveness, a risk factor for suicide. While animal models are not able to directly assess suicide risk, this specific proposal will provide a mechanistic explanation of TBI-induced impulsivity, while human studies in this Collaborative Merit application will provide the final link between impulsivity and suicidality.

The overarching objective of this project is to develop improved statistical models for predicting risk for suicide among Veterans receiving VHA services.

This is a prospective study of treatment outcomes for patients newly diagnosed with major depression

This study aims to examine patient characteristics associated with an opioid-related overdose among Veterans receiving VHA services; as a secondary aim, this study will develop improved statistical models for predicting risk for opioid-related outcomes among Veterans receiving VHA services.

The main objective of this study is to use data from STARRS to identify service-related predictors of suicide following separation from active duty service.

The Veterans Health Administration (VHA) created a Veterans Crisis Line (VCL) as a 24-hour point of contact for Veterans who are at high-risk for suicide. VCL responders have answered more than 3 million calls (since 2007), 350,000 chats (since 2009), and 85,000 texts (since 2011). Despite being a widely-used VHA healthcare service targeting a priority outcome, the effectiveness of the VCL has yet to be evaluated. Specific aims are as follows: Aim 1. To examine the effect of VCL use on immediate call outcomes as measured by call monitors; Aim 2. To examine the effect of VCL use on post-call healthcare utilization patterns among patients who receive VHA care; Aim 3. To examine associations with changes in distress on healthcare utilization, and healthcare utilization on risk for suicide attempts and suicide death among VHA users using the Suicide Prevention Action Network (SPAN) and Suicide Data Repository (SDR).

This project will investigate rates of death by suicide and self-directed violence (SDV) among Veterans with a variety of neurodegenerative conditions who received care within the national Veterans Health Administration (VHA) between 2001 to present. If new NDI data becomes available from the Mortality Data Repository (MDR) during the study (which is expected), we will expand follow-up to the most recently available NDI data. Conditions of interest include: Amyotrophic Lateral Sclerosis (ALS), Spinal Cord Injury (SCI), Epilepsy, Huntington’s Disease (HD), Parkinson’s Disease (PD), Multiple Sclerosis (MS), Cerebral Vascular Accident (CVA), and Traumatic Brain Injury (TBI). The specific aim of this project is to compare rates of all cause death and death by suicide, as well as non-fatal SDV among Veterans with these diagnoses, and to compare these rates with rates of all cause death, death by suicide, and non-fatal SDV among Veterans without these diagnoses.

Veterans Health Administration (VHA) created a Veterans Crisis Line (VCL) as a 24-hour point of contact for Veterans who are at high-risk for suicide. There is a paucity of research on the potential impact of VCL interventions and a need to examine the use of emergency dispatches (i.e., 911) because of their life- saving potential and possible negative consequences.

Significance/Impact: The study examines the potential impact of VCL initiated emergency dispatches on critical outcomes among VCL callers who are at high risk for suicide. It responds to the President's Roadmap to Empower Veterans and End a National Tragedy of Suicide (PREVENTS) and the HSR&D (HX-19-004) Targeted Solicitation for Health Services Research on Veteran Suicide Prevention.

Innovation: The study will involve the first analyses to link VHA databases to examine the associations of emergency dispatches with critical outcomes and obtain Veterans' and responders' experiences with emergency dispatches. Specific Aims: Aim 1: Determine the association of an emergency dispatch with suicide deaths. Objectives are to 1a) identify key correlates of receiving an emergency dispatch, 1b) determine the association of emergency dispatch with treatment engagement within 30-days, and 1c) risk for suicide death over 365 days. We expect an emergency dispatch to be associated with higher treatment engagement (H1) and lower risk for suicide deaths (H2). Aim 2: Determine the association of agreeing to receive an emergency dispatch with combined suicide deaths and attempts. Objectives are to 2a) identify key correlates of agreeing to the dispatch, 2b) determine the association of agreement with treatment engagement within 30 days, and 2c) risk for combined suicide deaths and attempts over 365 days. We expect caller agreement with an emergency dispatch to be associated with higher treatment engagement (H3) and lower risk for combined suicide deaths and attempts (H4). Aim 3: Explore the experiences of Veteran VCL callers who receive and responders who initiate emergency dispatches. Objectives are to 3a) gather data on Veterans’ experiences with the call, emergency dispatch, and subsequent care, 3b) gather data on responder experiences initiating emergency dispatches, and 3c) identify potential improvements in emergency dispatch policy and measurement. Methodology: Quantitative analyses will examine key correlates of emergency dispatches and agreement, and their prospective associations with treatment engagement and suicide outcomes. Qualitative interviews with Veteran callers and VCL responders will be used to understand their experiences with emergency dispatches, evaluate the ecological validity of quantitative findings and inform policy and research.

Implementation/Next Steps: Findings will be presented to Veteran stakeholders and VCL leadership and responders to identify potential policy changes and variables that should be measured for future research. They may also contribute to research on implementing new emergency dispatch procedures across VCL sites.

The proposed project seeks to conduct analysis of suicide among Veterans discharged from VA psychiatric inpatient units. To identify risk and protective factors among Veterans discharged from acute psychiatric inpatient units.

The purpose of this project is to use clinical data from chart reviews of VA medical records to identify risk and protective factors that differentiate Veterans who died by suicide in the six-month period following discharge from VA nursing homes from those who did not die by suicide, during the period from fiscal year 2002 to 2011.

The purpose of this project is to evaluate the initiate a program of research to further evaluate its effectiveness across multiple outcomes, including: 1) proximal outcomes of the calls themselves including reduced caller distress, suicidality, and acceptance of a referral, 2) intermediate outcomes such as successful linkage and engagement in local mental healthcare, and 3) distal outcomes including reduced risk for suicide attempts and suicide.

Abstract not available at this time. If you have more information, please contact us at SuicidePreventionRes@va.gov.

Little is known about the role of medications in predicting suicide-related outcomes and unintended death in older Veterans. Veterans 50 years and older have the highest number of lives lost to suicide, make up the majority (> 70%) of the Veteran population, and are highly likely to experience conditions (e.g., chronic pain, sleep disorders, musculoskeletal) associated with commonly prescribed medications that are potential markers for suicide risk (hereafter referred to as “high-risk” drug categories, including benzodiazepines, sedative- hypnotics, opioids, antidepressants, and antiepileptics). The role of these medications in relationship to risk of suicide and unintended death in older Veterans is likely complex and, yet, extremely informative. Simply access to “high-risk” medications, similar to access to firearms, may increase risk. Moreover, medications may be causally linked where central nervous system-acting medications increase vulnerability to risk of attempting suicide. In addition, the type and amount of medication use can serve as a valuable marker of the presence and severity of psychiatric symptoms and associated emotional and mental distress, in ways that diagnostic codes alone are unable to capture. It is also likely that polypharmacy is an important indicator of a complex of comorbidities that increases risk of suicide. All-in-all there are multiple potential pathways where medications may be strongly associated with suicide risk in ways not fully captured by other predictors. Thus, information on medication use could substantially enhance our ability to identify older Veterans at high risk of suicide, above and beyond known risk factors such as the presence of psychiatric diagnoses. This could provide extremely valuable products by giving us tools to better identify high-risk Veterans, who could then be targeted for enhanced screening and early intervention to prevent suicide. With mounting concern regarding misclassification of suicides as accidental deaths by drug overdose, better understanding the impact of medications on death by unintentional injury is also important to informing suicide prevention efforts. Furthermore, examining associations by such factors as age, gender, race/ethnicity, homelessness, Vietnam Veteran status, service connected disability, posttraumatic stress disorder, and traumatic brain injury supports the Department of Veterans Affairs' mission to meet the needs of these vulnerable groups. To this end, the primary goal of our study is to determine the role of medications as prognostic factors, above and beyond other factors, in predicting risk of suicide and unintended death in older Veterans. We propose in this current application to add new questions on medication prescribing and use to an existing CSR&D Merit Award project (CX001119; PI: Byers), which has formed a unique cohort for late-life suicide research. This cohort includes all Veterans (~5,000,000) who used VA health care services, were initially 50 years and older in fiscal year 2012- 2013, and followed to present. This cohort includes information on all psychiatric and medical diagnoses and death by suicide and unintentional injury and suicide attempt. We propose linking multiple National Pharmacy databases (i.e., VA and Medicare) to this cohort – to study medications as a prognostic factor in predicting suicide-related outcomes and unintended death. In doing this, we will characterize the use of “high-risk” medications and polypharmacy prior to suicide-related outcomes and unintended death among older Veterans (Aim 1), determine whether use, and certain patterns of use, of “high-risk” medications (Aim 2) and polypharmacy (Aim 3) provide additional prognostic value above and beyond other predictors, and assess differences of associations by vulnerable groups (Aim 4). If this hypothesis is true that certain medications and patterns of use can identify older Veterans at increased risk of suicide and unintended death, it has important implications for clinical care. The use and initiation of medications could be utilized to target risk assessments and prevention programs for older Veterans at high risk. This is something the VA is uniquely positioned to do.

This Merit Award resubmission in response to the RFA CX-18-023 addresses one of the top VA priorities, suicide prevention. Recognizing those at the highest risk of suicidal behavior with an imminent need for acute medical intervention remains a fallible subjective decision based on known risk and protective factors. Unfortunately, the contribution of each of these risk factors is small. Thus, there is an urgent need to develop adequate algorithms to predict imminent suicide risk. The overall objective of this application is to test the value of intrinsic brain activity as a marker of acute suicidal behavior and examine potential clinical correlates. Our central hypothesis is that a neural pattern classifier based on resting state functional connectivity will identify acute risk for suicidal behavior, by discriminating recent suicide attempters from current suicidal ideators, in a reproducible and specific fashion. This application is the progression of our pilot work that used machine learning to show that neural pattern classification of resting state-fMRI data allowed a specific differentiation of recent suicidal attempters (within three days of the attempt) from patients currently endorsing suicidal ideation with 79% accuracy. We plan to test our central hypothesis by using resting state functional connectivity to discriminate depressed Veterans who recently attempted suicide (n=80) from depressed Veterans with suicidal ideation (n=80), and non-suicidal stress controls (n=40). We will build on our previous work, replicating the same strategy that resulted in a trained classifier in a larger independent and more heterogeneous sample, and test whether the addition of demographic, clinical, cognitive and biological variables associated with suicide may improve the classifier accuracy (AIM 1). We will examine the temporal specificity of our classifier testing its ability to discriminate: a) clinically stable suicide attempters: attempters rescanned 5-8 days later when symptom severity had subsided, from suicidal ideators, and b) depressed patients with and without lifetime history of suicide attempts. We will also scan a stress-control cohort of age-, sex-matched non-suicidal controls hospitalized in medical-surgical units and attempt to distinguish them from suicidal ideators (AIM 2). Exploratory AIM1 will be a step towards translation, we will examine resting state functional connectivity obtained in 1.5T and 3T scanners. In exploratory AIM2 we will attempt to identify a responsible mechanism by using regression analysis between the most discriminating connectivity pathways between recent attempters and ideators and suicide attempt intent and lethality. We aim to test the reproducibility and specificity of a neural pattern classifier to discriminate recent suicide attempters from current suicidal ideators as a proxy measure of acute suicide risk. This neural pattern classifier, directly based on the function of the ultimate agent of human behavior, has the potential to significantly inform on suicide risk assessment, using an already widely available technology.

The objective of this HSR&D Career Development Award-2 Proposal is to facilitate Dr. Jason Chen's transition into an independent, VA mental health services research career focused on intervention development for Veterans at high-risk of suicide. The goal of the project is to develop a multicomponent intervention focused on increasing social connectedness among Veterans with recent psychiatric hospitalizations through supported participation in community activities. This intervention will be informed by input from Veteran, VHA clinical (e.g. psychiatrists, administrators), and community (e.g. non-profit organizations, family) stakeholders. Research Plan: Although multiple national efforts have been introduced to address Veteran suicide, suicide rates remain high. Systematic reviews have identified few interventions that effectively decrease suicide risk. One promising area for intervention is social connectedness which has been identified as a strong protective factor. However, few interventions directly target social connectedness among at-risk individuals. Increasing Veteran participation in community activities may be one way to improve social connectedness difficulties. The current project proposes the following research aims: 1) Identify Veterans' current behaviors, needs, and preferences for community engagement following psychiatric hospitalization, 2) Identify VHA staff and community stakeholder perceptions and perceived needs related to Veteran community engagement following psychiatric hospitalization, and 3) Develop and pilot a multicomponent, peer-support facilitated intervention for increasing social connectedness among Veterans at elevated risk of death by suicide. Expected outcomes from these aims include clinical toolkits for VA and community stakeholders, academic manuscripts and presentations, and two HSR&D IIR submissions over the course of the CDA award period. Career Plan: Dr. Chen has assembled a mentorship team who will support his development as a VA mental health services researcher. Team members include: Steven Dobscha, MD (Primary Mentor), Julie Lowery, PhD (Co-Mentor; Implementation Science/Qualitative Methods), Paul Pfeiffer, MD, MS (Co-Mentor; Peer Support Intervention Development), Sarah Ono, PhD (Consultant; Veteran Engagement/Qualitative Methods), and Alan Teo, MD, MS (Consultant; Social Support). Dr. Chen will also have three Operations Partners/Consultants: Aimee Johnson, LCSW (Office of Mental Health and Suicide Prevention), Tracy Weistreich, PhD (Office of Community Engagement/Center for Compassionate Intervention), and Jason Zimmerman, CPSC (Peer Support Lead). Dr. Chen and his mentorship team have developed the following training goals which align with his research aims: 1) Develop advanced qualitative health services research skills, 2) Acquire intervention development and evaluation skills for conducting clinical trials, 3) Gain didactic and applied training in implementation science, and 4) Achieve further competence in program development to support effective VA-community collaborations including peer support. Dr. Chen will achieve these training goals through coursework, mentorship/consultant meetings, and applied training during CDA research activities. Following the completion of these training goals, Dr. Chen will be well-prepared to become an independent VA HSR&D mental health services researcher with expertise in utilizing qualitative methodology, clinical trials, implementation science, and program development to enhance current Veteran suicide prevention efforts.

Veterans who disengage from Veterans Health Administration (VHA) care are at elevated risk of death by suicide. The most recent national Veteran suicide data report shows that rates among this group have continued to increase over time, despite rates having decreased among Veterans who remain engaged in VHA care. This suggests that continued engagement in VHA care may be protective against suicide. Little is known about what predicts disengagement from VHA care, limiting upstream prevention efforts for supporting care engagement. The proposed Suicide Prevention Research Impact Network (SPRINT) Planning Grant will focus on Veterans who disengage from care in order to identify and test strategies to retain or re-engage those who may be at high risk for suicide. We will accomplish the following aims: Aim 1) Identify predictors for disengagement from VHA care among Veterans at risk for suicide; Aim 2) Examine the feasibility of research recruitment and collect pilot data among Veterans at risk for suicide who have disengaged from VHA care. We will achieve Aim 1 by extracting and analyzing data from the VHA Corporate Data Warehouse identifying Veterans with a positive screen on the Columbia Suicide Severity Rating Scale. We will utilize mixed effects, multivariable logistic regression to evaluate demographics, clinical, and health utilization predictors of disengagement from care in this potentially high-risk group. For Aim 2, we will employ an opt-out mailing approach to recruit Veterans from the cohort identified in Aim 1 into a brief study to determine patterns of recruitment response and to pilot test a newly developed interview guide. Study findings will inform a future mixed-methods IIR focused on further understanding health care experiences among Veterans at risk for suicide who disengage from VHA care and developing tailored intervention strategies for preventing disengagement.

Preventing suicide is a top priority for the Veterans Health Administration (VHA). Despite ardent and sustained efforts over the last decade, the suicide rate for VHA patients remains significantly higher than civilians and non- VHA using Veterans. Suicide prevention efforts for high risk VHA patients focus on clinical (e.g., mental health) and service use (e.g., case management) factors. What has yet to be tested is an approach that targets factors in community living, which are better conceptualized as rehabilitative in nature. For it is not only mental and physical illnesses that heighten suicide risk in VHA patients, but also struggles with their sense of self-worth, meaning, and social connections in the community. To help patients with high risk of suicide, this application proposes to adapt and test a promising approach called PREVAIL, which uses Peer Specialists (i.e., Veterans with psychiatric disabilities who have been trained to help others with similar conditions). Peer Specialists do not devalue clinical care but engage in rehabilitative tasks of building a life of self-respect and connectedness in one’s local community by offering empathy, hope, and advice based personal experience of mental health recovery. PREVAIL is promising, but still has not demonstrated clinical effectiveness and requires adaptation to address the unique characteristics of Veterans and the VA health care system. This project proposes to use Intervention Mapping, a multi-method, systematic approach using diverse stakeholders, to adapt and pilot PREVAIL. The VHA is the single, largest employer of Peer Specialists and research shows that they can enhance standard clinical care in mental health, physical health, and rehabilitative outcomes. However, Peer Specialists have only just begun to be deployed in suicide prevention efforts. The primary aims of this study are to: 1) Use Intervention Mapping to identify which components of PREVAIL require adaptation to reduce suicidal ideation in high risk VHA patients and to identify implementation strategies useful for the VHA system; and 2) Pilot test the feasibility and acceptability of the adapted PREVAIL, rehabilitative measures, and suicide-related outcomes for use in a rigorous prospective study. With guidance from a steering committee comprised of researchers, VHA leadership, and patients, needs assessment interviews with diverse VHA staff, Peer Specialists, and patients will be conducted to inform the adaptation. Based on results from the needs assessment and the literature on suicide prevention, psychiatric rehabilitation, and peer-based approaches, the steering committee will help adapt PREVAIL. Twelve high suicide risk Veterans with unipolar or bipolar depression will participate in a 3-month “pre- pilot” and provide feedback on how the adapted PREVAIL may be revised. After making any necessary modifications to the intervention, a second group of 12 high suicide risk Veterans with unipolar or bipolar depression will be recruited to participate in a formal pilot test to further evaluate the feasibility and acceptability of recruitment, retention, and assessment procedures. Patients will be from the West Haven and Newington Connecticut medical centers. The Peer Specialists will be from VA Connecticut’s Errera Community Care Center, one of VHA’s leading centers of innovation in psychosocial rehabilitation and one of the largest employers of Peer Specialists. All participants will receive standard VHA care from the Connecticut campuses while participating in this study. Participants will be assessed at baseline, post-intervention, and 3-month follow-up in their level of functional impairment and community integration; sense of hope, quality of life, meaning, and purpose; and self-views and social support. Chart reviews will also be completed at 3-month follow-up to assess for changes in health care visits involving suicidal behaviors. If acceptability (> 50% enrollment of eligible participants) and feasibility (> 70% of enrollees complete follow-up assessment) are demonstrated, this study will result in a novel rehabilitation-oriented suicide prevention intervention to test in a fully-powered randomized controlled efficacy trial.

1. At four VHA medical centers, randomize a total of N=254 Veterans with recent suicide attempt and emotion dysregulation to DBT-SG + TAU or TAU alone to evaluate DBT-SG effectiveness. Relative to TAU alone, we hypothesize that at 18-month follow-up, participants in DBT-SG will show: (H1a, primary outcome) reduced number of suicide attempts; (H1b) increased survival time for suicide attempt; (H1c) reduced suicidal ideation. We will also explore condition differences in putative changes in emotion dysregulation and coping skills. 2. Conduct a 3-part formative evaluation, guided by the I-PARiHS framework, to identify DBT-SG implementation barriers and facilitators in outpatient mental health clinics at four VHA medical centers before, during, and after the effectiveness trial. At each phase of the formative evaluation (developmental, process, and post-evaluation), we will seek the input of 60 key clinical, administrative, leadership, and Veteran stakeholders using mixed qualitative-quantitative methods to identify how factors such as evidence for DBT-SG, inner and outer context, recipient characteristics, and facilitation capacity impede or assist DBT-SG implementation.

Background: The suicide rate among female Veterans increased 63% between 2000 and 2014 significantly higher than the 30% increase observed among male Veterans during this period. Despite a large volume of work examining risk factors, barriers to care, and care utilization among Veterans, little research has examined these issues as they relate to females. Available research has been limited by small female sample sizes, cross-sectional analysis, and other methodological limitations. As such, we know surprisingly little about the health and psychosocial factors, barriers to care, and healthcare utilization patterns associated with suicidal behaviors among female Veterans. Data on female risk for suicide and their healthcare utilization is needed to direct valuable suicide prevention resources and help VHA address this growing and serious problem.

Objectives: The goal of our research is to inform gender-tailored suicide prevention approaches, using a large, national sample of female and male Veterans with recent non-fatal suicidal self-directed violence (SSV: fatal and non-fatal suicide attempts). We aim to: 1) Develop and test explanatory models of female and male risk for repeat SSV over 12 months, and 2) Identify similarities and differences in patterns of healthcare utilization, coping strategies, and symptom change over time between female and male Veterans at risk for SSV.

