NIH/NIMH – Dysregulation and Proximal Risk for Suicide FOA (R01, R21 Clinical Trial Optional)

October 9, 2018 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

In 2015, the Centers for Disease Control and Prevention reported that there were nearly 45,000 suicide deaths in the United States, which is two and half times the number of homicide deaths in the same year. The annual suicide rate in the U.S. has continued to climb over the past sixteen years and suicide is the 10th leading cause of death, and the second leading cause of death in individuals age 10-34. Compounding the impact of this preventable loss of life, the rate of nonfatal suicide attempts is many times higher than the rate of suicide death and the economic impact of suicidal behaviors has been estimated to exceed more than $40 billion annually in the U.S. Our ability to understand the mechanisms that confer proximal risk for suicidal behavior remains a challenge. Prior research in this field has focused on single sociodemographic and psychiatric risk factors, primarily examined risk factors that are distal from suicidal behavior and not specific to suicide, and have not considered time-variant factors. New approaches are needed to rapidly identify who is at most risk, why people transition from suicidal thoughts to action, and identify targets for novel interventions for rapid reduction of high risk states.

In June 2016, in a continuing effort to engage experts focused on discovering and understanding the variety of behaviors and markers of suicidal behavior, the NIMH sponsored a workshop entitled Mechanisms Underlying Suicide Risk: Integrating Research Domain Criteria (RDoC) to Inform Novel and Personalized Interventions. With input from NIDA, NICHD, and NIAAA, a multidisciplinary group of researchers convened to consider how approaches consistent with the RDoC framework could provide new insight on underlying mechanisms of suicide risk. The RDoC Framework is particularly relevant because suicidal thoughts and behaviors are transdiagnostic, and measurement of suicidal processes needs to expand beyond self-report and focus on clinical symptoms. Two important suggestions emerged from the workshop:  1) It is important to look beyond single psychological and demographic factors or even single RDoC function domains and focus instead of the interaction of multiple domains. 2) The ability to accurately predict suicide behaviors must incorporate analysis of time-varying risk factors and focus on imminent/proximal risk (vs. distal risks).

A recent meta-analysis of 365 studies that examined longitudinal prediction of specific suicide thoughts and behaviors outcomes from sociodemographic and clinical diagnostic risk factors found that no single broad category or subcategory accurately predicted far above chance levels. Accurate prediction of suicide behaviors will likely require a complex combination of a large number of factors, across multiple levels of analysis, sensitive to dynamic changes across developmental stage and short-term (e.g. hours, days) temporal variation. The meta-analysis found that Arousal and Sleep/Wakefulness Patterns increased risk for suicide attempt at comparable degrees to Depressed Mood and Rumination. While the NIMH portfolio has supported studies that examine the RDoC domain of Negative Valence and suicide risk, fewer projects have examined the Arousal and Regulation domain and suicide risk.

The primary goal of this Funding Opportunity Announcement (FOA) is to solicit applications that propose to inform our understanding of proximal risk for suicide. Risk is a dynamic process and suicide attempts are often preceded by acute stressors. While many studies of suicide risk focus on emotion dysregulation, fewer studies have examined arousal and regulation and how these domains dynamically shape emotional and cognitive functions such as response to reward, frustrative non-reward, cognitive flexibility and control, or decision-making. Few studies in the NIMH portfolio on suicide risk have focused on proximal risk. This FOA seeks research applications that will address these gaps, provide understanding of the mechanisms of how dysregulation interacts with cognition, negative and positive valence to determine time-varying risk, and identify modifiable targets for timely interventions during high risk periods. For this FOA, the working definition of proximal risk is “dynamic factors that occur on the order of hours, days, and weeks.” Because the primary focus of the FOA is to reveal key mechanisms that determine imminent/proximal risk, approaches that harness technologies such as smart phones, wearable devices, and actigraphy, to assess behavior, physiological state, and thoughts with fine temporal resolution (e.g. hours, days) in naturalistic setting are encouraged, as are computational approaches that quantify and predict risk state.