Methods: This will be the first mixed-methods, longitudinal cohort study of Veterans with a history of SSV, and is guided by a public health, social-ecological framework to facilitate examination of the range of proximal and distal risks for SSV. First, we will identify and enroll 30 female and 30 male Veterans for whom a non-fatal SSV event was recorded in a suicide behavior report in VA's Corporate Data Warehouse (CDW). These 60 Veterans will participate in qualitative interviews to gather data on Veterans' perspectives and experiences with suicidal thoughts and SSV, their recovery needs and experiences with the recovery process, barriers and facilitators to care, and how clinicians and the healthcare system could better identify and address the needs of Veterans like them. We will use a grounded theory approach to analyze transcripts to develop a theoretical model of risk for SSV among female Veterans, directly informing survey construct selection, quantitative analysis plans, and interpretation of quantitative findings. For the longitudinal survey, we will use suicide behavior reports in CDW to identify and enroll at least 480 female and 480 male Veterans, who will complete health and psychosocial measures at baseline, 6- and 12-month follow up. Self-report questionnaires will be informed by the qualitative findings and include psychosocial and health-related measures such as coping efficacy, interpersonal conflict, positive relations with others, trauma, occupational problems, barriers to care, and mental health symptoms. Participants will be followed for 12 months to assess and document all SSV events (primary outcome: an SSV event following baseline), which will be ascertained via multiple sources. Health and utilization data will be obtained from CDW and medical record progress notes. Main quantitative analyses will use a latent variable modeling framework to simultaneously model males and females in a multi- group format to test models of female and male Veteran suicide risk. We will then use latent class and latent transition analysis to identify differential responses to healthcare utilization and how certain health and psychosocial variables cluster together by gender.

Significance: Findings from this study will provide previously unavailable evidence to support the selection of intervention targets as well as identify high-priority services and barriers to care to direct programing and research priorities for female Veterans at risk for SSV. This work has the potential to also benefit the broader population of female Veterans with mental health conditions or other risk factors for SSV.

In this project we will: 1) Develop standardized procedures for identifying, abstracting, harmonizing, and disseminating study-level data from trials of suicide-prevention interventions, and 2) Identify trials of suicide prevention interventions and abstract detailed study-level data in a standardized manner into a publicly accessible database.

This revised proposal responds to HSR&D's Targeted Solicitation for Health Services Research on Suicide Prevention. Same-day psychiatric emergency clinics are increasingly implemented and are a best practice in increasing access to mental health care and in suicide prevention. Our preliminary data indicate a high frequency of suicidal ideation and recent suicidal behavior among Veterans accessing same-day mental health evaluation, and yet fewer than half of Veterans with these risk factors engage in outpatient mental health appointments that are set following their initial acute evaluation. To reduce risk of suicide during the transition from acute to outpatient care, it is unclear if models that “bridge” the transition should emphasize telephone outreach, as delivered by Suicide Prevention Coordination teams, or suicide-specific psychotherapy, such as Collaborative Assessment and Management of Suicidality (CAMS). CAMS is a brief transdiagnostic evidence-based psychotherapy that is recognized by the Joint Commission and Zero Suicide Framework as indicated for Veterans experiencing active suicidal ideation and/or recent suicidal behavior. This single-site 4- year randomized clinical trial addresses pragmatic questions regarding the relative impact of rapid referral to CAMS versus compared to outreach delivered by Suicide Prevention Coordinators for Veterans who are accessing same day mental health evaluation and who are gauged to be at elevated risk for suicide. In a Hybrid Type 1 research design, we propose to recruit Veterans from the same-day clinic setting who report recent or current active suicidal ideation and/or suicide attempt within the past 3 months. Veterans will be randomized to timely initiation of CAMS or to telephone outreach from Suicide Prevention Coordinators. The primary outcome (Aim 1) is the 12-month rate of suicide-related behavior or psychiatric hospitalization. Aim 2 contrasts indicators of operational efficiency between randomized conditions, including Veterans' rate of missed appointments at referred ongoing mental health care and urgent care re-presentation. We will also evaluate secondary outcomes (e.g., suicidal ideation severity). Aim 3 will examine the mediating impact of outpatient mental health treatment engagement on primary outcomes. Aim 4 evaluates fidelity to CAMS and its association with outcomes. Fidelity and in-person outcomes are measured by use of information technology, called eScreening, that is integrated with the electronic medical record and is used coordinate rapid referral and measurement-based care. This project builds on our preliminary data which indicate that research recruitment and rapid referral to CAMS therapy in same-day setting is highly feasible, acceptable and potentially impactful. This project is innovative in its focus on transitional care interventions in the same day clinic setting and its integration of health information technology to facilitate rapid referral, extensible to the dissemination of other evidence-based treatments. This research directly responds to the National Prioritized Research Agenda for Suicide Prevention, which emphasizes a need for care models that deliver “suicide-specific intervention as soon as risk is identified” and addresses important gaps on the impact of timely suicide prevention strategies identified the White House report. The study also responds to the HSR&D Mental and Behavioral Health, Access, and Care Coordination Priority Areas. We expect that these data will inform best practices in suicide prevention in same day mental health services where many at-risk Veterans are seen.

Project summary: The rate of suicide among women Veterans has grown in recent years and is significantly higher than that of women who have not served in the military. The Veterans Crisis Line (VCL) is a VA suicide prevention initiative that connects Veterans in crisis, as well as concerned family or friends, with supportive resources to prevent suicide. The purpose of this study is to identify the characteristics of women Veteran VCL users and how they compare to male Veteran VCL users, identify the relationship between VCL contact characteristics suicide-related outcomes among male and female Veteran VCL users, and identify the experiences and recommendations of women Veteran VCL users. Through analysis of administrative clinical data and in-depth interviews with women Veteran VCL users, along with input from a multi-stakeholder advisory board, this research will serve to develop clinical recommendations and implementation strategies to strengthen suicide prevention initiatives specifically for vulnerable populations of women Veterans. Specific Aims: The specific aims of this study are to: (1) describe and compare the demographic and VCL contact characteristics (reason for call, call outcome, and VCL risk rating) among female and male Veteran VCL users; (2) examine the relationship between VCL contact characteristics (risk rating, referral, identified needs) and subsequent fatal and non-fatal suicidal self-directed violence (S-SDV), assessing for variation by Veteran gender, among female and male Veteran VCL users who use VHA services; (3) understand women Veterans’ experiences with and recommendations regarding VCL services, including the use of VCL for both acute and more upstream suicide prevention.

Suicide cognitions are significant risk factors for suicidal ideation and behaviors. Reducing the tendency to experience these thoughts may be life-saving. Dr. Dillon has developed and piloted an interpretation bias modification intervention that reduces both hostile interpretation bias and anger outcomes. The current project will use this paradigm to develop an intervention to reduce suicidal cognitions for Veterans with posttraumatic stress disorder (PTSD). In addition to targeting suicide cognitions, the project will also assess the impact of reductions in hostile interpretation bias on suicide risk and functioning. Hostile interpretation bias is a cognitive tendency that is associated with problematic anger. Moreover, recent research by Dr. Dillon and others shows a consistent association between anger and risk for self-directed violence. In fact, two recent ecological momentary assessment (EMA) studies conducted by Dr. Dillon in conjunction with Drs. Kimbrel and Beckham have shown that: 1) anger was the emotion most strongly associated with self-injurious thoughts and behaviors among Veterans with a history of self-directed violence; and 2) that anger was highly predictive of future self-injurious thoughts and behaviors among Veterans. Thus, we hypothesize that hostile interpretation bias may be a promising target for suicide prevention efforts. Accordingly, we propose to pursue the following specific aims: Aim 1(a). Develop a mobile interpretation bias modification intervention entitled Mobile Intervention for Suicidal Thoughts (MIST) to reduce cognitions that contribute to elevated suicide risk. We will develop content to target cognitive factors that contribute to suicide risk and program this content into a mobile application similar to an existing app developed by the team to target hostile interpretation bias, entitled MIRA. Aim 1(b). Use a successive cohort design to refine the MIST intervention among Veterans with PTSD, problematic anger, and elevated suicidal ideation. To refine the intervention developed in Aim 1(a), the intervention will be tested in two cohorts (each n = 5) of Veterans with PTSD, problematic anger, and suicidal ideation. After each cohort uses the MIST application for four weeks, a quantitative and qualitative evaluation will be conducted with each Veteran. Revisions will be conducted before the next cohort is treated. Aim 2.Assess the impact of reductions in suicide cognitions and hostile interpretation bias on suicide risk and functioning. After using the MIST intervention for four weeks, participants will use the MIRA intervention for another four weeks. For the duration of the study (all eight weeks of treatment), EMA data will be collected to evaluate the impact of both interventions on suicide risk and daily functioning.

Aim 1: In a national, stratified random sample of Veterans screened in primary care and specialty mental health settings, using quantitative surveys, characterize Veteran experiences with the VA Risk-ID screening process and clinical evaluation that takes place in response to screen results. Aim 2: Conduct semi-structured qualitative interviews with A) Veterans who participate in the three stages of VA Risk-ID screening; and B) clinical staff who participate in the three stages of screening. The analysis will prioritize identification of ways to improve screening and patient engagement in treatment after screening. Aim 3: Among Veterans screened with VA Risk-ID in primary care, examine the extent to which screening process and survey variables are associated with mental health treatment utilization variables over 6 months. Aim 4: A) In a national, stratified random sample of Veterans screened in emergency departments (EDs), using mixed methods, characterize Veteran experiences with the VA Risk-ID screening process and clinical evaluation that takes place in response to screen results; B) Among Veterans screened with VA Risk-ID in EDs, examine the extent to which screening process and survey variables are associated with mental health treatment utilization variables over 6 months.

Objectives: The goal of VHA’s Health Services Research and Development (HSRD) COnsortium of REsearch (CORE) initiative is to accelerate research that will lead to improvements to care delivered to Veterans. The mission of the “Suicide Prevention Research Impact NeTwork (SPRINT)” CORE is to accelerate health services Suicide Prevention (SP) research that will lead to improvements in care and result in reductions in suicide behaviors among Veterans.

This 2-year, open-trial pilot study will examine the feasibility and acceptability of a group intervention called Caring Cards (CC). CC is a peer approach to caring contacts for suicide prevention. In this study, Veterans who have a history of suicide risk the opportunity to make cards that are then sent to Veterans who are currently at high-risk for suicide. This study will directly benefit Veterans and contribute to the quality of services provided by VA by creating a safe, creative space for Veterans with lived experience related to suicide risk to join together to provide messages of hope, community, and resilience to their peers at risk for suicide. Helping Veterans support one another provides a bridge for social connection, which may help prevent Veteran suicide. This intervention may also improve Veterans’ satisfaction with VA healthcare and engagement with mental health treatment.

The aim of this intervention pilot grant is to examine the acceptability, feasibility, and utility of a group-based treatment designed to reduce suicidal thoughts and behaviors in a sample of high-risk, rural Veterans. United States (US) suicide rates are the highest they have been in three decades, with over 44,000 individuals dying by suicide each year [1]. According to recent reports, rates of suicide have been increasing for both men and women across all age groups in the US [1]. Similarly, following US military combat operations in Iraq and Afghanistan, suicide rates have steadily increased among active duty military and Veteran populations of all eras [2][3][4]. Currently, suicide rates are 22% higher among Veterans than civilians [4]. Consequently, suicide prevention has become a top priority for the Department of Veterans Affairs (VA). Efforts to decrease death by suicide among Veterans include the utilization of evidence-based psychotherapies (EBPs) that target suicidal thoughts and behaviors directly. One such EBP is Brief Cognitive-Behavioral Therapy for Suicide Prevention (BCBT-SP) [5]. Although efficacious, the evidence base for BCBT-SP is grounded in an individual therapy format with much less known about the impact of group-based delivery. Given the increasing rates of suicide among Veterans, in particular rural Veterans [6], a group-based protocol may offer a practical and cost-effective solution to reducing suicide rates while also increasing access to care. To this end, the primary aim of the current proposal is to test the acceptability and feasibility of BCBT-SP delivered in a group-based format to a sample of high-risk, rural Veterans. Given that this is a pilot project, reduction of suicidal thoughts and behaviors will not be emphasized, as we will likely be underpowered to detect treatment effects. Moreover, given that this is a single-arm study, we will be unable to compare treatment effects or rates of attrition to a control or treatment as usual (TAU) group. Nevertheless, a secondary aim of this proposal is to examine the utility of BCBT-SP by collecting outcome data on suicidal ideation and associated symptoms (e.g., anxiety, depression, hopelessness). This pilot will provide preliminary data to support a proposal to a federal funding agency to compare the efficacy of BCBT-SP delivered in a group-based format in-person versus telemental health in reducing suicidal thoughts and behaviors among high-risk, rural Veterans. The current proposal aligns with the South Central Mental Illness Research, Education and Clinical Center (MIRECC) mission by supporting the development and dissemination of an EBP designed to reduce suicidal thoughts and behaviors among an underserved population of rural Veterans.

In this proposal, the investigators extend their previous SPiRE feasibility and preliminary effectiveness study to examine STEP-Home efficacy in a RCT design. This novel therapy will target the specific needs of a broad range of underserved post-9/11 Veterans. It is designed to foster reintegration by facilitating meaningful improvement in the functional skills most central to community participation: emotional regulation (ER), problem solving (PS), and attention functioning (AT). The skills trained in the STEP-Home workshop are novel in their collective use and have not been systematically applied to a Veteran population prior to the investigators' SPiRE study. STEP-Home will equip Veterans with skills to improve daily function, reduce anger and irritability, and assist reintegration to civilian life through return to work, family, and community, while simultaneously providing psychoeducation to promote future engagement in VA care. The innovative nature of the STEP-Home intervention is founded in the fact that it is: (a) an adaptation of an established and efficacious intervention, now applied to post-9/11 Veterans; (b) nonstigmatizing (not "therapy" but a "skills workshop" to boost acceptance, adherence and retention); (c) transdiagnostic (open to all post-9/11 Veterans with self-reported reintegration difficulties; Veterans often have multiple mental health diagnoses, but it is not required for enrollment); (d) integrative (focus on the whole person rather than specific and often stigmatizing mental and physical health conditions); (e) comprised of Veteran-specific content to teach participants cognitive behavioral skills needed for successful reintegration (which led to greater acceptability in feasibility study); (f) targets anger and irritability, particularly during interactions with civilians; (g) emphasizes psychoeducation (including other available treatment options for common mental health conditions); and (h) challenges beliefs/barriers to mental health care to increase openness to future treatment and greater mental health treatment utilization. Many Veterans who participated in the development phases of this workshop have gone on to trauma or other focused therapies, or taken on vocational (work/school/volunteer) roles after STEP-Home. The investigators have demonstrated that the STEP-Home workshop is feasible and results in pre-post change in core skill acquisition that the investigators demonstrated to be directly associated with post-workshop improvement in reintegration status in their SPiRE study. Given the many comorbidities of this cohort, the innovative treatment addresses multiple aspects of mental health, cognitive, and emotional function simultaneously and bolsters reintegration in a short-term group to maximize cost-effectiveness while maintaining quality of care.

Anhedonia and amotivation are common in depressive presentations, and putatively thought to be caused by alterations in the ways in which the brain anticipates, evaluates, and adaptively uses reward-related information. However, reward processing is a complex, multi-circuit phenomenon, and the precise neural mechanisms that contribute to the absence or reduction of typical hedonic and motivational outputs seen in the clinic are still being elucidated. Heterogeneity in the clinical presentation of depression has long been a rule rather than an exception, including individual variation in symptoms, severity, and treatment response. This heterogeneity complicates understanding of depressive pathophysiology and thwarts progress toward personalized disease classification and treatment planning. If the goal of personalized medicine in psychiatric care is to be realized, biomarkers that account for the full range of depressive presentations need to be developed (and ultimately validated). Discovery of biomarkers that go beyond the level of aggregate disease definitions to account for neurobiological variation that presumably underlies distinct clinical manifestations is critical to this larger effort. The proposed work combines clinically motivated questions with in-depth study of neurobiological mechanisms to evaluate how reward system neurobiology contributes to expression of reward-related deficits, such as anhedonia and amotivation in major depressive disorder (MDD), with a particular emphasis on understanding depressive heterogeneity. Conceptually, we will use a multi-measure approach, by studying Veterans with i) a passive slot machine reward task to isolate brain responses to reward anticipation and receipt in the absence of confounding higher-order cognitive demands, and ii) a delay-discounting task to assess higher-order aspects of reward processing necessary for reward valuation and decision-making. Methodologically, we will use a multi-modality approach by combining fMRI, EEG, and behavioral assessment, to more fully characterize reward-related brain functions and their clinical correlates. In addition to evaluating reward effects between Veterans with MDD and healthy controls (HC), and examining depressive heterogeneity within a large (n=150) MDD group, we will also focus on understanding the relationship between reward processing and clinical features of high relevance to depression, with an emphasis on suicidality. Specific Aim 1 will establish MDD deficits in reward processing at the level of group averages (i.e., case-control comparisons of MDD vs. HC). Specific Aim 2 will examine the extent to which data-driven subtyping of MDD can derive “biotypes” in Veterans, based on our EEG and fMRI reward processing metrics, that segregate clinically relevant features. Specific Aim 3 will compare subgroups of MDD with varying levels of suicidality.

The purpose of this project is to support efforts related to internal implementation and evaluation to evaluate the effects of the VCL regarding suicide prevention among Veterans. PEPReC will conduct quantitative analyses of VCL use and outcomes, impacts of VCL changes (e.g., expansion of a national suicide hotline [988] that will facilitate connection to VCL), and VCL staffing.

The United States is currently experiencing a national epidemic of suicide for its youngest Service Members (SMs) still serving in the Department of Defense (DOD, 2019) and those that have already transitioned out of the military. For example, the rate of suicide for Veterans aged 18- 34 years old having more than doubled from approximately 22 suicide deaths per 100,000 in 2006 to 45 per 100,000 in 2016 (VA, 2018; VA 2019). It appears that a period of significant risk for these young Veterans is during their first year after separating from the military with recent estimates suggesting an increase of nearly 50% during this period (Kang et al., 2015; Shen, Cunha, & Williams, 2016). As a result of the troubling trends, two executive orders have been issued within the last two years calling for federal organizations to work closer with local, nonprofit and academia organizations to implement a public health approach to suicide prevention. Preventing suicide remains a top priority for the VA with similar sentiments of a public health perspective to suicide prevention being recently published National Strategy for Preventing Suicide (VA, 2018). In this strategy, the VA acknowledged that it must reach out to Servicemembers (SMs) and Veterans in the community before they experience an acute crisis (VA, 2018). Similarly, VISN 17 made a significant commitment to the Expiration Term of Service (ETS) Sponsorship program in order to engage SMs prior to them exiting the military. Preliminary analysis was conducted for a recent randomized control trial with post- 9/11 Veterans in New York City that received the support from ETS Sponsors with the results showing a moderate treatment effect for both reduced transition stressors and improved social support (Geraci, 2018). Aims. We propose a Hybrid Type 2 effectiveness-implementation trial to evaluate the expansion of ETS Sponsorship across six cities from FY 2020 to 2023 in Texas. Aim #1 will determine the effectiveness of the ETS sponsorship program, as evidenced by measures of transition stressors, social support, psychological distress, suicidal ideation and behaviors, and VA/non-VA service utilization. Aim #2 will determine the feasibility and potential utility of implementing the ETS Sponsorship program to six cities in Texas. SMs that transition to cities without an established ETS Sponsorship program will experience their transition from military to civilian life as usual (i.e., services available from the U.S. Army Soldier for Life-Transition Assistance Program). After cities have implemented the ETS Sponsorship program, transitioning SMs will have access to an ETS Sponsor in their city and warm handoffs to community services. Methods. We will use a stepped wedge design while using other cities as controls until they begin implementation. This design will allow us to extend implementation support to the maximal number of cities and enhance the formative evaluation (periodic reflections with key partners and SM interviews). The stepped wedge design also enables us to make efficient use of all data available for within-site and between-site comparisons. For the within-site comparison, cities will act as their own controls in a program evaluation that compares cities pre- versus post- implementation. The comparison examines cities as they cross-over from control to intervention states. The between-site comparison evaluates the intervention period for a city vs. all other intervention and control periods for all cities. Outcomes of interest are measured for all transitioning SMs at each city within the given intervention time period. We randomized at the city level and will use individual SMs as the unit of observation for primary quantitative outcome measures. Six cities will participate in the program evaluation, with two cities allocated to each of the three start dates or steps. Hierarchical models will be run in which SMs are nested within city analyzing the results of the pre-implementation and postimplementation assessments. Hierarchical random effects models examine within- and between-group change across time and by condition.

Despite the enrichment of VA suicide prevention services and implementation of the national suicide hotline, Veteran suicide completions occur 20 times per day and suicide attempts numbered over 15,000 in 2012. These data underscore the urgency of developing additional interventions targeting suicidal Veterans. The construction of a Suicide Safety Plan (SSP); a best practice, is mandated throughout the VA system, and a vital component of the VA's coordinated effort at suicide prevention and recovery. Safety Planning in Veterans presenting to an emergency room has been shown to decrease suicide behavior. To our knowledge, there are currently no recommended guidelines or mechanisms for refinement of the SSP in adult populations beyond its initial development. Project Life Force (PLF), a novel suicide safety planning group intervention has been designed to fill this critical gap and provide a mechanism to develop and enhance suicide safety planning over time. PLF, a 10-session, group psychotherapy intervention, combines Dialectical Behavioral Therapy (DBT) skill based and psychoeducational approaches, to enhance suicide safety planning development and implementation. Veterans revise their plans over several weeks while learning distress tolerance, emotion regulation, and friendship building/interpersonal skills to incorporate into their safety plans and also receive lessons on gun safety and minimizing access to lethal means, augmenting physical well being and strategies how to share their plan with family/significant others and their treatment team. Importantly, the group format mitigates loneliness and fosters increased belongingness, both key risk factors for suicide. Additionally, PLF's weekly format facilitates VA-mandated monitoring for any Veteran placed on the suicide high risk list. PLF received pilot SPiRE funding from the VA Rehabilitation and Research Development in 2015 to finalize the development of the intervention's manual and pilot the intervention in Veterans. Preliminary data suggests high levels of feasibility, and acceptability. 100% of participants developed updated safety plans and increased use patterns and a significant decrease in suicidal ideation. This project's aim is to conduct a multi-site (James J Peters VAMC and Philadelphia VA) randomized clinical trial (RCT) of PLF versus treatment as usual (TAU) that includes individual telephone review of safety plans in 265 suicidal Veterans with follow up to one year. The primary outcome variable is suicidal behavior, using a rigorous, multi-method assessments follow-up. Secondary outcomes include depression, hopelessness and treatment utilization. Exploratory analyzes will examine whether changes in suicide coping and levels of group cohesion in PLF mediate treatment response. Methodological rigor includes ongoing adherence ratings for PLF and assessment training/monitoring by an independent third site (Columbia University).

We have developed an internet based manualized group intervention that builds a COVID-19 resiliency/action plan titled- “Project Life Force- COVID 19”. This is 9 sessions and each session focuses on a step of the “action plan” (similar idea as a suicide safety plan) with particular focus on teaching coping skills, mindfulness. Differentiating covid 19 anxiety from physical symptoms, how to secure food, better exercise, access mental and physical health care, recognize warning signs, stay positive, practice gratitude and maintain connection with people despite social distancing. Pilot project has VISN 2 MIRECC funding and is currently enrolling subjects.

Rural, as compared to urban Veterans have compounded suicide risk, including limitations in access to mental and physical health care, increased firearm ownership, lower quality of life, and socioeconomic inequalities in income, education, and community resources. Recent advances in addressing the rural Veteran suicide risk problem, include building community partnerships such as “Together with Veterans”. However, there exist no “suicide-specific” clinical interventions that leverage this growth in community partnerships nor directly target rural Veterans who do not seek VA care. Our proposal aims to address this gap by directly linking a tested telehealth safety planning and lethal means safety group intervention tilted “Project Life Force” (PLF) with Veterans identified through community partners in rural Arkansas. We propose to pilot the implementation of PLF for rural Veterans (PLF-RV), in Baxter County, Arkansas. The “Project Life Force” (PLF) intervention is a manualized, 10-session suicide safety-planning and lethal means safety group, now fully converted since March 2020 to a telehealth intervention. PLF-RV will use the original curriculum, and procedures as the original PLF project, but instead of recruiting participants from VA facilities, recruitment will be performed by Veteran Service Organizations and the Regional Medical Facility. Using a type 1 hybrid effectiveness-implementation design, we will determine effectiveness of our telehealth clinical intervention and better understand the context for implementation using a multi stakeholder process evaluation. Specifically, we will (a) test clinical feasibility, acceptability, and initial effectiveness of the PLF-RV intervention, and (b) identify barriers and facilitators that may impact implementation of PLF-RV. The data from this pilot will allow us to apply for a larger MERIT either through Office of Rural Health or HSRD for wider scale implementation of PLF RV. Our overarching goal is for PLFRV to serve as a prototype for future suicide prevention 2.0 collaborative efforts integrating “suicide-specific” interventions with community engagement.

This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19- 006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine neurobiological mechanistic studies in animals with human imaging and biomarker analysis to understand the manner in which TBI influences impulsivity and suicidal behavior. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. Recent research increasingly highlights mild traumatic brain injury (mTBI) as a risk factor for suicidal thoughts and behaviors, including death by suicide. A study by Co-I Brenner found that Veterans with mTBI died by suicide at 1.8 the rate of the general Veteran population. The elevated suicide risk in Veterans with TBI is also consistent with previous research in civilians. Nevertheless, the study of suicide among those with mTBI is limited and there exists minimal understanding of the mechanism underlying this enhanced suicide risk in mTBI. There is a growing appreciation of the role of dysfunction in the circuits and white matter tracts underlying decision making in individuals with mTBI and history of a suicide attempt. However, neuroimaging studies examining the intersection of suicidal behavior and mTBI are limited. Moreover, how impulsivity and mTBI influences the development of suicidal behavior is also unclear. This project aims to address this gap with a neuroimaging project examining facets of impulsivity in Veterans with mTBI and a suicide attempt history. The James J. Peters VA (JJPVA) site proposes to investigate in male and female OEF/OIF/OND Veterans (n=140), the relationship of cognitive and behavioral impulsivity using a 2 (mTBI+/-) x 2 (history of suicide attempt (SA)+/-) design approach. Specifically, we will be examining four groups of Veterans: mTBI+/ SA+, mTBI+/SA-, mTBI-/SA+ and mTBI-/SA-. This project complements the animal studies being conducted at the New Jersey VA site by utilizing the same paradigms in humans during fMRI: the Go/No-go (motor) and Delay discounting (cognitive) task to assess impulsivity in both animals and humans. A primary objective of this study is to characterize alterations in brain activity and functional connectivity related to motor and cognitive impulsivity during fMRI in our four groups of Veterans. The secondary objective is to examine the relationship between white matter integrity using diffusion tensor imaging (DTI), and dynamic causal modeling with data from our two behavioral tasks of impulsivity performed during fMRI, along with psychometrically-validated measures of impulsivity. The third objective will be to determine similarities and differences in impulsivity data from animal TBI models and humans. All Veterans will receive rigorous diagnostic assessments, measures of impulsivity, clinical assessments of suicidal behavior, and a MRI scan (including structural MRI, DTI, and fMRI while performing impulsivity tasks). Blood will also be obtained for biomarker analysis, conducted by the Indianapolis VA site. Identifying potential neurobiological biomarkers for heightened suicide risk in Veterans with mTBI is essential for developing targeted care. The proposed research is translational as similar parallel analyses will be performed in humans and animals for investigating common neuronal circuits activated by impulsivity and genomic biomarkers.

This project identifies VA Suicide Prevention Team members’ successes, challenges and needs around rural Veterans’ suicide prevention, develops recommendations for supporting Suicide Prevention Teams’ outreach and engagement in rural areas, and plans for an intervention to support rural Veterans in FY 22.

One of the key challenges in suicidality research is that outcomes may be multi-determined and rare. The causes of suicidal behaviors may consist of a combination of factors, which vary over time, and between individuals and groups. Risk factors may be distal or proximal, and distal exposures may increase risk for suicide given changes in proximal risk factor(s). Despite literature on suicidality among lesbian, gay, bisexual, and transgender (LGBT) persons, little research has examined LGBT Veterans. We hypothesize that LGBT status is a pre-disposing factor that increases risk due to minority stress, the stress of prior and potentially ongoing discrimination, including military sexual trauma, that may be further increased due to proximal factors such as comorbid mental health and medical conditions, a lack of engagement in care, system and providers lack of awareness or insensitivity to their unique needs, and pain among other factors. With the 2011 repeal of the Don't Ask, Don't Tell (DADT) policy, LGB personnel are currently able to openly serve in the US military, while the status of T personnel remains uncertain. While LGBT Veterans, especially those who served prior to repeal of DADT, may suffer similar discrimination, stigma and stress, they may each have dissimilar suicide risks. One study in the VA found that the prevalence of gender identity disorder diagnosis was >5 times higher than in the general US population, and that the rate of suicide-related events was > 20 times higher than the VA population. However, the engagement of LGBT Veterans in VA care is difficult to estimate: sexual orientation and gender identity (SO/GI) data is not collected in a structured manner. The VA's Evidence Review: Social Determinants of Health for Veterans found “only two articles examined sexual orientation for Veterans and non-Veterans and included only women. No articles addressed gender identity for Veterans and non-Veterans”. In addition to LGBT status, there is less study of other suicide risk factors such as pain and opioid prescriptions as well as potential protective factors such as receipt of complementary and integrative health services, which may treat both pain and PTSD. Little is known about how race/ethnicity, gender, morbidity, and treatment intersect with sexual orientation/gender identity to impact suicidality risk. Using VA electronic health record data, will identify LGBT Veterans to ascertain pathways to suicidal behavior, and assess both risk and protective factors related to LGBT individuals in all gender, age, and racial and ethnic groups. In a current project (IIR 16-262), our team is developing natural language processing (NLP) and machine learning (ML) tools to study CIH services' effect on opioid prescribing among Veterans with musculoskeletal disorder diagnoses (MSD) and PTSD. In another project (CRE 12-012), we identified 15,000+ Veterans with suicide attempts near the MSD diagnosis date, and 17,000+ suicide deaths in the cohort (N=5.2 million). That work informs this proposal. Because suicide attempts (SA) might not be captured if a Veteran presents at a non-VA hospital, we will integrate CMS data and develop NLP and ML tools to extract information from VA clinical notes as part of care. The objective and aims of this study are to: Aim 1: Develop informatics tools to identify LGBT Veterans and suicide attempts and events. Aim 2: Characterize suicide risk factors in a national sample of veterans. Aim 3: Examine the differential effect of risk factors on suicide by LGBT status. Achievement of these objectives and Specific Aims promise to expand our understanding of potential areas of unmet need and outreach to all individuals at risk for suicide. This area of VA health services research is in its infancy. Next steps will include: examinations of service(s) use after policy changes and VHA directives such as repeal of DADT (2010) and DOMA (2013), and VHA Directives 1340 and 2011-024 as noted in the letter of support from the VA's LGBT Health Program (10P4Y); using SHEP data to examine differences in satisfaction with care; and sorely needed data on differences in outcomes of care for LGBT Veterans.

Suicide prevention among rural veterans is an urgent VA priority. The COVID-19pandemic has exacerbated rural-urban disparities in health access and in suicide risk. Telehealth can improve health care access for rural veterans but there is insufficient evidence about its effectiveness for reducing suicides among veterans. In 2016, VA’s Offices of Rural Health (ORH) and Connected Care (OCC) began distributing video-enabled tablets to veterans with access barriers to facilitate their participation in home-based telehealth. VA-issued tablets present an opportunity to pilot a scenario in which veterans face fewer barriers to accessing home-based telehealth. The proposed project will be the first study to examine the impact of telehealth tablets issued by the VA during the COVID-19 pandemic on suicide-related hospitalizations and suicide deaths. We will use a modified difference-in-differences study design to compare suicide outcomes for veterans who received VA-issued tablets during COVID-19 and veterans who never received VA-issued tablets, one year before and one year after tablet shipment date. Given concerns of the rural/urban technological digital divide, we will stratify our analyses by rurality in order to assess the differential effectiveness of tablets across rural and urban veterans. While worse broadband access could result in tablets being more effective for urban veterans, the positive effect of tablets could be greater for rural veterans due to larger barriers to mental health care access they face at baseline. Subgroup analyses of “ReachVet” veterans who the VA identifies as highest risk of suicide will inform whether the VA needs to adopt differential strategies for veterans with different levels of suicide risk. These findings will inform future research, policy and implementation efforts for VA’s suicide prevention strategies, VA’s distribution of telehealth tablets and VA’s home telehealth policies.

SUMMARY Dr. Haghighi's research specialty is in medical epigenetics with applications to traumatic brain Injury (TBI), depression, and suicidal behavior. These epigenetic studies involve how genes are differentially transcribed and regulated, within human clinical and postmortem brain samples, providing a snapshot of potential transcriptional regulatory abnormalities associated with disease neuropathology. Dr. Haghighi's clinical studies show how environmental exposure affects the epigenome. Specifically, in her studies involving traumatic brain injury, she investigates how response to repeated blast-exposure induces long-term transcriptional regulatory changes resulting in symptoms of sleep disturbances, anxiety, cognitive deficits and depression and PTSD. Additionally, she investigates how the role of stress, specifically chronic stress, induces epigenetic changes associated with depression and suicide in the Veteran population.

Suicidal behavior is a complex phenomenon, ranging from low-lethality, low-intent impulsive acts to high- lethality high-intent suicidal acts, and thus likely to be associated with multiple underlying subtypes. Genetic associates of suicidal behavior have been identified in several studies, yet the effect sizes for are usually modest, possibly because of the heterogeneity in the suicidal population and the behavior. Using the Million Veteran Program Gamma computational platform, we propose a unique combination of statistical and machine learning methods to develop our subtypes based on Electronic Patient Records and self-reports; followed by a careful genomic analysis of the resulting subtypes compared to two control groups chosen from the same cohort, with and without mental health disorders. This project aims to develop sophisticated diagnosis tools for preventing future suicidal behavior in US Veterans at high risk. Moreover, the biomarkers identified from this study will be directly applied for validation in the PI and co-investigators' longitudinal study of high-risk VA patients, a natural validation sample from the same population; promising a combination of the power of both studies.

We propose a set of studies focused on the association of suicide with neuroinflammation and compromise of the blood-brain barrier, with the goal of identifying a pattern of quantifiable abnormalities that could serve as a biomarker for imminent suicidal risk in our Veterans. Autopsy studies are uniquely suited to do this, because they capture the state of the brain at the time of the suicidal act. Findings from our laboratories and others indicate that susceptibility to suicide includes inflammatory activation in the brain and systemically, accompanied by compromised integrity of the blood-brain barrier: (1) Most directly, we reported increased densities of microglia or other phagocytic cells associated with blood vessels in dorsal prefrontal white matter of people who died by suicide, Similar results are reported in cingulate white matter. (2) Studies of brains from individuals who died by suicide and studies of blood and CSF from live individuals who had previously attempted suicide found elevations of inflammatory cytokines. (3) Various infectious diseases are associated with increased risk of suicide, as is a history of hospitalization for any infection. (4) Laboratory animals exposed to stress show elevated levels of inflammatory cytokines, increased permeability of the blood-brain barrier, behavioral abnormalities, and activation of microglia. (5) We have reported an association of suicide with a polymorphism and decreased frontal and cingulate transcripts for CD44, which is involved in the normal function of the BBB. (6) Biochemical measures suggesting BBB impairment are reportedly associated with attempted suicide and with suicidal ideation. (7) In MDD subjects who died by suicide, compared with nonpsychiatric non-suicide cases, we found differential methylation of genes associated with cell death, both in whole cortical homogenates and in purified neuronal fractions. We also found significantly lower methylation in the promoter of the gene for CCL3, a powerful inflammatory cytokine synthesized by microglia and astrocytes and an attractant for microglia and white blood cells, but this difference was not present in the purified neuronal fraction. Taken together, these findings lead us to hypothesize a suicidal state characterized by impaired BBB function, elevation of pro-inflammatory cytokines, and abnormalities in DNA methylation of genes stimulating inflammation, all of which can be assessed in live individuals. To confirm this phenotype, we propose three specific aims, each employing the same set of 90 autopsy brains, already collected. In order to distinguish features of suicide from those of psychiatric illness, we employ a 3-group design with 30 cases of psychiatric disease and suicide, 30 cases of psychiatric disease without suicide, and 30 cases with neither psychiatric disease nor suicide, all from a well-characterized collection with a single collection protocol at a single autopsy service. To optimize our ability to distinguish features of suicide from those of psychiatric disease, in addition to finding the best matches between groups by age and sex, we sought to limit all of the psychiatric cases to a single clinical group, which was best achieved with schizophrenia spectrum disorders. Our specific aims, for each of which we will assay cerebral cortex and white matter from dorsal and ventral prefrontal regions, are: (1) To evaluate functional BBB impairment by stereological assessment of perivascular deposits of fibronectin. (2) To quantify a panel of cytokines, and to look for structural evidence of BBB impairment by assaying isolated microvessel fractions for vascular tight junction proteins and matrix metalloproteases.(3) To identify transcriptional correlates of BBB alterations with a genome-wide methylation survey on microvessel fractions of cortex and white matter from each region, using the Illumina Infinium MethylationEPIC microarray .These data will allow us to establish the underlying abnormalities for development of a suicidal profile to better, identify and treat veterans at risk of suicide. Knowledge and application of this profile will save Veterans’ lives by identifying potential targets for novel clinical interventions.

Schizophrenia spectrum disorders and suicidal behavior are major public health problems affecting Veterans. Each year, the VA provides care to approximately 100,000 schizophrenia patients, accounting for nearly 12% of the VA's total healthcare costs. At the same time, recent studies indicate that Veterans exhibit higher suicide risk compared with the general U.S. population. The PI's ongoing clinical cognitive neuroscience research at the VA uses neuroimaging and psychophysiological approaches and primarily focuses on these two areas: elucidating the neurobiology of schizophrenia and suicidal behavior. Identification of promising new targets for intervention in schizophrenia and suicide prevention are critically important goals of the VA. The PI's track record of federal funding and peer-reviewed publications in these two areas has helped advance the field. The PI's new VA CSR&D Merit Award aims to identify the neural correlates and psychophysiology of normal emotional reactivity and regulation in healthy control Veterans and pathological severity of emotion dysregulation in Veterans with major depressive disorder (MDD) at low (non-suicidal psychiatric controls) and high-risk (suicidal ideators and suicide attempters) for suicide. Participants receive baseline functional MRI scans and a psychophysiological paradigm that provides a reliable, non-verbal, low-cost measure of emotion processing (i.e. affective startle modulation). The psychophysiology session is repeated at a 6-month follow-up; clinical symptom assessments are done at baseline, 6-, and 12-month follow-up. Understanding brain circuitry anomalies underlying dysregulated emotional expression and psychological mediators that give rise to and predict suicidal behavior and distinguish between ideators and attempters has clear public health importance. This newly-funded VA Merit study promises to help uncover the mechanisms by which biological and psychological factors give rise to suicidal behavior and may aid in prospectively identifying Veterans at greatest risk for suicide. The goal of the PI's current schizophrenia-spectrum research (funded by her previous VA CSR&D Merit Award) is to begin to translate pre-clinical scientific research in schizophrenia into the clinical arena. In order to identify promising new targets for intervention in schizophrenia, a better understanding of its pathological circuitry and underlying genetic susceptibilities is required. Her work uses diffusion tensor imaging (DTI) and structural MRI to characterize white matter abnormalities in frontal-temporal regions. DTI fiber tractography allows quantification of the integrity of white matter connectivity in the brain. Various susceptibility genes are implicated in white matter abnormalities and schizophrenia (e.g., NRG1 and ERBB4). Together with her multidisciplinary VA-Icahn School of Medicine at Mount Sinai (ISMMS) colleagues who bring expertise in genetics, the PI's work investigates a model of white matter disorganization in schizophrenia. Data are currently being analyzed and published from her recent VA Merit study of 60 individuals with schizotypal personality disorder (SPD) and 60 healthy controls who received MRI and were genotyped. This work evaluates white matter organization and examines the relationship between white matter connectivity (fractional anisotropy and tractography DTI measures), white matter volume (structural MRI), allelic variation in two underlying susceptibility genes (NRG1 and ERBB4), and cognitive impairment/deficit symptoms across the spectrum. SPD participants are studied as our choice of phenotype as they represent a form of schizophrenia without the confounding artifacts of chronic antipsychotic treatment, long-term psychosis, and hospitalization. Impact: This Research Career Scientist Award will allow the PI to augment her highly collaborative VA research and mentoring of promising VA MIRECC fellows and clinician-scientists. The PI's current VA Merit is the first study at the JJPVAMC to conduct research 3T MRI scans. The PI's goal is to further expand her MRI research program in schizophrenia and suicidal behavior at the JJPVAMC.

The overarching goal of this VA OMHSP operations funded project is to develop, design, and implement a reoccurring national survey of Veterans (ASCEND) that will: (1) Serve as a national surveillance system to document prevalence and trends over time in non-fatal suicidal self-directed violence (NF-SSDV; i.e., suicide ideation [SI] and suicide attempt [SA]) across the life course (e.g., lifetime, post-military service, past-year); and (2) Provide estimates of the impact of social and community risk and protective factors (e.g., social determinants of health, social capital, and interpersonal needs) on SI and SA among Veterans. ASCEND also plans to examine the following aims related to the COVID-19 pandemic in the ASCEND pilot survey of approximately 500 Veterans: (1) Describe the extent to which Veterans report experiencing suicidal ideation and suicide attempt during the COVID-19 pandemic; (2) Describe Veterans’ perceptions of the impact of the COVID-19 pandemic on their lives, how they cope with the COVID-19 pandemic, and the extent to which Veterans report experiencing COVID-19 related stressors and fear of contamination/illness; (3) Examine how these factors relate to risk for experiencing post-COVID-19 suicidal ideation and suicide attempt; (4) Explore whether the prevalence of post-COVID 19 suicidal ideation and suicide attempt differs based on gender, rurality, and VHA use. The ASCEND survey will focus on the Veteran population as a whole, rather than only those using VHA services, and is expected to inform policy and service development, program evaluation, and quality improvement for Veteran suicide prevention.