This effort is consistent with NIMH Strategic Research Objective 2 which seeks to chart mental illness trajectories to determine when, where, and how to intervene as well as Objective 3 which strives to develop new treatments or tailor existing treatments for personalized interventions. It is consistent with NIDA strategic priorities, including an emphasis on addressing real world complexities of substance use and substance use disorders, such as psychiatric comorbidities (including within the context of overdose deaths), and increasing the public health impact of NIDA supported research (Goal 4). This FOA also speaks to multiple objectives in the Prioritized Research Agenda for Suicide Prevention: short-term objective 1.B aimed at identifying biomarkers and interactions associated with current and future risk; short-term objective 1.C aimed at identifying cognitive dysfunction/neural circuitry profiles associated with risk that may be amenable to current intervention;  long-term objective 1.C which specifically sites insomnia as an area of investigation; and objective 2.B which aims to develop improved decision-making tools.

Applications submitted in response to this FOA must explicitly explore how interactions between at least one construct in the domain of arousal and regulation and one or more constructs in other RDoC domains are linked to imminent risk for suicide ideation, behaviors, and attempts (including interrupted or aborted attempts). Studies that are focused solely on static suicidal traits, past behavior, or distal risk will not be considered responsive to this FOA. To be considered responsive, applications must integrate at least two levels of analysis (e.g. behavior/cognition, neural circuits, genetics, molecular and cellular processes), consistent with the RDoC Framework.. Investigators are encouraged to include transdiagnostic samples, when appropriate.

Examples of projects that might be appropriate for this FOA seeking constructs associated with imminent risk for suicidal ideation, behaviors, and attempts include investigations that examine:

  • efforts to harness technologies such as smart phones, wearable devices, and actigraphy, to assess behavior, physiological state, and thoughts with fine temporal resolution (e.g. hours, days) in naturalistic settings
  • sleep-related modulation of cognitive and/or emotional domains
  • disordered eating or substance use and dynamic effects on other RDoC functional domains
  • contextually inappropriate reactivity to external and internal stimuli and how it modulates affective processing, cognition, and decision-making
  • dysregulation following childbirth and its relation to mood, motivation, and cognition
  • changes in arousal and regulation in response to behavioral, pharmacological, or neuromodulatory interventions and consequent effects on domains such as decision-making, risk-taking, and perspective-taking
  • heightened sensitivity in response to social interactions including “contagion” by negative reports in social networks
  • proximal risk factors that arise during specific sensitive periods in development or reflect differences between males and females.

Studies appropriate for this FOA may include studies which are not clinical trials, as well as those which would be considered mechanistic clinical trials that include pharmacological, physiological or behavioral manipulations of known efficacy in order to understand the pathophysiology of mental disorders. See: https://grants.nih.gov/grants/guide/notice-files/NOT-MH-18-004.html.  . Studies that are early stage trials of novel treatements or tests of clinical efficacy/effectiveness will not be considered responsive for this FOA.

In developing projects, applicants should consider whatdata in their application can be publicly shared. When possible, investigators funded by NIMH under this FOA are expected to share data via the NIMH Data Archive (https://data-archive.nimh.nih.gov/ndct/about ). The NIMH Data Archive is willing to work with applicants to determine what data can be shared (e.g., electronic medical record data; National Death Index acquired data). The NIMH Data Archive can also provide a private cloud-based storage site that will facilitate the proposed work. Applicants who are interested in exploring this possibility should contact the NIMH Data Archive help desk (ndahelp@mail.nih.gov) . To facilitate aggregation of data across studies in publicly shared databases, NIMH strongly encourages investigators to include common data elements such as the PhenX Suicide Specialty Collectionhttps://www.phenx.org/node/4

Protection of Human Subjects: Applications with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, administrators) should address provisions for human subject protections and consenting procedures for all participant groups, accordingly. NIMH has recently updated issues to consider in conducting research with individuals at risk for suicide:  https://www.nimh.nih.gov/funding/clinical-research/conducting-research-with-participants-at-elevated-risk-for-suicide-considerations-for-researchers.shtml. The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application’s Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. Additionally, the NIH has recently issued new guidelines for clinical research:  https://grants.nih.gov/policy/clinical-trials.htm.

Deadlines:  November 5, 2018 (letters of intent); December 5, 2018 (full proposals)

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Filed Under: Funding Opportunities