BACKGROUND: Veterans are at elevated and increasing risk for suicide, relative to civilians. In particular, female Veterans are nearly twice as likely to die by suicide, compared to female civilians. In addition, 70% of Veterans who died by suicide did not use any Veterans Health Administration (VHA) care in the year before death. Consequently, female and non-VHA Veterans have been identified as two target populations in the VA National Strategy for Veteran Suicide Prevention. Yet most suicide prevention research has focused on VHA users and male Veterans. Knowledge is thus limited regarding whether VHA and non-VHA users differ with respect to who dies by suicide, precipitating circumstances of death, and regarding gender differences within these domains. Moreover, while mental health (MH) care offers an important opportunity to recognize and intervene upon suicide risk, knowledge is limited regarding barriers to accessing MH or suicide-specific care, particularly in relation to whether these differ by gender or VHA use. These gaps preclude determining the most effective and patient-centered means of preventing suicide among both female and male Veterans, particularly those who not using VHA care. SIGNIFICANCE/IMPACT: The present study has strong implications for understanding and preventing suicide among non-VHA users and female Veterans, both of whom have been vastly understudied. This is particularly crucial considering: (1) the 2016 Female Veteran Suicide Prevention Act, which directs VA to determine the most satisfactory and effective MH and suicide prevention programing for female Veterans; and (2) the 2019 Executive Order on a National Roadmap to Empower Veterans and End Suicide, which directs VA to work side-by-side with communities to reduce suicide among all Veterans, not only those using VHA services. This study will increase knowledge of female and male Veterans who died by suicide, including circumstances surrounding death, and the extent to which suicide decedents accessed MH care prior to death. Such knowledge can be garnered to tailor prevention efforts across Veteran groups. Moreover, by engaging with living Veterans, this study will improve understanding of Veterans’ experiences and willingness to seek MH care in general and when suicidal, while also informing the extent to which their experiences, barriers, and preferences differ by gender and VHA use. This knowledge is timely and critical as VA seeks to engage more Veterans in care. INNOVATION: This study will be the first to identify factors differentiating VHA and non- VHA suicide decedents and to explore female and male Veterans’ experiences and preferences for seeking help when suicidal. This study is also innovative in conceptualizing non-VHA users as comprising Veterans who were lost-to-care and who never used any VHA care. SPECIFIC AIMS: This study uses mixed-methods to compare three groups of Veterans (VHA users, never users, and lost-to-care) across three aims: (1) Identify factors that differentiate Veteran suicide decedents (e.g., circumstances of death, MH care use); (2) Examine differences in willingness to seek MH care, barriers to using MH care, and MH care experiences; and (3) Describe and compare Veterans’ experiences, preferences, and barriers to help-seeking when suicidal. Gender differences will be examined across aims. METHODOLOGY: For Aim 1, probabilistic linkage of data from national sources will be combined for Veteran suicide decedents to evaluate circumstances of death (e.g., interpersonal and socioeconomic stressors, MH problems), as well as VHA MH care use (for VHA and lost-to-care decedents). For Aim 2, Veterans will be surveyed about their willingness to seek MH care, barriers to doing so, and MH care experiences. For Aim 3, qualitative interviews will explore Veterans’ experiences, barriers, and preferences for seeking help when suicidal. Female Veterans will be oversampled. IMPLEMENTATION/NEXT STEPS: Intended impacts include greatly enhancing knowledge and facilitating new opportunities for implementing patient- centered, gender-sensitive suicide prevention strategies for all Veterans. Findings will be consolidated, and key stakeholder input obtained to propose actionable clinical and policy changes.

Objectives: The goal of the proposed study is to adapt and expand an existing lethal means counseling (LMC) intervention for peer delivery among firearm owning Veterans. Veteran interventionists will be trained in conducting the adapted intervention and it will be piloted with at least 15 firearm owning Veterans. This intervention will then be evaluated for initial feasibility and acceptability through use of self-report questionnaires and qualitative interviews. Research

Design/Methodology: Between 9-15 Veteran, clinician, and research stakeholders will be recruited to participate in an expert panel to provide feedback on aspects of the intervention that may require adaptation. Furthermore, the expert panel will provide input on methods for assessing intervention fidelity, as well as methods for evaluating the importance of interventionist/participant fit. Based on this feedback, the intervention will be adapted. Then, at least 3 firearm owning Veteran interventionists will be trained to conduct the adapted version of the lethal means counseling intervention. Finally, the adapted intervention will be piloted by the Veteran interventionists with at least fifteen firearm owning Veterans. Initial intervention feasibility and acceptability will be assessed using quantitative and qualitative measures.

Findings: It is hypothesized that the peer-delivered lethal means counseling intervention will be feasible and acceptable. As this is a small single arm trial, statistically significant intervention utility is not anticipated. However, initial trends in Veteran participant openness to changing firearm storage practices and actual change in storage practices over time will be examined to inform future research.

Findings: It is hypothesized that the peer-delivered lethal means counseling intervention will be feasible and acceptable. As this is a small single arm trial, statistically significant intervention utility is not anticipated. However, initial trends in Veteran participant openness to changing firearm storage practices and actual change in storage practices over time will be examined to inform future research. ical Relationships/Impact/

Significance: This investigation has the potential to benefit Veterans and the Department of Veterans Affairs (VA) in several ways. Veterans will benefit by engaging in lethal means counseling, which may increase openness to safe firearm storage practices and will in turn reduce suicide risk. This investigation could yield long-term benefits for the VA by a) expanding suicide prevention efforts into community settings; b) minimizing Veterans’ suicide risk prior to development of suicidal thoughts; and c) incorporating Veterans in ongoing suicide prevention efforts.

Substance Use Disorders (SUDs) are common in Veterans Health Administration (VHA) patients and are closely linked to some of the most pressing problems facing Veterans including overdose, suicide risk and homelessness. The VHA is a national leader in providing access to high-quality SUD treatment as well as the development of an evidence-base to inform and improve care for Veterans with SUDs. However, key gaps remain, particularly for Veterans who have co-occurring SUDs and psychiatric and/or medical conditions. Nonetheless, there is the clear potential to expand the positive impact of substance-oriented services within the VA by improving access to behavioral health treatments and integrating these services into addictions treatment. Mark Ilgen, Ph.D. has developed a research portfolio focused on tailoring SUD treatment to address patient comorbidity by conducting Veteran-centric health services research on addiction. The two primary thematic aims of this work are: Aim 1: to improve treatment outcomes and reduce risk of adverse events among Veterans with co-occurring SUDs and chronic pain; and, Aim 2: to decrease the risk of suicide among Veterans with SUDs. These two thematic areas directly relate to positive treatment outcomes, as well as reducing the likelihood of adverse events, among Veterans with SUDs. Dr. Ilgen’s contributions to these areas are evidenced by his grant-funded research with support from the VA Health Services Research and Development (HSR&D), the VA Office of Mental Health and Suicide Prevention, the Department of Defense, National Institute on Drug Abuse, and the National Center for Complementary and Integrative Health. The Research Career Scientist Award will support his continued research, as well an expanded role in mentorship and training of the next generation of HSR&D researchers. This research portfolio has the potential to address some of the most-critical and vexing behavioral health-related priorities in VHA and improve care for some of the most challenging and highest-risk Veterans treated within the VHA system.

The main objective of this study is to develop and test the use of public messaging to increase treatment seeking among Veterans at risk for suicide and resistant to seek mental health care following separation from military service.

The main objective of this study is to generate preliminary information on campaign-relevant indicators from a cohort of recently transitioned enlisted Army and Marine Corps Veterans who have not used VHA services in preparation for a future study of the effectiveness of VA campaigns to increase help seeking. Specific Aims: (Aim 1) Recruit a nationally representative sample of recently transitioned Army and Marine Corps Veterans (N=1,000) for a large-scale investigation of the effectiveness of VA suicide prevention messages to increase help seeking. (Aim 2) Collect baseline information to characterize the study cohort. (Aim 3) Identify initial audience segments in support of subsequent message testing. Distinct homogenous subgroups (i.e., audience segments) with similar communication needs and preferences will be identified that may influence message receptivity and exposure effects for future message testing. Inclusion criteria: 1) U.S. Army or Marine Corps Veteran who separated from military service in the past 12 months (any discharge type); 2) has not utilized any VA health care (but can be enrolled in VA); 3) >18 years old; 4) served four years or less on active duty; 5) enlisted rank (i.e. not an officer); 6) capable of understanding the goals of the study; 7) willing and able to provide consent; and 8) has internet access to complete study procedures. Additional exclusion criteria: are currently institutionalized. Next Steps: This pilot study will lay the groundwork for a subsequent HSRD IIR proposal testing the impact of VA suicide prevention campaigns on recently transitioned Veterans (the “2020 Cohort”) with a population-based longitudinal study.

The main objective of this study is to identify feasible, acceptable suicide prevention messages to motivate persons vulnerable to suicide with co-occurring risk for opioid overdose to disclose distress and seek formal mental health treatment.

Background: Suicide is one of the leading causes of death in the United States and worldwide, with suicide rates among U.S. military veterans doubling (27.7 per 100,000) the rate of civilian levels (14.7 per 100,000). Despite a rise in prevention efforts, rates have continued to increase. Theories of suicide and rehabilitation psychology stress the importance of the person-environment interaction in contributing to one's disability experience. Specifically, research has consistently found that the most frequent precipitant of suicide is a problem with a romantic partner. Conversely, people with better relationship functioning are less likely to have suicidal thoughts. The International Classification of Functioning, Disability and Health (ICF) identifies social engagement and communication as important components of functioning. Prevention of suicide in at-risk veterans is of vital importance and the quality of one's intimate relationship is an understudied intervention target for suicide prevention. This proposal refines and evaluates preliminary efficacy of the first couples-based suicide-specific intervention?Treatment for Relationships and Safety Together (TR&ST). Significance/

Innovation: Suicide prevention is the top clinical priority for VA/DoD. The importance of including family members in Veterans? suicide-related care is a critical component of the National Strategy for Preventing Veteran Suicides 2018-2028 and key finding from VA/DoD patient focus groups conducted for the 2019 VA/DoD Clinical Practice Guidelines for the Assessment and Management of Patients at Risk for Suicide. Innovative aspects of this CDA-2 proposal directly address several components of national reports and include: 1) The first couples-based suicide-specific intervention and the first suicide-specific intervention to target interpersonal functioning factors identified by suicide theories and rehabilitation psychology (i.e., effective communication and interpersonal engagement); 2) Veteran-centric choice between home-based telemental health and office-based care in order to increase access; and 3) Improved data analytic quality of Veteran suicidality by examining both Veteran and partner reports of suicide related risk factors (the first suicide- specific treatment study to do this). Methodology: The proposed 5-year study consists of two phases. Phase 1: treatment refinement with 10 couples (N=20) and Phase 2: pilot Randomized Controlled Trial (RCT) of TR&ST compared to VA Standard Suicide Intervention with 60 couples (N=120). The intervention period is 13 weeks and the entire study period is approximately 7 months. Couples in both phases will be quantitatively assessed at baseline, mid-treatment, post-treatment, and 3-months post-treatment (and qualitatively interviewed following each TR&ST module). The primary outcome to be evaluated is change in suicidal ideation severity. Secondary outcomes concern changes in interpersonal functioning. Aims: Aim 1 (Phase 1): Refine TR&ST in a population of Veterans with active suicidal ideation. Aim 2 (Phase 2): Evaluate treatment feasibility and acceptability of TR&ST. Aim 3 (Phase 2): Compare TR&ST vs. VA Standard Suicide Intervention on suicidal ideation severity and interpersonal functioning (i.e., communication, bonding, relationship satisfaction, and belonginess and burdensomeness) over 7 months. Next Steps: This Career Development Award is the first step toward developing a vital program of research within VHA focused on enhancing interpersonal functioning and suicide-related care by involving family members in treatment. If Aims are achieved, future work includes 1) an adequately powered RCT of TR&ST vs. VA Standard Suicide Intervention 2) a more direct evaluation of telehealth for couples-based or family involvement in suicide-specific interventions, and 3) examination of moderators or groups of interest (such as women Veterans).

Aim 1: Evaluate the bivariate association between altitude and death by suicide, suicide attempts, and suicidal ideation at the individual level, including identification of the level of altitude most strongly associated with suicide and suicidal behavior in Veterans. Aim 2: Identify geographic features and social determinants of health that are predictive of: (1) Higher levels of Veteran suicide; and (2) Living at higher levels of altitude. Aim 3: Identify individual-level features from the EHR that best distinguish Veterans who live at higher altitudes from Veterans who live at lower altitudes. Aim 4: Utilize advanced statistical approaches to develop a “hybrid” predictive model of Veteran suicide derived from both individual-leave and geospatial features, including altitude.

This Career Development Award (CDA-1) for VA psychiatrists (RFP #CX-20-020) will provide training in both the clinical care and neuroimaging research of Veterans at high-risk for suicidal behavior. This proposal will gather concurrent behavioral and fMRI data investigating dysfunction of midbrain dopaminergic circuitry manifested during abnormal reward processing in Veterans, examined across levels of suicide attempt (SA) history and lethality of intent. Over the past two decades, the rate of suicide in Veterans has risen out of proportion with the general population, mandating suicide prevention as a top research priority for the Veterans. Health Administration. Our ability to develop effective, neurobiological-based interventions for suicidal behavior is hindered by the lack of a clearly defined clinical pathway to completed suicide. While most cases of suicide are comorbid with a diagnosable mental illness, there is no one psychiatric disorder that is uniquely associated with elevated risk. Against a transdiagnostic background, identifying unique psychopathologies related to constructs of reward processing in Veteran's with a history of SA will allow for the development of treatments targeting suicidal behavior rather than comorbid disorders This proposal will investigate in male and female OEF/OIF/OND Veterans (n=60) the relationship of reward processing to neural activity in midbrain nuclei as it relates to suicidal behaviors. To this end, our study population will include Veterans with and without history of suicide attempt, inclusive of a variety of other comorbidities. From this realistic, transdiagnostic sample of Veterans, we will examine how abnormalities in the neural substrates of reward processing relate to history of SA. Impulsive preference for an immediate reward is associated with a higher incidence of suicide attempt. However, high lethality intent often involves significant planning suggesting an alternative reward-related pathology in this high-risk subgroup. While there is often an acute disconnect between the severity of the preceding suicidal intent and the medical lethality of the attempt, the chronic risk of completed suicide is greatly increased in individuals with a history of high lethality intent. Delineating the unique psychopathology associated with the level of intent will be helpful in developing targeted interventions in high-risk subgroups. This proposal will investigate neural activity in dopaminergic midbrain reward circuits associated with trait pathological reward processing across levels of suicide attempt history and lethality of suicidal intent in Veterans. Identifying unique neurobiological underpinnings?such as abnormal reward processing and midbrain/dopaminergic dysfunction?that predispose a Veteran to a suicide attempt will allow us to develop novel interventions. The goal of this line of research is to define clinically useful neuroimaging biomarkers of suicide vulnerability to be used in future studies towards the development of targeted and more effective pharmacotherapeutic interventions.

This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for suicidal ideation in veterans. The investigators hypothesize that the administration of a naturally occurring dietary supplement, uridine, will rapidly reduce suicidal ideation in veterans. The purpose of this study is to determine whether 4 weeks of uridine supplementation is an effective treatment for suicidal ideation in veterans, when compared to a group taking a placebo. In summary, while piloting a much-needed alternative to intravenous ketamine for suicidal veterans, this research also aims to participate in establishing the neurochemical biomarkers of suicidal ideation, and treatment response. To test the novel intervention uridine as a rapid-acting oral treatment for Veterans with SI since uridine has the potential to fill this role lies in the broad overlap in the brain mechanisms and neural effects shared by uridine, ketamine and the anti-suicidal drug lithium. This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for suicidal ideation in veterans. The investigators hypothesize that the administration of a naturally occurring dietary supplement, uridine, will rapidly reduce suicidal ideation in veterans. The purpose of this study is to determine whether 4 weeks of uridine supplementation is an effective treatment for suicidal ideation in veterans, when compared to a group taking a placebo. This research addresses two critical unmet needs related to suicidal behavior among veterans: 1) The unmet need for a rapid-acting treatment for veterans who are experiencing suicidal thoughts; and 2) The unmet need for valid objective measurements, or biomarkers of veteran suicidality, to improve diagnosis and guide treatment development. Through pilot testing the novel anti-suicidal treatment uridine, while pairing it with brain scans performed before-and-after treatment, the goal of this study is to improve our understanding of suicidal ideation in the veteran population.

The evidence is clear: team-based behavioral healthcare improves outcomes and satisfaction for individuals with mental health conditions. However, healthcare teams do not develop naturally and require targeted support to form, function effectively, and be sustained. Using facilitation techniques and common measures, this QUERI Program will enhance and inform team-based care for Veterans with behavioral health conditions. Specific aims include: Understand and enhance coordination, quality, equity, and outcomes of care for Veterans treated within interdisciplinary VA treatment teams and via shared care across healthcare disciplines; Advance measurement-based care delivery strategies that enhance personalized, proactive, and patient-driven care for Veterans; and Apply implementation methods by developing, evaluating, and refining new tools and resources to support the use of facilitation to implement clinical programs and practices that are responsive to VA priorities.

This project adapts an effective suicide prevention intervention for a VHA setting that complements existing suicide prevention efforts and develops a virtual external facilitation implementation strategy to support implementation. The Implementing Caring Contacts for Suicide Prevention in Non-Mental Health Settings QUERI Partnered Implementation Initiative (PII) is implementing and evaluating an evidence-based suicide prevention intervention—Caring Contacts—in VA EDs and urgent care centers. Caring Contacts (CC) is an intervention that involves sending patients who are suicidal brief, non-demanding expressions of care and concern over the course of a year. Studies of CCs have demonstrated significant reductions in suicide deaths, attempts, and ideation.

This study has the following aims: Aim 1: To describe baseline knowledge of lethal means safety among VA employees. Aim 2: To determine if a course on lethal means safety is effective at increasing knowledge on the subject. Aim 3: To examine evaluations completed by VA employees who completed the lethal means safety training.

Suicide is one of the leading causes of death among military personnel. While multiple risk factors have been implicated in suicide behavior, sleep disruption is consistently associated with elevated suicide risk. Unfortunately, the exact link between sleep disruption and suicide risk is unclear, and research is mixed regarding which mechanisms are driving the sleep-suicide link. We propose to conduct a longitudinal, multimodal assessment of the sleep, suicide, and hypothesized mechanisms driving the link between sleep and suicide. One hundred and forty Veterans hospitalized for suicide attempt or ideation with plan and intent will be recruited during inpatient hospitalization. Veterans will be provided with activity monitors called actigraphs while on the unit and an Ecological Momentary Assessment (EMA) program will be downloaded onto their phones upon hospital discharge. Participants will be assessed daily for 8 weeks using EMA and actigraphy, with follow up assessment at 2, 4, 6, and 8 weeks and 6 months post-hospital discharge. Sleep, suicide, emotion regulation, emotional reactivity, and impulsivity making will be assessed using a combination of actigraphy, sleep diaries, EMA, in-laboratory tasks and self-report measures. EMA devices will be able to capture daily changes in mechanisms of interest, sleep parameters, and suicide behaviors. The primary objective of the study is to gain a clearer understanding of the relationship between sleep and Veteran suicide during a particularly high-risk transition period from inpatient to outpatient psychiatric care. A combination of dynamic structural modeling (DSEM), latent growth modeling, and multiple linear regression will be used to evaluate the utility of our conceptual model in predicting the combined effects of sleep disturbance, emotion reactivity and regulation, and impulsivity in the prediction of suicide risk.

Understanding of factors impacting the risk of suicide among Veterans transitioning from active duty following discharge is limited, despite this group having suicide rates approximately three times higher than the overall Veteran population. One potential reason for this gap in knowledge is due to the difficulty of attempting to integrate health data from the different areas where transitioning service members (TSM) may be obtaining care for mental health issues including suicide-related behavior (e.g., documented attempts, ideation, and self-harm). For example, information about TSM’s risk factors for suicide and engagement in mental healthcare could be found in Veterans Health Administration (VHA) records, Veterans Crisis Line (VCL) records, and/or in private health insurance records. To bridge this research/data gap, we are proposing a novel strategy to integrate All Payer All Claims (APAC; private health insurance) data with VHA data (e.g., Corporate Data Warehouse; CDW) in order to (1) increase understanding of the factors that underlie suicide risk for TSM by increasing the representativeness of the study population and completeness of their mental health history, as well as (2) create methods that will allow us to incorporate data from other sources such APAC in a future Merit proposal.

Project Summary/Abstract: Among all medical, mental health and substance related disorders, Major Depressive Disorder (MDD) is the leading cause disease burden worldwide; MDD is a major cause of suffering and disability for those receiving their care from the Veterans Health Administration (VHA). Current treatments have limited effectiveness as only about 30% of patients achieve remission with the first antidepressant treatment. By regulatory convention, the term treatment-resistant depression (TRD) is used when a depressed patient has not responded to two or more adequate treatment trials in the current episode. So defined, patients with TRD account for a disproportionately large share of treatment resources and, despite such efforts, are at the highest risk to become chronically ill, develop a complicating substance abuse disorder and/or die by suicide. The CSP 576, VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D), showed that adjunctive aripiprazole resulted in a significantly greater likelihood of remission as compared to switching to bupropion. Secondary analyses of VAST-D demonstrated that the advantage of adjunctive aripiprazole among 12-week remitters was sustained across up to six months of therapy and was evident whether or not patients had co-occurring PTSD. In 2019 the U.S. Food and Drug Administration (FDA) reviewed intranasal esketamine as a new therapy for treatment of TRD. The safety and efficacy of esketamine was evaluated in a series of phase III studies that ultimately led to the FDA approval of esketamine (Spravato) for the treatment of TRD in adults. The proposed study will be an open-label, parallel-group, randomized clinical trial of up to 6 months treatment of adjunctive intranasal esketamine vs. adjunctive aripiprazole in Veterans with TRD. This study will assess the efficacy, safety, and acceptability of adjunctive intranasal esketamine in direct comparison to adjunctive aripiprazole for therapy of TRD. The primary hypothesis is that participants receiving adjunctive intranasal esketamine will be significantly more likely to achieve remission after six weeks of treatment as compared to those who receive adjunctive aripiprazole. Depressive symptoms will be assessed by independent evaluators without knowledge of treatment assignment using the Quick Inventory of Depressive Symptomatology clinician rating (QIDS-C), which is a well-validated tool that commonly and is easily translated across other depression inventory scales. The study is powered to be able to detect an absolute difference in remission rates of 10% or larger at 6 weeks. Secondary outcomes of interest include symptom reduction across 6 months of randomized therapy, side effects and other tolerability indices, suicidality, and measures of quality of life and cost-effectiveness.

The proposed Enterprise Wide Collaborative Rural Access Solution is designed to support an ongoing partnership between the VA Offices of Rural Health and Suicide Prevention to establish a multilevel, evidence-based suicide prevention program for rural Veterans. This proposal will describe the key intervention components of the Rural Veteran Suicide Prevention Program, which integrates multiple evidence-based practices and existing VA programs (e.g., suicide risk management in primary care, crisis support, firearm safety, and) into a comprehensive portfolio of best practices that work synergistically to: Strengthen VA and community partnerships to empower and mobilize communities around suicide prevention; Improve access for all rural Veterans and; Effectively target known risk and protective factors for suicide. Program

Objectives: The goal of this proposal is to build on existing work and partnerships to establish an Enterprise Wide Collaborative Rural Access Solution for Rural Veteran Suicide Prevention. To accomplish this will require: integrating existing population and clinical level interventions into a comprehensive suicide prevention program for rural Veterans; and strategically and systematically expanding the comprehensive program into a scalable and sustainable model to benefit rural Veterans and communities nationwide. Our past efforts to develop effective rural suicide prevention programs, combined with a deliberate plan for dissemination provide a sound foundation from which to complete this work. Towards this end, the overarching objectives for the next five years are: Objective 1: Build and strengthen community relationships (public/private partnerships) to create a high performance healthcare network supporting at-risk rural Veterans. Objective 2: Carry out a staged roll-out of best practices towards an enterprise-wide collaborative rural access solution. Objective 3: Evaluate implementation and impact of this multilevel suicide prevention program for quality improvement.

In partnership with Tribal communities, the overall goal of this project is to advance suicide prevention for Native American Veterans, a group at high-risk of suicide. We will develop and strategically test a model of suicide prevention that integrates VA evidence-based, system-wide approaches with culturally grounded Native American perspectives, traditions, and practices. We envision a 3-year plan for the project to achieve this overall goal. The purpose of this project is to expand partnerships, implement piloting using developed materials and adapted tools, and prepare for national dissemination. We will achieve these goals through several objectives: Through mentorship and training, develop SPT workforce capacity to build and sustain bi-directional partnerships with Tribal communities to serve Native Veterans in suicide prevention; Refine and then pilot adapted educational materials and suicide prevention tools with Tribal community partners; Develop and refine appropriate evaluation metrics relevant to the time-intensive tasks required in work with Tribal communities to assist OMHSP in workload metrics; Explore new data sources containing all Veterans (not just those accessing VHA care) for improved estimates of extent and scope of suicide and suicide related behaviors among Native Veterans; Develop an implementation guide to Tribal-VHA partnership development and sustainability, and a national plan for dissemination.

BACKGROUND: In 2017, the age-adjusted suicide rate for female Veterans was 2.2 times that of female non- Veterans. This may relate to a substantial increase in the proportion of female Veterans using firearms as their means of death, particularly among women using Veterans Health Administration (VHA) care. Firearms are now the leading means of suicide among female Veterans. Lethal means safety (LMS; i.e., reducing access to lethal means when suicide risk is elevated) is a highly-recommended suicide prevention strategy. Yet prior firearm LMS research has primarily focused on male Veterans, despite female Veterans idiographically differing in their firearm access, ownership, and use. Data suggest that female Veterans more often obtain firearms and store them loaded and nearby to increase safety following interpersonal violence (e.g., sexual assault, intimate partner violence). Given high rates of interpersonal violence among female Veterans, it is critical to ensure firearm LMS efforts are tailored and delivered to female Veterans from a trauma-focused lens. Further, nearly 40% of female Veterans report having household firearms that they do not personally own, which often occurs through spouses or partners. Thus, including family members in firearm LMS efforts may be particularly important for female Veterans. Prior research also suggests that Veterans rarely initiate firearm discussions with their VHA providers, who seldomly assess firearm access, despite its association with suicide risk. Thus, a multi-systemic perspective that encompasses the perspectives of female Veterans, their spouses or partners, and VHA providers is essential. SIGNIFICANCE/IMPACT: Effective suicide prevention necessitates a well-informed, patient-centered approach. Yet firearm knowledge specific to female Veterans remains limited and has largely relied upon extrapolating data from male Veterans. By understanding the experiences and perspectives of female Veterans, their spouses/partners, and VHA providers, findings will inform development of gender-sensitive conceptual understanding and interventions for approaching firearm LMS in this population. Findings can be used to delineate a tailored firearm LMS intervention for female Veterans that can subsequently be piloted for acceptability, feasibility, and ultimately efficacy. INNOVATION: This study is innovative in its focus on understanding the inherent needs and preferences of female Veterans, rather than extrapolating findings from male Veterans. It will be the first to interview female Veterans, spouses and partners, and VHA providers regarding experiences and preferences for firearm LMS. This is highly innovative as spouses and partners have rarely been included in Veteran suicide prevention research, despite increasing the likelihood of female Veterans’ firearm access. Findings are expected to result in knowledge essential for developing a gender-specific conceptualization and intervention for addressing firearm LMS with female Veterans to ultimately provide a patient-centered approach to a high-priority, understudied problem. SPECIFIC AIMS: Our aims are to: (1) Describe female Veterans’ experiences, perspectives, and preferences regarding firearm access and LMS, and explore the role of interpersonal violence within this; (2) Explore the perspectives and experiences of female Veterans’ partners and spouses regarding engaging in firearm LMS (e.g., ability, willingness); and (3) Describe VHA mental health (MH) and primary care (PC) providers’ experiences and perspectives on discussing firearm access and LMS with female Veterans, including challenges and facilitators. METHODOLOGY: Qualitative interviews will be conducted with: female Veterans who own firearm(s) or reside in a household with firearm(s) and have experienced suicidal ideation or attempt (Aim 1); partners and spouses of female Veterans (Aim 2); and VHA MH and PC providers who work with female Veterans (Aim 3). IMPLEMENTATION/NEXT STEPS: Results will be synthesized to develop a patient-centered, gender-sensitive firearm LMS intervention for female Veterans, and resources for family members and VHA providers. Key operations partners will be engaged in this process to ensure feasible recommendations and wide dissemination of findings.

The overarching goal of this project is to design and implement a recurring national survey of Veterans (ASCEND) that will: 1) Serve as a national surveillance system to document prevalence and trends over time in non-fatal suicidal self-directed violence (NF-SSDV; i.e., suicide ideation [SI] and suicide attempt [SA]) across the life course (e.g., lifetime, post-military service, past-year); and 2) Provide estimates of the impact of social and community risk and protective factors (e.g., social determinants of health, social capital, and interpersonal needs) on SI and SA among Veterans. ASCEND also plans to examine the following aims related to the COVID-19 pandemic in the ASCEND pilot survey of approximately 500 Veterans: (1) Describe the extent to which Veterans report experiencing suicidal ideation and suicide attempt during the COVID-19 pandemic; (2) Describe Veterans’ perceptions of the impact of the COVID-19 pandemic on their lives, how they cope with the COVID-19 pandemic, and the extent to which Veterans report experiencing COVID-19 related stressors and fear of contamination/illness; (3) Examine how these factors relate to risk for experiencing post-COVID-19 suicidal ideation and suicide attempt; (4) Explore whether the prevalence of post-COVID 19 suicidal ideation and suicide attempt differs based on gender, rurality, and VHA use. The ASCEND survey will focus on the Veteran population as a whole, rather than only those using VHA services, and is expected to inform policy and service development, program evaluation, and quality improvement for Veteran suicide prevention.

Background: Despite accessible and effective suicide prevention strategies offered by the Veterans Health Administration (VHA), Veteran suicide remains elevated compared to the general US population, indicating a continued need to identify Veterans at risk for suicide and provide interventions to prevent suicide. Suicide prevention can be enhanced when health care systems integrate dynamic social determinants of health (SDH), such as housing instability, justice involvement, and unemployment.

Significance/Impact: The goal of this HSR&D Veteran Suicide Prevention project is to address prevention activities that occur upstream by examining how services addressing SDH may also prevent suicide among Veterans, key objectives in the VAs National Strategy for Preventing Veteran Suicide 2018-2028.

Innovation: This study will integrate a public health perspective to suicide prevention through a lens of SDH. Rather than focusing specifically on medical intervention, this study will explore based both on a natural experimental design using existing administrative data and on gathering the perspectives of key informants and Veterans how addressing SDH can decrease suicide risk, taking into account the complex needs of Veterans who may be at risk for suicide. Specific Aims: This study aims to determine whether VHA services tailored to address SDH may also have an added benefit of preventing suicide mortality; identify organizational assets and opportunities to improve how SDH-focused services address suicide risk among Veterans; and engage Veterans in identifying ways to integrate suicide prevention into VHA programs that respond to SDH. Methodology: The proposed research is a concurrent mixed methods design. Retrospective quantitative analyses will examine how VHA services tailored to Veterans SDH (i.e., housing instability, justice involvement, unemployment) may protect against suicide mortality and morbidity. A mixed methods environmental scan will include a questionnaire of staff/key informants and qualitative interviews. Qualitative interviews with Veterans with a history of suicide risk will explore how services to address SDH respond to those needs.

Implementation/Next Steps: This project will lead to actionable implementation projects: increased linkages to services for SDH among Veterans with histories of suicidal crisis as well as enhanced training for providers to integrate suicide prevention into services addressing SDH, and vice versa. We have convened an array of VA operations partners Social Work, VHA Homeless and Justice Programs, employment programs, and VA Office of Mental Health and Suicide Prevention to facilitate removing siloes around SDH and suicide prevention in VA, amplifying VAs current infrastructure to bolster suicide prevention.

In Aim 1, we will use neurocognitive task scores collected shortly before the SB, to determine which tasks (and therefore, alterations in which cognitive domains) can prospectively predict short-term risk of SB (within the next 3 months). In Aim 2, we will conduct computational modeling on the behavioral data, to extract additional meta-variables, describing latent cognitive processes such as response caution (impulsivity); subjective value of rewarding, punishing, and neutral feedback; perseveration; and tendency to explore new responses, to determine which of these meta-variables can prospectively predict SB. In Aim 3, we will combine these neurocognitive task scores and meta-variables, along with standard indicators of suicide risk such as demographic, self-report, and clinical assessment, in a statistical prediction model, to determine whether inclusion of these cognitive variables and meta-variables can significantly improve prediction of short-term risk for SB in this high-risk Veteran sample.

This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine human biomarker analysis, with human imaging studies, and with neurobiological mechanistic studies in animals, to understand the manner in which TBI influences impulsivity and suicidal behavior. Preventing suicide is a major priority for the VA. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide, particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. At the Indianapolis VA (INDVA) site, in order first to test our overarching hypothesis, and second to gain a more comprehensive understanding, we propose to translationally integrate human studies of subjects with TBI and suicidality with animal model studies of TBI, using blood biomarkers as a bridge. This will be accomplished via the following Aims: Aim 1 is Human biomarker studies. Aim 1. 1. will focus on state aspects, by conducting transcriptomic analyses on blood samples collected in Indianapolis. We will have two groups: suicidality with TBI (n= 70) and suicidality without TBI (n= 70). We will not be conducting imaging studies, but rather use a longitudinal design, by testing the subjects first during an acute inpatient psychiatric hospitalization for suicidality (severe ideation, plan, attempt), and then 3-6 months later for a follow-up visit in a low suicidality state. We hypothesize that inflammatory and serotonin related transcripts will be decrease between acute inpatient and non-acute follow-up testing, but less so in suicidality with TBI compared to suicidality without TBI. Aim 1. 2. will focus on trait aspects, by conducting transcriptomic analyses on samples from the Bronx VA (JJPVA) (n=140). We hypothesize that inflammatory and serotonin related transcripts will be increased most in suicidality with TBI compared to suicidality without TBI, TBI without suicidality, and non-TBI, non- suicidality. Aim 2 is Animal model brain and blood biomarkers convergence studies. We will conduct transcriptomic analyses of brain and blood samples from the animal model studies (n= 160) at the New Jersey VA (VANJHCS), a more experimentally tractable way of studying TBI and impulsivity. We hypothesize that we will identify biomarkers that are co- directionally changed in brain and blood. Aim 3 is Translational convergence of human and animal model biomarker data, using Convergent Functional Genomics analyses. We hypothesize that the candidate state and trait biomarkers that track suicidality (ideation, attempts) related to TBI (TBI-S) in the human studies will cross- validate with the brain-blood biomarkers from the animal model studies. We will also test hypothesis driven a series of known biomarkers related to inflammation (IL6, IFNG), serotonin (5HT2A, SLC6A4), and TBI (UCH-L1, GFAP- FDA approved in 2018). Exploratory Aim 4 will focus on convergence of biomarkers and phenomic data (neurobehavioral testing, imaging). We hypothesize that we can link different biomarkers to different behavioral aspects in the same individual and across individuals, resulting in a better understanding of the pathophysiological links between TBI, impulsivity, and suicidality. We will use a PhenoChipping approach (Niculescu et al. 2006)6, that clusters phenomics and genomics data. The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI is a risk factor for suicidality. Moreover, increased impulsivity is one of the most prevalent symptoms following TBI, and is itself a risk factor for suicide, depression and drug abuse. Thus, finding objective biomarkers of increased risk of suicide and understanding the mechanisms responsible for high impulsivity following TBI are key to severing the link between TBI and suicide.

Evaluation of a clinical pilot of CBT-SP via Telehealth in VISNs 19 and 10 for feasibility and acceptability. Lessons learned to be provided to OMHSP (SPP) to inform the national rollout of CBT-SP as an EBP for Suicide Prevention 2.0.

1. Objectives(s): 1) Develop personalized and longitudinal risk scores for acute suicidal behavior. 2) Conduct genome-wide association studies (GWAS) of suicidal behavior in the Million Veteran Program (MVP) and then incorporate genomic findings into the risk scores for acute suicidal behavior. 3) Implement improved decision-support systems based on the products of Aims #1 and #2, to derive more effective clinical management of patients at-risk for suicide. 2. Research Design: The proposed research involves a retrospective data analysis of existing databases, including VA administrative databases, such as the Corporate Data Warehouse (CDW), the Suicide Prevention Application Network (SPAN), and the National Death Index (NDI) database, all available genomic and phenotypic data available through MVP (on MVP participants), and all availability probability and risk scores generated by the Office of Mental Health and Suicide Prevention’s (OMHSP) REACH-VET algorithm. No prospective data will be collected as part of this study. 3. Methodology: Aim 1 will be enabled by the development of a knowledge base containing demographic, clinical, laboratory, pharmaceutical, and procedural information currently available in the Veterans Health Administration database, the Corporate Data Warehouse (CDW) (N≈24 million VA patients). Unstructured data (e.g., clinical notes) will be captured, with natural language processing (NLP) analyses helping to define complex phenotypes. Machine learning and model selection methods will be used to analyze data. Aim 2 will involve conducting GWAS analyses within the MVP program, and will enable us to identify novel genetic variants associated with suicide attempts and suicidal ideation among Veterans enrolled in the MVP cohort. We will then incorporate and integrate these genomic findings with the “non-genomic” results from Aim 1 to develop a comprehensive algorithm for understanding and prediction of suicidal behavior. Aim 3 will initially involve assessing the effectiveness and limitations of existing VA suicide prevention programs, and then will simulate applications of algorithms develop in Aim 1 and Aim 2 in synthetic populations of veterans. These Aims will require use of CDW data for all VA Users (~24 million records) as well as the combined genetic and clinical data from the MVP cohort.

Anticipated Benefit to VA Healthcare The proposed study will establish the feasibility and effectiveness of treating insomnia in the primary care environment as a suicide prevention strategy. By treating insomnia, a common problem that is both a risk factor for suicide and highly prevalent in common conditions associated with suicide such as depression and posttraumatic stress disorder (PTSD), we expect to reduce the severity of suicidal ideation (SI) among Veterans experiencing SI, insomnia and a co-occurring condition. Project Background Suicide is the tenth leading cause of death in the U.S., is a major concern of the Department of Veterans Affairs (VA), and occurs at elevated rates among Veterans. Veterans with common chronic conditions such as PTSD and depression are at increased risk for suicide. Although evidence-based treatments exist for these conditions, a significant number of Veterans do not engage in or complete such treatments leaving them at higher risk for suicide. This application builds upon VA HSR&D funded pilot work that demonstrated the feasibility of delivering a brief version of cognitive-behavioral therapy for insomnia (CBT-I) within primary care to Veterans experiencing SI. The pilot data suggest that our brief, primary-care based insomnia treatment was delivered with high fidelity, acceptable to Veterans and associated with significant reductions in insomnia and depression symptoms, and reduced SI intensity. The next stage of this program of research is to establish the feasibility of delivering our brief, primary care based, insomnia intervention utilizing primary care-mental health integration (PC-MHI) clinicians (as opposed to research staff) and to establish the effectiveness of the intervention on reducing the severity of factors that contribute to suicide risk and to improve other clinical markers in a definitive trial. Project Objectives The ultimate goal of the broader program of research is to reduce suicide among Veterans by intervening upon sleep disturbance as a modifiable risk factor for suicide. In this application we focus on insomnia, which is the most common sleep disorder among Veterans and is robustly associated with suicidal thoughts and behaviors. The primary objective of this proposed clinical trial is to test whether (and how) using brief behavioral insomnia treatment can not only improve sleep, but reduce other risk factors for suicide including the severity of depression, PTSD and suicidal ideation among Veterans at risk for suicide. Secondary objectives are to: (1) gather initial data on barriers and facilitators to implementation to aid future implementation efforts in VA primary care and (2) determine if the intervention improves attitudes towards psychotherapy treatments that address the co-morbid conditions. Project Methods In order to achieve these objectives we will conduct a real-world, randomized clinical trial among 240 Veterans experiencing either co-occurring depression or PTSD recruited from primary clinics at three VA sites. These Veterans, who will also endorse SI and insomnia, will be randomized to receive either a brief course of CBT-I or a sleep hygiene intervention of similar length. Assessments of suicidal thoughts and behaviors, insomnia, depression, and PTSD will be conducted at baseline, post-treatment, and every 6 weeks thereafter until 6 months post-treatment. Mixed effects modeling and structured equation modeling will be applied to determine how improvements in sleep and other symptoms (e.g. depression, PTSD) contribute to reductions in SI severity. In addition, we will collect, code and analyze participant and provider feedback to assess barriers and facilitators of implementation in real-world clinical practice.

Approximately 800,000 people die from suicide each year and the recent data show that the suicide rate in the United States has increased 33% from 1999 to 2017. United States military veterans have an increased risk of suicide compared with the general population, and approximately 18 to 22 veterans die from suicide each day. It has been reported that up to 90% of individuals who complete suicide have an underlying psychiatric disorder. Suicidal ideation in war veterans is often associated with post-traumatic disorder (PTSD) or depression, conditions that often coexist. In addition, as a fundamental factor in the provocation of depression, chronic stress is associated with suicidal thoughts and behaviors. Also, a history of prior exposure to trauma or to chronic stress is an extremely potent risk factor for PTSD. In preclinical models, chronic stress has been shown to induce changes in behavioral paradigms that can be used to measure aspects of suicidal behavior such as impulsive, aggressive, and depressive-like behaviors. Recent evidence indicate that inflammation, as manifested by increased levels of pro‐inflammatory cytokines, contributes to the pathophysiology of suicidality. However, there is a critical need for studies that are designed to determine the role of specific components of the immune system in suicidal behavior in order to identify novel therapeutic targets. The complement system is part of the innate arm of immunity, but also regulates many aspects of the adaptive immune response. Complement can be activated via the classical, lectin or alternative pathway with complement component 3 (C3) as the converging point of the activation pathways. Our recent study showed an important role of C3 in chronic stress-induced depressive-like behavior in mice. However, it is not known whether chronic stress- induced complement activation mediates suicidal behavior. We hypothesize that classical pathway mediates stress-induced complement activation leading to suicidal behavior. In supporting this, our published and preliminary studies found that (1) C3 and C1qa (a key component of classical pathway) are highly expressed in the prefrontal cortex (PFC) of depressed suicide subjects; 2) exposure to chronic stress conditions induces increases in C1qa and C3 protein levels in mouse PFC; and (3) inhibition of C3 by gene knockout (C3 KO) significantly ameliorated chronic stress-induced aggressive and depressive-like behavior, and infiltration of monocytes into mouse PFC. To further understand the role of complement activation in suicidal behavior, we propose the three Specific Aims to 1) determine the role of complement activation pathway in suicide (with depression or PTSD diagnosis) subjects; 2) investigate whether complement classical pathway is critical to stress-induced suicidal behavior; and 3) determine whether central complement system mediates stress- induced suicidal behavior. Given the important role of immune pathways in suicidal behavior, identifying novel regulatory mechanisms may provide avenues to develop newer therapeutics for suicidal behavior.

Background: Veterans disproportionately account for to 22% of all known suicides in the US. Screening for suicide risk at the first contact with an organization is a best practice in the national Zero Suicide framework and vital to enhancing access to appropriate care. Transition Care Management (TCM) programs are positioned to screen post-9/11 Veterans at the critical moment of enrollment in healthcare. Unfortunately, many Veterans who present for the first time in VHA with recent suicidal thoughts do not receive same day suicide risk evaluation (SRE), partly due to cumbersome screening processes. eScreening is a web-based Gold Standard Promising Practice electronic screening system with real-time scoring and integration into CPRS/VistA. Our eScreening effectiveness pilot in 1,372 post-9/11 Veterans and our 2-site multicomponent implementation strategy (MCIS) pilot showed increase speed and rate of SRE and sustainment of eScreening in two pilot sites. More research is warranted to test both.

Significance/Impact: This project responds to HSR&D Priority Areas of: Suicide prevention, Increasing the real-world impact of research, and Implementation science. Our data will inform best practices in suicide prevention through early identification. This project will also allow for real-world integration of research into practice and inform implementation efforts for technology.

Innovation: eScreening is a unique program developed with feedback from Veterans. To our knowledge, this is the first study to integrate VHA developed mobile patient-report screening technology to improve screening in TCM programs. It is also the first to examine the impact of electronic screening on rates of suicide risk evaluation and referral to care. Specific Aims: Aim 1. Evaluate the effectiveness of eScreening, compared to paper and verbal screening, on rate and speed of screening completion (suicide screening & evaluation, PTSD, depression, alcohol) and referral to mental health care in 8 TCM programs, guided by the RE-AIM outcomes of PRISM. Aim 2: Evaluate the feasibility, acceptability, and potential impact of the MCIS, guided by the RE-AIM outcomes of PRISM, adoption, implementation, and maintenance using mixed methods. We will also document and calculate replication costs across sites. Aim 3. Describe and compare high and low eScreening reach sites guided by contextual constructs of PRISM using qualitative comparative analysis to explore factors influencing the reach of eScreening and the use of the eScreening MCIS. Methodology: We propose an 8 site 4-year, stepped-wedge, mixed-method, Hybrid Type 2, pragmatic trial to compare eScreening to screening as usual while evaluating potential impact of the MCIS in TMC programs. Aim 1 outcomes will be collected via deidentified chart pull at the start and end of the pre-implementation phase, the 9-month intervention period, and 9-months post intervention. Aim 2 outcomes will be collected quantitatively from TCM staff questionnaires and qualitatively from interviews. Aim 3 data will be collected at the same intervals as Aim 2. Next Steps/Implementation: We will use the findings of this research to inform suicide prevention early identification best practices and enterprise scale-up of eScreening with our VACO partners.

Up to 75% of Veteran and military suicide decedents die without initiating mental health treatment. Rural Veterans are more likely to die by suicide and less likely to receive mental health services than urban Veterans. Primary Care Mental Health Integration (PCMHI) programs within VA are ideally situated to help rural Veterans with phone-based services. Connecting to Veterans remotely is now more important than ever given the current pandemic. This proposal seeks to prevent suicide and improve mental health functioning in rural Veterans by implementing an effective intervention (Cognitive Behavioral Therapy for Treatment Seeking, CBT-TS) into routine clinical care in 4 regions using rigorous implementation strategies. CBT-TS is a treatment engagement program designed to assist Veterans to make more informed decisions about seeking mental health treatment. It is effective in increasing mental health treatment utilization among Veterans at risk for suicide. Across 7 funded trials of CBT-TS (among individuals with alcohol use disorder, military personnel with PTSD, Veterans and military personnel at-risk for suicide, and VA primary care), patients who received CBT-TS were 2-3 times more likely to seek mental health treatment than controls (Stecker et al, 2012; 2014; Possemato et al., 2018).

Women Veterans are twice as likely as civilian women to die by suicide and report gender specific barriers to receiving VA care. Given that women are the fastest growing demographic of Veterans, gender-sensitive approaches are needed to reduce suicide risk and enhance engagement in care. A retreat-based suicide prevention program has unique potential to build group cohesion (analogous to cohesion that develops during military service), reduce thwarted belongingness, and promote holistic health for women Veterans. It would also serve as an ideal opportunity to identify and engage women Veterans who may be at heightened risk for suicide. Research has shown that retreat programs improve quality of life and relationship functioning, and reduce mental health symptoms (e.g., depression, PTSD) for women. However, this modality has yet to be leveraged within VA as a selective suicide prevention strategy. Building on VA and grassroot retreat programs already underway, research is needed to explore a retreat’s promise as a mechanism for delivering evidence-based suicide prevention practices to women Veterans. Employing a participatory process with Veterans, providers, and experts, the proposed qualitative project will develop a retreat-based suicide prevention program for women Veterans. We will: 1) conduct focus groups with women Veterans from higher risk for suicide groups to determine interest, preferences, and perceived barriers and benefits to attending a retreat; 2) conduct semi-structured interviews with women’s mental health, suicide prevention, community (e.g., Women Veterans Network), and multidisciplinary (e.g., Whole Health) experts to identify barriers and facilitators of establishing retreat programs and appropriate content; and 3) review available retreat, wellness-based, and suicide prevention programs’ structure and content. In collaboration with consultants and Veteran Engagement Group, we will integrate data to design a retreat-based program in line with best practice recommendations and women Veteran preferences. We will prepare a future funding proposal to pilot the developed program.

To conduct a fully powered randomized controlled trial evaluating the effect of adding a standard TMS course of treatment to Brief Cognitive Behavioral Therapy (BCBT) to reduce suicide behaviors in a sample of Veterans hospitalized for suicide behavior.

Objectives The Chronic Effects of Neurotrauma Consortium’s (CENC) Warfighter Epidemiology Cohort was developed to identify phenotypes of comorbidity among deployed Post-9/11 Veterans in order to compare emergence of neurosensory, neurodegenerative, pain, and mental health comorbidity in Veterans with traumatic brain injury (TBI). The Long-term Impact of Military Relevant Brain Injury Consortium (LIMBIC) extension of the Warfighter Epidemiology Cohort will extend the work begun by CENC in which we identified a cohort of Post-9/11 Veterans and comorbidity phenotypes. We also obtained Department of Defense trauma registry (DODTR) data, where available, and Military Health System (MHS) inpatient, outpatient, and pharmacy data that was included in the DoD Mental Health Data Cube. We now propose to expand upon this important data source for over 5 million deployed Service members to include a broader cohort of Post-9/11 era (deployed and non-deployed) Veterans and additional data sources that provide unique opportunities to examine long-term comorbidity phenotypes and develop risk models for comorbidities of interest such as neurodegenerative disease, substance use disorders (SUD), psychological comorbidities, and self-harm behaviors. Research Design and Methodology This retrospective cohort study will accomplish the following goals: 1) Using all sources TBI severity algorithm and NLP/text embedding methods, identify phenotypes of mild traumatic brain injury (mTBI) in DoD and DoD+VA data that incorporate acute injury, mechanism of injury, and blast exposure. A2) Identify prevalence of key comorbidities and outcomes at baseline, before and after mTBI exposure, and in VA (where relevant) and compare those rates by TBI severity and study group. 3) Use deep learning models that incorporate mTBI phenotype, acute and chronic treatment approaches, and emergence of diverse comorbidities to develop risk scores for poor military outcomes and developing key comorbidities. We will use data in DaVINCI to identify a cohort of Veterans who receive longitudinal VA care (at least once a year for three or more years between FY2002 and FY19 [at least one of which is after 2007 when TBI screening was mandated]). We will also identify individuals who did not receive VA care. We will then categorize those with and without VA care as deployed and not deployed, creating four study groups: a) deployed with VA care; b) deployed without VA care; c) not deployed with VA care; d) not deployed without VA care. We will compile VA and DoD data sources and identify key comorbidities (e.g., neuroendocrine dysfunction, SUD, self-harm behaviors) and TBI characteristics. Those data will be used for machine/deep learning models that will develop TBI phenotypes, comorbidity phenotypes, and model risk scores for developing key comorbidities, and optimal processes of care for mTBI. The number of study subjects entering and finishing the study is 5 million. Conducting these analyses for the four study groups will inform TBI pathways of care and illuminate specific target areas to improve acute TBI care and subsequent support systems for chronic care following TBI.

The VA is committed to reducing suicide in the U.S. Veteran population. Over 6,000 Veterans die from suicide each year, and this risk is particularly high following a psychiatric hospitalization. This may be due to problems with engagement in care and poor social connectedness. Although the VA has implemented tools to address Veteran suicide risk, suicide after psychiatric discharge remains an ongoing problem. This has highlighted the need to develop new interventions and approaches to post-discharge mental health care within the VA. In response, this project is a randomized control trial of an intervention an intervention called Prevention of suicide: Education, Awareness, Connection, and Engagement (PEACE). This intervention is comprised of two synergistic and promising components to prevent suicide: 1) a mobile mental health app, which aims to improve social connectedness after discharge; and 2) a manual-based intervention called the Veterans Affairs Brief Intervention and Contact Program (VA-BIC), which promotes engagement in care. The overall goal of this study is to determine if the PEACE intervention combined with standard discharge care reduces suicidal ideation as compared to a control group receiving only standard discharge care.

Objectives: This project aims to 1) Identify the effect of PEACE on suicidal ideation after psychiatric hospitalization, compared to standard care alone; 2) Identify the effect of PEACE on social connectedness and engagement in care after psychiatric hospitalization, compared to standard care alone; and 3) Compare the effect of PEACE on suicide attempts and suicide deaths after psychiatric hospitalization, compared to standard care alone.

Women Reserve/National Guard (RNG) veterans are a growing US population that emerging data indicates are at elevated suicide risk. To address this preventable tragedy, we propose to build on our initial ORH study findings and refine our suicide risk screening, including new questions specific to Covid-19 sequelae with the potential to exacerbate suicide risk. We will then pilot the revised and augmented interview in a national sample of RNG women veterans. New in FY21, we plan to interview the healthcare providers identified by our rural RNG women participants. We hope to better understand providers’ comprehension of risk and current screening for this veteran subpopulation, and their recommendations for, and barriers to, risk reduction/suicide prevention interventions. Findings will advise our development of suicide prevention interventions unique to the needs and preferences of high risk rural RNG women veterans and their providers. Products delivered will include: 1) a refined suicide risk screening interview (including Covid-19 factors) specific to rural RNG women veterans that is ready for national implementation; 2) recommendations for provider needs/training for suicide risk reduction with this subpopulation; and 3) identification of suicide prevention intervention preferences and priorities identified by RNG women veterans and the providers who treat them.

The VA Office of Mental Health and Suicide Prevention has identified firearm lethal means safety counseling (LMSC) by healthcare providers as a critical component of VA's suicide prevention efforts. Engaging Veterans in a productive discussion about firearm access and safety can be clinically challenging, yet there is a lack of standardized manuals to assist clinicians with these important conversations. This project tests a manualized firearm LMSC intervention. Primary objective of this study is to pilot a DBT firearm lethal means safety clinical package that includes a therapist manual and patient handouts. Qualitative interviews will assess for satisfaction and acceptability of the intervention to Veterans, and the intervention will be revised based on feedback from Veterans.

Background: Many Veterans experience impairing symptoms of anxiety and seek treatment in primary care, yet anxiety is highly undertreated in this setting. Primary Care-Mental Health Integration (PCMHI), in which mental health clinicians embedded in primary care provide brief treatment, affords an opportunity to address this treatment gap. However, behavioral interventions that are compatible with the brief PCMHI treatment format and able to accommodate a wide range of anxiety presentations are needed. Accordingly, Veterans Anxiety Skills Training (VAST) was designed to be evidence-based, transdiagnostic, feasible for PCMHI, and Veteran-centered. VAST comprises empirically-supported cognitive-behavioral therapy (CBT) techniques adapted into a manualized modular intervention specifically designed for delivery in PCMHI. As VAST is being piloted at a single site with study therapists, the next scientific step is a multi-site randomized controlled trial (RCT) to evaluate its effectiveness using PCMHI providers in routine care.

Significance/Impact: This study addresses Veteran care priorities of mental health and suicide prevention, MISSION Act priorities of increasing access to care and improving patient satisfaction with Veterans Health Administration (VHA) care, and Health Services Research and Development (HSR&D) focus areas of quality, effectiveness, and efficiency as well as implementation science research methods. Improving anxiety treatment in PCMHI will address a major gap in VHA treatment options, given the high prevalence of anxiety in primary care, tendency for patients with anxiety to seek treatment in primary care rather than specialty mental health settings, and absence of Evidence-Based Psychotherapy (EBP) protocols addressing non-trauma related anxiety.

Innovation: Modular (vs. standard) intervention designs offer advantages in efficiency, patient and provider satisfaction, efficacy, effectiveness, implementation, and sustainability. Other innovative aspects include the transdiagnostic approach and examination of fidelity to inform future implementation. Specific Aims: The specific aims are to: (1) Compare patient clinical outcomes for VAST vs. PCMHI usual care between baseline and 16 weeks (post) in a multi-site RCT in which PCMHI providers deliver VAST, and examine whether treatment gains are more likely to be maintained for VAST vs. PCMHI usual care at 28 weeks (follow-up); (2) For participants assigned to receive VAST, explore patient-level predictors of (a) early (8 weeks) and (b) overall (16 weeks) treatment response; and (3) Conduct a mixed-methods process evaluation of VAST implementation to examine rates of, barriers to, and facilitators of achieving and sustaining high-fidelity intervention delivery. Methodology: In this multi-site, hybrid type I effectiveness-implementation RCT, 178 adult Veterans with elevated anxiety symptoms will be recruited from primary care at two VHA sites. PCMHI providers will be randomized to deliver either VAST or usual care (routine PCMHI care, meaning whatever care the provider deems appropriate), and participants will be randomized to condition. VAST (up to six biweekly 30-minute sessions) consists of a standard initial and final session as well as up to 4 CBT skills-based modules. The primary outcome (Overall Anxiety Severity and Impairment Scale) and secondary outcomes (anxiety and depressive symptom severity, functioning, quality of life, suicidality) will be assessed at baseline, 4, 8, 12, 16 (post) and 28 weeks (follow-up). Multi-level modeling will be used to evaluate the hypothesis that patient clinical outcomes will improve more from baseline to 16 weeks for participants receiving VAST compared to PCMHI usual care. Multivariate logistic regression will be used to explore predictors of early (8 weeks) and overall (16 weeks) VAST treatment response. A mixed- methods process evaluation will examine the proportion of PCMHI providers who achieve and sustain high- fidelity VAST delivery as well as barriers to and facilitators of high-fidelity delivery.

Implementation/Next Steps: VAST will be disseminated to VHA PCMHI leadership and providers nationwide using several strategies, and a follow-up hybrid III trial will facilitate formal implementation in VHA PCMHI.

The overall goal of our proposed work is to develop and implement an effective suicide prevention intervention for rural VA facilities to decrease suicide risk in veterans living in rural settings. To achieve this goal, we propose to study our VA adaptation of WHO BIC (which we will refer to as VA BIC) in rural veterans during high-risk care transition scenarios. We will study the effectiveness of VA BIC in four high-risk care transition scenarios common to rural VA facilities. This project has three objectives. First, we will adapt the VA BIC for use during high-risk care transition scenarios including emergency room care, medical hospitalization and acute treatment in a drug dependence rehabilitation program. Second, we will confirm that the VA BIC is effective at reducing suicidal ideation and other related measures of suicide risk during high-risk care transition scenarios including psychiatric hospitalization, emergency room care, medical hospitalization and residential substance treatment facility. Third, we will disseminate the VA BIC to other rural VA facilities and assist these facilities with implementing VA BIC at their local sites in order to reduce the burden of suicide in rural veterans during high-risk transition care scenarios.

Background: Seventeen Veterans die by suicide on a daily basis, and Veterans often seek care in Emergency Departments (EDs) prior to a suicide attempt. Lethal means safety (LMS) interventions, which aim to reduce access to common methods of suicide such as firearms or toxic medications, are considered important components of suicide prevention programs and are recommended for Veterans with elevated suicide risk.

Significance/Impact: The Veterans Health Administration (VHA) considers suicide prevention a clinical and research priority. In 2019, VHA began screening all Veterans seeking ED care for elevated suicide risk. The VA’s National Strategy for Preventing Veteran Suicide highlights “efforts to reduce access to lethal means of suicide among Veterans with identified suicide risk.” However, no LMS intervention has been developed to accompany this initiative and prior LMS interventions have not been developed for US Veterans or VHA settings. The proposed work will address this critical gap in VHA suicide prevention efforts by developing and testing a Veteran-centered, ED-based LMS intervention for multiple methods of suicide.

Innovation: Several evidence gaps must be addressed in developing such an intervention. No prior LMS intervention has been shown to be efficacious in promoting medication and firearm safety, and prior interventions have not accounted for the various, person-specific mechanisms by which individuals change behaviors. The proposed intervention will incorporate multiple evidence-informed elements specifically chosen to target different but complimentary behavioral mechanisms highlighted within the Health Belief Model (e.g., self-efficacy) as critical to behavior change. Elements include those that equip staff with evidence-based communication strategies, and provide Veterans with practical, patient-centered support to facilitate LMS behaviors. To ensure that this intervention meets the needs of at-risk ED patients and is sustainable long-term if shown to be efficacious, we will engage Veteran and clinical stakeholders to develop the intervention. Engaging stakeholders in intervention development, an emerging VHA priority, is critical for ensuring feasibility, acceptability, and credibility. As one Veteran remarked during a focus group, “I appreciate you all askin’ us what we’re thinkin’, rather than just sayin’, ya know, here’s what it is and here’s what it’s gonna be.” Specific Aims and Methodology: Aim 1: Identify contextual factors that may inform development of the intervention. I will conduct semi- structured qualitative interviews with up to 30 at-risk Veterans who recently received VHA ED care to identify intrapersonal, interpersonal, and institutional factors that should be considered during intervention refinement and adaptation in Aim 2. Aim 2: Leverage the expertise of a diverse sample of stakeholders to refine intervention elements, adapt them for use among Veterans and within VHA EDs, and develop a final intervention protocol and related materials. Building on prior studies and knowledge gained from Aim 1, I will employ a stakeholder-engaged process to refine, adapt, and finalize the LMS intervention protocol and materials. I will use two evidence-based methods to engage stakeholders and build consensus (Nominal Group Technique, online modified-Delphi process). Aim 3: Pilot the ED-based LMS intervention among 40 Veterans to assess feasibility and acceptability. I will assess feasibility of recruitment, staff fidelity to the intervention, and Veteran engagement, including after ED discharge, and acceptability of the intervention among participants, intervention staff, and ED staff. Next Steps/Implementation: Results from this pilot study will support an IIR application to test the efficacy of this intervention in promoting LMS behaviors among at-risk Veterans. If found to be efficacious, consistent with VHA’s public health approach to suicide prevention and my long-term career goals, my future work will aim to adapt and disseminate the intervention across various VHA (e.g., primary care) and community settings.

Background: Lithium (LI) and clozapine (CLOZ) are the most evidence-based medications for preventing fatal and nonfatal suicidal behavior (SB). Unfortunately, both medications also can cause numerous medically serious side effects (SSEs). The VA is conducting a large randomized trial of LI for SB, and VA program offices are considering encouraging greater LI and CLOZ use. This study features a comprehensive database analysis and national survey to gather data to maximize the success of any effort to expand LI and CLOZ use. Specific Aims: 1) Rapidly Assess the Current Safety of LI & CLOZ & Identify Opportunities for Expanded Use; 2) Refine Knowledge about the Timing of SSE Risks and the Implications for Clinical Care; 3) Examine Use Across Providers & Identify Perceived Barriers / Facilitators to LI and CLOZ use; and 4) Integrate Results & Develop Policy Recommendations, Provider Guide, & Communication Tool.

Significance: This study will markedly advance knowledge about how to safely use LI and CLOZ. These advances will include identifying the safest populations to target for expanded use, and how to best manage patients once LI and CLOZ are started. Understanding will be obtained about barriers besides SSEs that may impede wider LI and CLOZ use, and input will be obtained from providers on how to surmount these barriers. Findings will be integrated in several ways, including synthesis into a useful guide and communication tool. Priority Area(s): Suicide Prevention, Mental & Behavioral Health, and Predictive Analytics. Uniqueness: No prior study has examined the SSEs of LI or CLOZ as comprehensively, evaluated prevention and treatment strategies as thoroughly, or condensed its findings into tools for providers and patients. Methodology: Aim 1: Cox Regressions with Propensity Scores stratification will be used to facilitate the rapid estimation of risks associated in patient groups possessing plausible SSE risks factors (e.g., particular medical, psychiatric, or substance use diagnoses). Aim 2: Cox regression with marginal structural models will evaluate the emergence and development of risks over time, seeking to identify clinically-useful “Decision Points”, and incidence rates will be derived to promote patient-provider communication regarding SSEs. Survey: A brief nationwide mental health prescriber survey focused on Barriers and Facilitators to Lithium use. Open response survey components will help ensure that any unanticipated barriers or facilitators to LI or CLOZ use will likely be identified. An all-cause mortality analysis and an example Predictive Model will help integrate results, as will an Advisory Board. A user-friendly Provider Guide and Patient-Provider Communication Tool will be developed. Expected

Results: For LI and CLOZ, we expect to find some patient groups at lower risk than others for SSEs (e.g., male patients may be at lower risk for renal effects). We also expect immediate release LI to be associated with less renal risk. For CLOZ, we expect treatment of weight or metabolic risks at initiation to be beneficial. We also expect to find a “trial window” during which risks of SSEs are fairly negligible, which may increase the willingness of patients to try LI or CLOZ. We expect the survey to find that SSEs are perceived as barriers to use, but also other barriers (e.g. a preference for medications without monitoring requirements). Next Steps: The study is expected to yield immediate policy recommendations (e.g., patient groups to target or not in any prescribing initiative) and valuable tools, since results are so directly transferable to patient care. Next steps might include immediate efforts by program offices to expand Li or CLOZ use. Alternatively, an implementation trial or staggered implementation could be initiated. Pilot testing of real-time risk calculators or qualitative studies of patient, provider or other key informant attitudes towards LI and CLOZ could also occur. Other Areas: This study will also support the safe use of these uniquely-valuable medications in non-suicidal patients. The survey findings will provide data that may inform future Provider Behavior interventions.

This project intends to extract from clinical progress notes concepts that are central to the 3-step theory of suicide (3ST), that is hopelessness, psychological pain, connectedness, and capacity for suicide, and test their potential to improve the accuracy of VHA's suicide risk prediction models: REACHVET and STORM. We have the following three specific aims:1. Develop a suicide-specific ontology for machine recognition of the key concepts of 3ST (hopelessness, connectedness, psychological pain, capacity for suicide) in progress notes of clinical encounters with Veterans who attempted or died by suicide. 2. Extract information on the presence and intensity of hopelessness, connectedness, psychological pain, and capacity for suicide in clinical progress notes and describe change in these concepts in proximity of a suicide or suicide attempt. 3. Determine the predictive validity of hopelessness, connectedness, psychological pain, and capacity for suicide regarding Veteran suicide attempt and mortality.

The specific aims of this study are: (1) to investigate the relationship between trait measures of impulsivity and suicide attempt history in Veterans with bipolar disorder; (2) to investigate the neural circuitry underlying two models of state impulsivity and their relationship to suicide attempt history in Veterans with bipolar disorder; and (3) to identify which combination of impulsivity measures differentiates those with a history of suicide attempt from those without suicide attempts and healthy controls at a baseline timepoint and can be used to predict suicidal behavior longitudinally over 1 year.

Background: Despite accessible and effective suicide prevention strategies offered by the Veterans Health Administration (VHA), Veteran suicide remains elevated compared to the general US population, indicating a continued need to identify Veterans at risk for suicide and provide interventions to prevent suicide. Suicide prevention can be enhanced when health care systems integrate dynamic social determinants of health (SDH), such as housing instability, justice involvement, and unemployment.

Significance/Impact: The goal of this HSR&D Veteran Suicide Prevention project is to address prevention activities that occur “upstream” by examining how services addressing SDH may also prevent suicide among Veterans, key objectives in the VA’s National Strategy for Preventing Veteran Suicide 2018–2028.

Innovation: This study will integrate a public health perspective to suicide prevention through a lens of SDH. Rather than focusing specifically on medical intervention, this study will explore—based both on a natural experimental design using existing administrative data and on gathering the perspectives of key informants and Veterans—how addressing SDH can decrease suicide risk, taking into account the complex needs of Veterans who may be at risk for suicide. Specific Aims: This study aims to determine whether VHA services tailored to address SDH may also have an added benefit of preventing suicide mortality; identify organizational assets and opportunities to improve how SDH-focused services address suicide risk among Veterans; and engage Veterans in identifying ways to integrate suicide prevention into VHA programs that respond to SDH. Methodology: The proposed research is a concurrent mixed methods design. Retrospective quantitative analyses will examine how VHA services tailored to Veterans’ SDH (i.e., housing instability, justice involvement, unemployment) may protect against suicide mortality and morbidity. A mixed methods environmental scan will include a questionnaire of staff/key informants and qualitative interviews. Qualitative interviews with Veterans with a history of suicide risk will explore how services to address SDH respond to those needs.

Implementation/Next Steps: This project will lead to actionable implementation projects: increased linkages to services for SDH among Veterans with histories of suicidal crisis as well as enhanced training for providers to integrate suicide prevention into services addressing SDH, and vice versa. We have convened an array of VA operations partners—Social Work, VHA Homeless and Justice Programs, employment programs, and VA Office of Mental Health and Suicide Prevention—to facilitate removing siloes around SDH and suicide prevention in VA, amplifying VA’s current infrastructure to bolster suicide prevention.

While 70% of Veteran suicide deaths result from firearms, the rates are even higher in many rural areas. Interventions to promote safe firearm storage practices to prevent suicide are most effective when they account for socio-culturally informed views around firearm ownership, and research suggests that Veterans prefer to engage in conversations about firearms with credible messengers from within firearm culture or with those whom they have established a trusting relationship. While engaging family caregivers of Veterans in conversations and practices to promote safe firearm storage could be an impactful strategy, to date there have been few formal efforts in that area. Recent adoption of S.A.V.E. training through the VA Caregiver Support Program is an important step but does not focus on safe firearm storage practices in any detail. Furthermore, military caregivers themselves are at elevated risk of suicide but to our knowledge there are no interventions that address lethal means safety messaging for caregivers living in homes with firearms. In Year 1 of this project, we will assess current practices, resources, and gaps in addressing lethal means safety with military caregivers through qualitative interviews with VHA staff working in suicide prevention and caregiver support programs across 8 rural VHA facilities that have been identified as treating proportionately greater numbers of firearm-related injuries and deaths. At the same 8 sites, we will engage caregivers through deliberative discussion focus groups to establish common goals, language, and knowledge regarding firearm risk and safe storage options. With both groups of stakeholders, we will gather input on how existing messaging about safer storage practices (both in-home and temporary out-of-home storage) could be adapted to be more relevant and acceptable for rural caregivers. Finally, we will build capacity to disseminate firearm safety messaging and materials to rural caregivers through VHA programs and position our project to expand to community-based partners and caregivers who do not use VHA services in Year 2. Anticipated outcomes of Year 1 include: description of current practices among Suicide Prevention and Caregiver Support Program staff related to suicide prevention and firearm safety messaging targeted to rural caregivers; identification of barriers, facilitators, and opportunities to implementing suicide prevention and firearm safety messaging targeted to rural caregivers; adaption of existing firearm safety messaging and materials to be relevant for rural caregivers; and capacity-building for future collaboration with VHA staff and caregivers at 8 facilities to pilot a caregiver-centered intervention to promote safe firearm storage options. We expect results of this work to inform a firearm safety messaging and outreach intervention program for caregivers that is specific to rural VHA settings and informed by VHA staff who work in suicide prevention and caregiver support and caregivers served in those settings. Our team, who lead a number of other projects focused on prevention of firearm suicides and injuries, will be positioned to collaborate on development of a culturally-responsive firearm risk reduction program that engages all rural stakeholders including VHA providers and program staff, Veterans and their families, and firearm retailers and other community partners.

This demonstration project will establish feasibility and preliminary effectiveness of a lethal means safety (LMS) suicide prevention module—consisting of a brief video and PowerPoint slides—incorporated into concealed carry and firearm safety classes taught in Southeast Louisiana. In collaboration with local firearm owners and instructors, we developed a suicide prevention module for concealed carry classes that focuses on raising awareness about high rates of firearm suicides among Veterans and civilians, educating about warning signs of a suicidal crisis, promoting options for preventing firearm suicide through safer in-home storage practices and/or temporary out-of-home storage, and encouraging firearm owners to destigmatize conversations about mental health, firearms, and suicide prevention. The video is adapted from a similar effort in Utah but features two Veterans. We will conduct a 6-month pilot study with up to 6 concealed carry and firearm safety instructors and up to 200 concealed carry and firearm safety class students. Fidelity of implementation will be measured through post-class check-ins with instructors and observations at select classes. Acceptability among instructors will be measured through quantitative and qualitative feedback. Changes in knowledge, attitudes, and behaviors among students will be assessed through quantitative measures administered immediately before and after classes and a brief semi-structured phone interview at 1-month post-class. To our knowledge, this will be the first study to measure acceptability and impact of LMS suicide prevention messaging delivered in community concealed carry and firearm safety classes. What we learn will inform future VA and community efforts to implement similar messaging in firearms courses, and support efforts to voluntarily incorporate LMS messaging in firearms courses in our state and others.

Despite the existence of effective drug treatments and emergent psychotherapies for bipolar disorders (BD), Veterans with BD often drop out of treatment during acute manic or depressive episodes. Clinical experience also suggests that onset of acute mania or depression can lead individuals with BD to disengage from treatment when they most need it. Re-engaging Veterans with BD in treatment is especially important given an established link between BD and poor psychosocial functioning and high rates of suicide among Veterans with BD. A clinical tool that identifies early signs of acute bipolar states could thus improve functional outcomes by enabling well- timed interventions to reduce mood episodes’ severity and their deleterious psychosocial impact. mHealth refers to the use of mobile and wireless devices as part of patient care and offers many potential opportunities for early detection and intervention with acute mood states in this population, but these mHealth approaches have not been investigated in Veterans with BD. The overall purpose of our research program is to develop, validate, and disseminate mHealth tools that can promote social and community functioning and prevent suicide among Veterans with BD by promoting more timely and effective delivery of evidence-based treatments. The goal of this Small Projects in Rehabilitation Research (SPiRE) proposal is to obtain feasibility and acceptability data on a set of smartphone programs (“apps”) as possible means of detecting the onset of acute depression or mania and indicators of increased suicidality and changes in social functioning/participation in Veterans with BD. The project has three aims: (1) to assess the feasibility of enrolling and retaining a sample of 30 Veterans with BD for a three-month trial with passive and active smartphone monitoring, (2) to assess the acceptability of daily symptom ratings and ongoing smartphone monitoring through voice recordings and location services in this population, and (3) to explore the potential utility of voice and continuously collected location data in detecting acute bipolar states and predicting suicidality and changes in social participation in Veterans with BD. The above stated aims will be accomplished through daily self-report assessments, voice sample recordings, and continuously and passively monitored location data using three smartphone apps, in addition to biweekly phone assessments of bipolar symptoms, suicidality, and social participation in a sample of 30 Veterans with BD receiving care at the Minneapolis VA Health Care System. Apps will allow the analysis of daily self-ratings, vocal patterns (especially speech rate), and movement (i.e., increases or decreases in routine and non-routine movement in the community) as potential markers for bipolar episodes, suicidality, and social participation, which will be evaluated in the biweekly phone assessments. Study feasibility will be based on the project’s successful recruitment and retention of the proposed sample, while the acceptability will be in part determined based on the exit interviews at the end of each participant’s study participation (i.e., after the three-month follow-up or earlier in the case of study withdrawal). These exit interviews will provide valuable information regarding acceptability of use of these smartphone apps in Veterans with BD, such as participants’ perceptions about study procedures/apps and potential clinical uses of this type of data, and, if withdrawing from the study early, perceived barriers to study completion. Finally, the study will allow a preliminary exploration of the ability of voice samples and location data to predict changes in bipolar symptoms, suicidality, and social participation as pilot data for future larger studies.

Explore the potential utility of offering a single, low-dose ketamine infusion, as a safe, rapid, and effective treatment for suicidal ideation in patients presenting to Psychiatric Emergency Room.

Preventing suicide is the VA’s top clinical priority. Family and friend caregivers help veterans engage in mental health treatment, and support veterans as they manage their mental health conditions, including those associated with increased suicide behaviors and risk. Supporting family caregivers in their role could increase the ability for caregivers to help their veterans manage their mental health treatment and conditions, thereby reducing suicide risk. The VHA Program of Comprehensive Assistance for Family Caregivers (PCAFC) provides a monthly stipend, health insurance, and systematic training to caregivers to improve the care provided to the Veteran and to enhance caregiver skills. PCAFC trainings and supports include access to trainings, e.g. coaching a care-recipient to accept help and being a mental health advocate.   Our objective is to describe and evaluate the effect of participation in PCAFC on Veteran suicidal behaviors and overall mortality. First, we describe the suicide-related mortality and overall mortality among Veterans in PCAFC compared to similar Veterans not participating in PCAFC. Second, we evaluate the effect of PCAFC on predicted risk of suicide among Veterans in PCAFC compared to similar Veterans not participating in PCAFC

The objective of the proposed project is to us grounded theory methodology to understand LGBTQ Veterans' decisions to seek or not seek support when experiencing suicidal ideation. The PI will recruit approximately 20 LGBTQ Veterans from VACHS and VACWM through flyers and program coordinators. Qualitative interviews will be conducted.

This VA Career Development Award will ensure my expertise in VA healthcare implementation research and health equity through formal training and applications of my knowledge through small research studies. The research studies in this project develop and pilot methods to engage rural VA patients in selecting and tailoring implementation strategies to implement the Safety Planning Intervention, a suicide prevention intervention. Rural VA patients represent a marginalized group related to suicide and mental health care—they experience suicide disparities and lack of equitable access to mental health care. Therefore, methods identified and refined in this research may generalize to other marginalized VA patients and will innovate implementation science to increase health equity.

Major depressive disorder (MDD) and alcohol use disorder (AUD) are serious mental illnesses and commonly co-occur among Veterans. Adequate treatment of depression and comorbid AUD is of major clinical importance at the VA, yet the efficacy of current pharmacotherapy for depression is only modest and remission rates are particularly low in depressed patients with AUD. The delay of weeks or months before the onset of antidepressant effects of traditional antidepressants is also problematic, particularly given the elevated risk for suicide in this population. Furthermore, despite the fact that 40% of patients with MDD have comorbid AUD in their lifetime, AUD patients have been excluded from most antidepressant trials for depression. Thus, there is a critical need to develop effective pharmacotherapy for MDD and AUD. There is a growing body of literature showing that a subanesthetic single intravenous (IV) infusion of ketamine has rapid and robust antidepressant effects. Ketamine was also associated with a rapid reduction in suicidal thoughts in randomized controlled trials. In addition to treating MDD, emerging evidence indicates that ketamine, an NMDA receptor antagonist, might be an effective treatment for AUD by stabilizing glutamatergic system. Building on this evidence, we recently tested ketamine in patients with comorbid MDD and AUD. Our pilot data showed that ketamine may be safe and effective in reducing depression and alcohol consumption. The primary goal of this proposal is to test repeated intravenous ketamine (0.5 mg/kg; once a week; a total of 4 ketamine infusions) as a treatment for MDD and AUD in a total of 60 Veterans. We propose an 8- week, randomized, double-blind, placebo-controlled trial. The study will have two phases: 1) a 4-week treatment phase and 2) a 4-week follow-up phase. All patients will be evaluated daily by using ecological momentary assessment and will receive usual standard care during this trial. There are five objectives. Aim #1: To evaluate whether ketamine is superior to active placebo (midazolam) in treating depression in Veterans with comorbid MDD and AUD. We hypothesize that ketamine is superior to active placebo in clinical response for treating depression. The clinical response will be defined as a ? 50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Aim #2: To evaluate whether ketamine is superior to active placebo (midazolam) in reducing alcohol use in Veterans with comorbid MDD and AUD. We hypothesize that ketamine is superior to active placebo in reducing drinking as measured by the Time Line Follow Back (TLFB). Aim #3: To evaluate whether ketamine is superior to active placebo (midazolam) in reducing alcohol craving during the 8-week study period. We hypothesize that ketamine is superior to active placebo (midazolam) in reducing alcohol craving as measured by the Alcohol Urges Questionnaire (AUQ). Aim #4: To evaluate whether ketamine is superior to active placebo (midazolam) in reducing suicidal ideation. We hypothesize that ketamine is superior to active placebo (midazolam) in reducing suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation category. Aim #5: To evaluate the safety and tolerability of repeated ketamine infusions in Veterans with comorbid MDD and AUD. We hypothesize that repeated ketamine infusions are safe and well tolerated in this population. Conclusion: This is the first randomized controlled trial examining the therapeutic potential of repeated ketamine for comorbid MDD and AUD. If successful, our pharmacological approach could help Veterans suffering from this condition.

Curating an ever-growing library of community level environmental and social determinants of health variables - Support SPP and NIH Cancer grant. Develop a well-functioning partnership with GeoBISL to host ORNL currated geospatial data Include a new geospatical dta domain in CDW for enterprise use, ETA Summer 2022. Need ORNL support to enable on-going updates

Deep-learning and other modeling approaches to understanding suicide risk and identifying at risk individuals for intervention. Examining free-text predictors of suicide death among patients not identified as HRF at the time of the event. Will control for REACHVET predictors. Developing methods for deep-learning based NLP algorithm development, and/or augmentation of annotation-based development methods. Use of facility variation in clinical practice to evaluate effects of practice on clinical outcomes. Initial focus is on psychotropic prescribing practices.

Conducting an environmental scan of community-level suicide prevention resources and characterizing the community context in Arkansas counties. Objective 1: Recruit and engage community partners to identify existing suicide prevention activities and needs, then collaboratively develop a plan for PREP implementation • Objective 2: Evaluate the implementation of the PREP project in 2 counties and use the results to develop methods, measures and scale up plans to expand to 4 additional counties • Objective 3: Manualize the process, procedures, and recommendations for implementing the PREP Project state-wide • Objective 4: Collaborate with Community Partners to identify and disseminate findings, integrate activities into state funded efforts, and collaboratively submit grants to ensure sustainment

Aim 1: Identify Social Determinents of Mental Health via NLP. Aim 2: Compare the relative benefits of alternative NLP approaches, based on accuracy, imporved measurement over only structured data and implementation complexity. Aim 3: Integrate into OMHSP decision support dashboards and predictive analytics (e.g., STORM/RV). Work is occuring on ROCKIES and VINCI. *****ROCKIES concepts include: (1) Loneliness, (2) Access to Lethal Means (3) Intravenous Drug Use, (4) Detoxification Therapy, (5) Justice-involved, (6) Premil/Mil/Postmilitary Sexual Trauma, (7) Food Insecurity, and (8) Job Instability. *****VINCI concepts include: (1) Inter-personel Relationships, (2) Social Connectedness.

To develop automated, natural language processing (NLP) methods to determine which Veterans have access to firearms and which have substance use disorders. To compare NLP assessments of firearm access and substance use disorders to template-based evaluation of firearm access by human reviewers and ICD-10 coding of substance use disorders by human coders. To identify elements of lethal means safety counseling that may be detected in notes using NLP methods.

Using natural language processing on outpatient PTSD progress notes to identify the conduct of suicide ideation assessment and review the documentation quality.

The toll of suicide goes way beyond the death of an individual. Those exposed (defined as knowing the person) to a suicide death are at elevated risk for mental illness, physical disorders, impaired social functioning, and fatal and nonfatal suicide behavior. Conclusions from the handful of studies that have examined this topic among Veterans are limited by distinct samples, limited sample sizes and other methodological issues. Additionally, the numbers of women and minority race/ethnicity service members and Veterans in these studies were too small to examine what are likely critical differences by sex and race.

Significance: This study will provide foundational information on an understudied risk factor for suicide in a cohort of Veterans at increased suicide risk post 9/11 Veterans within six years following military separation. It will provide information to inform suicide postvention strategies that target the population of suicide bereaved post-9/11 Veterans as well as those targeting women and American Indian/Alaskan Native (AI/AN) Veterans. Innovation and Impact: (1) Use of VA data to provide the most reliable prevalence estimates for suicide exposure among Veterans to date; (2) Oversampling of vulnerable but understudied populations -- Women and AI/AN Veterans; (3) inclusion of two comparison groups to elucidate the common and unique contribution of suicide exposure to health outcomes and patterns of VA service utilization; and (4) Assessment of the formal and informal supports Veterans receive for mental health problems associated with suicide using both survey and VA healthcare utilization data. Specific Aims: (1) Evaluate differences in the prevalence of posttraumatic stress disorder (PTSD), prolonged grief disorder (PGD), and in suicidal ideation, attempts and planning among Veterans exposed to suicide compared with those exposed to other causes of sudden death and with unexposed Veterans. We will also evaluate differences by sex and race. (2) Identify modifiable moderating factors for the association between suicide exposure and negative outcomes and modifiable moderating factors for the association between suicide or sudden death exposure and negative outcomes relative to those with neither exposure. (3) Describe treatment experiences, interests, reported suicide attempts, and patterns of VA service utilization among those exposed to a suicide death compared to Veterans exposed to other sudden deaths and to unexposed Veterans. (4) Contextualize quantitative findings through interviews with a purposive sample of Veterans exposed to suicide. The interviews will focus on modifiable factors at each level of the socio-ecological model of suicide prevention to better understand targets for intervention. Methodology: This explanatory sequential mixed methods study examines outcomes associated with suicide exposure in a nationally representative sample of post-9/11 Veterans enrolled in VA healthcare. We will collect data in three waves. Wave 1 will implement a national population probability sample using a brief survey to assess exposure history (suicide, other sudden death, neither) and exposure characteristics (e.g., time since exposure) among 11,400 Veteran respondents. Wave 2 will survey Wave 1 respondents, stratified by exposure history (suicide, sudden death, neither), to assess outcomes and variables of interest among 4,500 Veterans (1,500 respondents per exposure group). Wave 3 involves interviews with a purposive subsample of 32 Waves 2 survey responders who have been exposed to suicide but differ in outcomes. Quantitative analysis is the priority of the study; the qualitative component will contextualize the quantitative findings. Next Steps/ Implementation: This work will direct VA and the field towards an understanding of the most critical outcomes among veterans exposed to suicide, the mechanisms that may lead to deleterious outcomes, and lay a foundation for understanding the effective treatments and supports needed for Veterans who experience a suicide loss, including women and AI/AN Veterans.

This is a time of unprecedented loneliness and social isolation. Loneliness in particular is a powerful predictor of suicidal ideation, suicide attempts, functional decline, and death. Loneliness can and should be addressed by health systems. Due to risk for loneliness and negative health outcomes, a group of particular concern is older adults with medical or psychiatric comorbidity who have limited treatment engagement. Caring Contacts is an intervention that can address loneliness and poor treatment engagement. However, it has only been evaluated in a narrow population of psychiatric patients and not examined amongst patients impacted by the COVID-19 pandemic or other disasters.

Significance: This project addresses VA's top clinical priority (suicide prevention), an overarching priority of the Office of Research and Development (clinical trials), and multiple Health Service Research and Development priority areas, including social determinants of health, aging, access to care, mental health, suicide prevention, and population/whole health. The impact of this project is very high because it will advance scientific understanding of key gaps related to the mechanisms and outcomes of Caring Contacts, while also evaluating a timely, pragmatic, low-cost, and scalable intervention for Veterans affected by lack of social connection and treatment engagement. If effective, it will have applicability as a response to treatment disengagement and future disasters. Innovation and Impact: We have taken an empirically-grounded suicide prevention intervention and adapted it for Veterans with poor treatment engagement in VA outpatient care. This study is innovative in testing an intervention responsive to the COVID-19 pandemic and its aftermath, and unique in using a health services intervention strategy to target loneliness. The intervention's peer support component is highly novel for its low resource demands and potential for scalability. Specific Aims: The overarching objective of this project is to evaluate "Crisis Caring Contacts" (CCC), an adaptation of Caring Contacts tailored to reduce loneliness in the context of the pandemic. To reach this objective we will achieve these aims: 1) Among older Veterans with poor treatment engagement, evaluate the effectiveness of Crisis Caring Contacts in decreasing loneliness, compared to enhanced usual care; 2) Evaluate the effect of Crisis Caring Contacts on other important outcomes, including treatment engagement and suicidal ideation; 3) Explore potential moderators of treatment response to Crisis Caring Contacts; and 4) Explore the effect of Crisis Caring Contacts on all-cause mortality and suicide attempts. Methodology: Our approach is to conduct a multisite, pragmatic randomized controlled trial of CCC. We will target Veterans age 60 and over with active psychiatric or medical diagnoses who have had limited treatment engagement in VA outpatient care. Those in the CCC treatment arm will be sent 10 postcards over 10 months by a Peer Support Specialist. Those in the enhanced usual care arm (control) will be sent non-personalized, general health resource information. We will examine self-report and administrative data outcomes over 24 months of follow-up. Next Steps/Implementation: We will collect pre-implementation data from our study sites and share this with our operational partner, the Office of Mental Health and Suicide Prevention (OMHSP). Crisis Caring Contacts is highly suited to future implementation due to its scalability, ease of creating an operational dashboard to identify Veterans who could receive the intervention, and ability to add study materials to an implementation toolkit for VA Caring Contacts interventions.

Background: Opioid prescribing has declined 64% between 2012 and 2020 in the Veterans Administration (VA),1 with high dose prescriptions declining 77%. Although this change likely will prevent prescription-related harm to Veterans, some reports signal adverse events - events that are not well understood - including suicide. Where harm has occurred, it is crucial to know what factors, modifiable and nonmodifiable, played a role. Efforts to examine causal mechanisms for suicide through trials present ethical challenges. Large database assessments may not reveal crucial information that is lacking from medical records. Psychological autopsy research provides a method to collect and analyze discrete, descriptive data concerning the clinical contexts for suicide during opioid transitions, including taper or stoppage.

Significance: The solicitation to which this proposal responds (HX-21-024) prioritizes learning about “benefits and harms of tapering and/or discontinuation.” At present, several federal agencies have declared a commitment to averting suicide during opioid taper. But thus far, we lack a deep understanding as to why the suicides occur, which makes preventive and mitigating action difficult to plan. The next logical step in preparing a health system response is in-depth study of the events themselves. Innovation and Impact: Whereas much research has gone toward discerning statistical associations between prescription opioid change and outcomes (including suicide), this project takes a different approach, by applying techniques of psychological autopsy. The pre-requisite challenge to such research is the ability to recruit bereaved survivors who may perceive stigma and who often harbor distrust of health care systems. Our team has invested years in building connections to the community, and allying with suicidologists, so that recruitment becomes possible. Also, by assessing differences between Veteran and non-Veteran suicides, we are positioned to assist VA of its unique assets and liabilities, with the goal of mitigating the latter. Specific Aims: Aim 1. Characterize the patient and clinical context factors associated with suicide among 100 persons (50 Veterans and 50 non-Veterans) who have died by suicide in the context of opioid transition (stoppage or reduction) through survey, structured interview of bereaved family members, and medical record review. Aim 2. Identify factors that may be unique to suicides following opioid transition in Veterans as opposed to non-Veterans, with attention to differences in experience for Veterans in and outside of VA care. Methodology: We will recruit, from the public, family survivors of Veterans and non-Veterans with pain who have died by suicide in the context of an opioid transition. We will work with survivors to solicit medical records from within or outside VA, to review them, and to carry out structured interviews traditional for psychological autopsy. From review of the resulting reports, a multidisciplinary research team (including experts in opioid taper, suicide, addiction, health services research and medical anthropology) will apply the Social-Ecological Framework to identify common personal and contextual factors, to identify aspects of clinical interaction that appear salient to these events, and to identify notable contrasts between those suicides occurring among Veterans as opposed to non-Veterans during opioid transition. Next Steps/Implementation: We intend to present findings quarterly to our patient/family Stakeholder Team and to VA partners (Office of Mental Health and Suicide Prevention, VA National Program Director for Pain Management), so that early and actionable insights are triaged for action. The collation of our research findings and our stakeholder response and feedback allows this project to serve as the first step of the Intervention Mapping process (“Needs Assessment”), which leads in turn to design of preferred outcomes, intervention design and testing.

On average, 18 Veterans die by suicide each day. In fact, from 2009 to 2018, more than 64,000 Veterans died by suicide, which is roughly the same number of U.S. military fatalities that resulted from the wars in Vietnam, Iraq, and Afghanistan combined. While heritability estimates for suicidal thoughts and behaviors range from 30- 55%, the genetic basis of suicide remains largely unknown. Our research team has led and participated in many of the largest genome-wide association studies (GWAS) of suicidal thoughts and behaviors to date, including each of the largest conducted in Veteran and military samples. Our most recent work has involved conducting a GWAS of suicide attempts among more than 400,000 Veterans enrolled in the Million Veteran Program (MVP). This study identified multiple pan-ethnic and ancestry-specific genome-wide significant loci associated with risk for attempting suicide among Veterans. Moreover, pathway analyses found evidence of overrepresentation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. In parallel, we have been studying a broad array of environmental risk factors for suicidal thoughts and behaviors in Veterans, such as sexual trauma, PTSD, depression, substance use disorders, borderline personality disorder, chronic pain, traumatic brain injury, and sleep disturbance (among others). We are also actively working to identify novel environmental risk factors, including geospatial factors [e.g., socioeconomic status (SES), rurality], many of which have not been previously examined in large-scale genetic studies of suicide risk. We believe that complete understanding of a complex phenotype requires understanding of relevant genetic risk factors, relevant environmental risk factors, as well as the ways in which these risk factors interact. Accordingly, during the next phase of our program of research, we propose to conduct the largest gene-by- environment genome-wide interaction study (GEWIS) of suicidal thoughts and behaviors to date. This work will enable us to identify new ways to improve the identification of high-risk Veterans, while also greatly increasing our understanding of the biological basis of suicide. Our long-term goal is to develop effective screening and intervention strategies to reduce the occurrence of suicide and suicidal behavior among Veterans. The overall objective of this specific application is to discover novel, replicable GxE interactions that increase Veterans’ risk for suicidal thoughts and behaviors. The rationale for this research is that identification of genetic variants, environmental factors, and GxE interactions that are reliably associated with suicidal thoughts and behaviors could lead to improved identification of high-risk Veterans and the discovery of additional clinically-meaningful biological pathways. Such findings could, in turn, lead to new and improved treatment and prevention approaches. In Aim 1, we will determine the environmental risk factors most strongly associated with the occurrence of suicide attempts, suicidal ideation, and suicide deaths within the MVP cohort. In Aim 2, we will conduct the largest GEWIS of suicidal thoughts and behaviors to date to identify novel, replicable GxE interactions predictive of suicide attempts, suicidal ideation, and suicide deaths among Veterans. In Aim 3, in order to evaluate the clinical utility of our findings, we will work with our operational partners to determine if the addition of our top genetic risk factors, environmental risk factors, and GxE interactions improves the predictive utility of the Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) suicide risk algorithm within the MVP cohort. Findings obtained from the proposed work could fundamentally shift understanding of the biology of suicide, lead to new and improved treatments, and improve VA’s efforts to identify and intervene with Veterans at risk for suicide. As such, the present application has tremendous potential to advanced VA’s mission and improve Veterans’ health, safety, and well-being.

Veterans Health Administration (VHA) has long known that Veterans who have recently had a suicidal crisis such as those in acute psychiatric hospitalization are at increased risk for suicide. In response, VHA developed a suicide prevention strategy and enhanced usual care (EUC) for high-risk Veterans by adding care coordination, safety plans, and access to a 24-hour crisis hotline. There has also been a broad array of innovative suicide prevention trials across VHA. However, the only intervention that has shown promise in reducing risk for suicide attempts in Veterans is Safety Planning, that has already been implemented across VHA. Despite these efforts, suicide rates following such crises have plateaued and there has been no observable reduction in risk in this population, requiring the development and testing of additional strategies that complement these already implemented approaches. Research suggests that treatments to reduce suicidal behavior may need to focus on both the motivation to live and the motivation to die to obtain optimal effects. The PI developed a revised version of Motivational Interviewing to Address Suicidal Ideation (MI-SI-R) to help Veterans resolve ambivalence about living by increasing the motivation to live, that is delivered as one-to-two in-person sessions with a telephone booster session. In a preliminary randomized controlled trial (RCT) in psychiatrically hospitalized Veterans, MI-SI-R plus EUC was associated with 50% fewer suicide attempts and 41% lower likelihood of suicidal ideation compared to EUC alone. Furthermore, post-hoc analyses suggested that MI-SI-R had a stronger impact on suicide attempt risk among those with an attempt history, but a stronger impact on suicidal ideation among those without a suicide attempt history, which requires replication. Additional research is also needed to deepen our understanding of MI-SI-R and its hypothesized mechanistic model by examining its efficacy among patients with different psychiatric disorders and its putative motivational mechanisms. We are proposing an RCT comparing MI-SI-R plus EUC (MI-SI-R+EUC) to EUC alone in a sample of 470 high- risk Veterans with recent suicidal crises from three VHA Medical Centers, with “high-risk” defined as a suicide attempt within a month or suicidal ideation > 5 on the Beck Scale for Suicidal Ideation. Half (n = 235) will be randomized to MI-SI-R+EUC (three sessions in-person, via Video Connect, or telephone) and the remaining participants (n = 235) will receive EUC alone. All participants will be asked to complete telephone follow-up assessments at 3, 6, 9, and 12-months after randomization. This will allow us to determine the efficacy of MI-SI- R+EUC in reducing risk for suicide attempts (Aim 1) and reducing overall suicidal ideation (Aim 2) when compared to EUC alone. We will also explore the possibility that MI-SI-R+EUC has a differential impact among patients with different suicide attempt histories and different psychiatric disorders and investigate putative motivational mechanisms (Exploratory Aim 3). This study is significant because suicide prevention is a VHA priority and targets a population that is known to be at very high-risk with a brief intervention that has high potential for implementation. It is innovative because it tests a revised intervention that targets the motivation to live making it novel among interventions that have been tested in full-scale trials, explores potential conditions that may impact its efficacy, and examines hypothesized motivational mechanisms.

In addition to their metabolic and cardiovascular protective effects, statins reproducibly engage multiple pathophysiological factors implicated in suicidal behavior - neuroinflammation, increased oxidative stress, excitotoxicity, and endothelial dysfunction. Add-on statins have been also reported to improve therapeutic control in physical and mental health. The Veterans’ persistent higher rates of suicide have remained unabated challenges and, and thus, demanding new ways of understanding and engaging in preventative efforts. The long-term objective of our group is to uncovering new modifiable targets, novel and repurposed treatments in suicide prevention, and identifying individuals at risk who are likely to most benefit from specific interventions. Macro-epidemiological approaches using electronic medical records in suicide research are irreplaceable for their capability to account for multiple interactive risk factors, moderators and confounders, and potential for immediate impact. The primary aims of the proposed research project are to: 1) Estimate potentiating interactions between traumatic brain injury (TBI), a very common condition in US Veterans, and inflammation-mediated medical conditions (IMCs: allergies, infection, and autoimmune conditions), in predicting suicide in US Veterans. Our preliminary data support hypothesizing synergistic interactions. 2) Estimate the suicide protective effect of sustained vs. unsustained statin treatment 3) Identify demographic and clinical Veteran characteristics and pharmacological statin features (dose, lipophilia, potency, duration) conducive to stronger attenuating effects of statins on suicidal behavior. We will test these hypotheses on a Veterans Health Administration (VHA) retrospective cohort (individuals with clinical encounters in VA Medical Centers nationwide beginning in 2004 and followed for 13 years) including 5,446,318 Veterans with 28,749 suicides. The Cox proportional hazard model will be applied to evaluate the interactions between TBI immune mediated conditions , with Relative Excess Risk due to Interaction (RERI), the Attributable Proportion (AP) due to interaction, and the Synergy Index (SI) to test synergism on an additive scale (Aim 1). A Cox proportional hazard model will also be applied to testing risk attenuation with statins, with propensity scoring for time-independent confounding and marginal structural Cox proportional hazards (Aim 2). Finally, we will identify the demographic, clinical (diagnostic codes, medications, laboratory markers of inflammation (e.g., white blood count) and pharmacological characteristic of Veterans expected to benefit the most from sustained statin treatment using an aggregate machine learning approach (the SuperLearner integrative methodology). Considering the high prevalence of TBI history and its ongoing sequelae,( “a silent epidemic”) , especially in the VA, and confirming their synergistic interaction with IMCs may contribute to developing suicide risk-attenuating interventions specifically for those subpopulations. The PI’s preliminary data nested in Danish registers, our team’s piloting confirming preliminarily a reduction in rates of psychiatric hospitalization (considered a proxy measure of suicide risk) with statins in US Veterans diagnosed with schizophrenia or bipolar disorder and treated with psychotropic medication (Appendix 4C), and our successful evaluation of potential heterogenous effects of an alternative modifiable suicide risk using the specific machine learning algorithms proposed in this project (Appendix 4B) support our hypotheses, integration, and purpose, and overall, project completion capability. Using tailored repurposed medications, such as statins, targeting specifically molecular, cellular and histological mechanisms directly implicated in suicidal behavior, to individuals at risk who are identified by machine learning to potentially derive the greatest benefit from treatment , may provide a much-needed breakthrough in suicide risk management and prevention.

Death by suicide has been steadily increasing in the last 20 years, and this risk is elevated among veterans, particularly those with traumatic brain injury and psychiatric diagnoses. However, in the last 50 years, improvements in identifying those at greatest risk for suicide, typically via self-report, have been limited. Therefore, we propose that complementary and objective neurobiological markers of suicidal thoughts and behaviors (STBs) can improve the identification of those at greatest risk. Preliminary brain markers related to STBs have been identified in the cognitive control network (CCN), limbic network (LN), and the default mode network (DMN). However, reliable and predictive brain markers of STBs remain elusive as there are several methodological limitations in the previous literature. This study will address these limitations and investigate neural markers of STBs using two different neuroimaging methods: resting-state fMRI and brain activity during the suicide Implicit Association Task (s-IAT). Resting-state provides a stable and reliable measure of intrinsic brain connectivity, whereas the behavior on the s-IAT (known as the d-score) measures the strength of a participant’s implicit association between self and death. The d-score on the s-IAT is a better predictor of future STBs than self-report, but little is known about neural activity related to the s-IAT. DESIGN AND METHODS. This application utilizes a close collaboration with the Translational Research Center for TBI and Stress Disorders (TRACTS), which has a comprehensive psychiatric and neuroimaging database of over 800 post-9/11. This dataset provides the unique opportunity to compare STB groups with control groups matched on psychiatric diagnoses, like depression and PTSD, that are differentiable only by the absence of STBs (psychiatric controls; PCs). Using this existing dataset, resting-state fMRI will be used to identify brain markers related to both a history of suicide attempt (SA) and current suicidal ideation (SI). Next, we will determine if these brain markers predict future STBs using state-of-the-art machine learning techniques. Lastly, an additional 100 veterans will complete the s-IAT with concurrent fMRI as part of their participation in TRACTS. This will allow us to investigate the feasibility of detecting neural makers related to implicit associations between self and death (d-score). Aim 1: Identify neural signatures of previous suicide attempt and current suicidal ideation (n = 800, ~5% with history of suicide attempt, ~10% with suicidal ideation). Hypothesis 1. We will identify neural markers in the LN, CCN, and DMN, that differentiate those with STBs from PCs. Aim 2: Determine if the STB neural markers identified in Aim 1 predict future STBs 1-2 years later at a follow- up assessment (n=400; ~5% attempt suicide within the next 1-2 years and ~10% reporting current SI at follow- up). Hypothesis 2: Models using the SA and SI neural markers identified in Aim 1 will predict which individuals report STBs at a follow-up assessment with acceptable diagnostic accuracy (sensitivity and specificity). Aim 3: Acquire preliminary fMRI data on the suicide Implicit Association Task (s-IAT) to determine the feasibility of measuring brain activation related to self-death associations (d-score). Hypothesis 3: We will discover preliminary neural markers of this STB-related cognitive process, which will partially overlap with resting-state markers of STBs, and also include brain regions associated with self-referential processing. Training Aims. This CDA will provide training in 1.) The assessment, prevention, and neurobiology of suicide, 2.) Advanced statistical and machine learning techniques, 3.) Task-based fMRI, and 4.) Preparation to submit a competitive CDA-II. IMPACT. This project will provide a foundation for a future CDA-II proposal investigating these neural markers of STBs in high-risk populations and as targets for brain stimulation with the long-term goal of using these neural markers to develop new treatments and improve suicide prevention.

Dr. Amy Byers' research is predominately focused on suicide prevention in older Veterans. This work is highly relevant to and has very high impact on Veterans and VA healthcare. Veterans 50 years and older have the highest number of lives lost to suicide and make up the majority (> 70%) of the Veteran population. Older adults and, in particular, older Veterans accumulate a significant amount of life experiences, including suffering multiple comorbidities, losses, and traumas, that impact their mental and physical well-being. Even further adding to the complexity, mental health care often occurs in non-mental health settings under the influence of personal and society notions and stigmas about mental illness and about aging. Dr. Byers' Lab is uniquely positioned to conduct research at this level of complexity. Dr. Byers has developed a deep, clinically relevant understanding of the nature of mental health in late life, its course, treatment and impact. Her research covers multiple sub-areas of late-life mental health, i.e., late-life suicide, late-life posttraumatic stress disorder, mental health services use with age, geriatric depression, and gerontological biostatistics. In particular, understanding suicide-related outcomes in older adults/Veterans requires substantially different conceptual and methodologic considerations, which Dr. Byers and her team are uniquely qualified to undertake. There are 4 over-arching research areas and Aims that Dr. Byers will actively pursue during the proposed Research Career Scientist Award period: 1) To characterize and identify patterns of health services use and diagnostic profiles at a national level among older adults/Veterans who have experienced late-life suicide or mental health disorders; 2) To identify predictors of late-life suicide; 3) To advance late-life suicide and mental health research in prominent health disparity and vulnerable groups; and 4) To advance suicide and neuropsychiatric research in Veterans incarcerated and returning to community in later life. In summary, the first 3 Aims are supported by an on-going VA CSR&D Merit Award (I01 CX001119; PI: Byers). Aim 2 and 3 are further supported by a Genius Award (PI: Byes) from the UCSF Older Americans Independence Center (NIA-funded Pepper Center). Aim 4 is supported by a NIMH Multi-PI R01 grant in collaboration with Dr. Lisa Barry from University of Connecticut (MH117604; Multi-PI: Byers/Barry). Additionally, Dr. Byers and Dr. Barry were recently awarded a NIMH/NIA Supplement to the parent grant to determine the burden of Alzheimer's disease and related diseases in older adults/Veterans with a recent history of incarceration. There are many seminal contributions by Dr. Byers' Lab in terms of highly cited papers in high impact journals in support of these on-going activities. To name a few, she was the first to determine the high occurrence of late-life mood and anxiety disorders at a national level, first to determine and characterize nationally that the majority (~70%) of older adults with mood or anxiety disorders did not use mental health services, first to identify comorbidity profiles in Veterans 65 years and older who were last seen in primary care prior to a suicide attempt, first to determine in a national cohort that risk of suicide attempt was increased in Veterans recently diagnosed with mild cognitive impairment or dementia (in press at JAMA Psychiatry), first to provide evidence that hormone therapy is an indicator of suicide risk among midlife to older women Veterans (even independent of psychoactive drugs), and seminal work showing a nearly 5-fold greater risk of a subsequent suicide attempt in older Veterans transitioning from prison to community. Dr. Byers is investigating other unique patterns of potential markers and predictors of late-life suicide risk (supported by I01 CX001119), including “high-risk” medication use (i.e., benzodiazepines, sedative-hypnotics, opioids, antidepressants, antiepileptics, and antipsychotics) and polypharmacy patterns, and conducting seminal research to determine specific medications causally linked to risk of suicide in older Veterans. Moreover, she is actively pursuing more research on vulnerable groups (female, minority, homeless, and PTSD), including Veterans transitioning from incarceration to community in later life.

This project uses MRI to examine regions of interest in female veterans with and without suicidal behavior.

Abstract not available at this time. If you have more information, please contact us at SuicidePreventionRes@va.gov.

Abstract not available at this time. If you have more information, please contact us at SuicidePreventionRes@va.gov.

Abstract not available at this time. If you have more information, please contact us at SuicidePreventionRes@va.gov.