Identification of Positive Valence System Related Targets for Novel Suicide Prevention Approaches (R21 Clinical Trial Optional) | Apply Online

Opportunity Summary:

The National Institutes of Health (NIH) funding opportunity titled "Identification of Positive Valence System Related Targets for Novel Suicide Prevention Approaches" (Funding Opportunity Number: PAS-21-215) is an R21 grant program focused on early-stage, exploratory research that can point to new suicide prevention strategies. The central idea is that suicidal thoughts and behaviors are not only tied to negative mood states, stress, and threat responses, but may also be driven by disruptions in positive affect (PA) and reward-related functioning. This opportunity aims to support projects that clarify how positive emotions, pleasure, motivation, and reward processing operate in people at elevated suicide risk, and then identify behavioral and brain-based targets that could be changed to reduce risk.

A key requirement is that proposed studies include clinical populations with high suicide risk. This can include people who have attempted suicide and individuals who are acutely suicidal, which signals that the FOA is intended to capture mechanisms that are directly relevant to real-world, high-acuity clinical settings. At the same time, applicants are allowed to include comparison groups when useful, such as non-suicidal psychiatric patients, people at elevated risk who do not have a formal diagnosis, or healthy controls. Projects are encouraged across the full developmental spectrum, meaning studies can focus on adolescents, adults, older adults, or span multiple age groups if that best addresses the scientific question.

The scientific emphasis is on the Positive Valence Systems (PVS) domain within the Research Domain Criteria (RDoC) framework, which covers the processes involved in responding to reward and other positive outcomes. Applicants are expected to define a specific construct of interest in one of two ways: either explicitly as an RDoC PVS construct (for example, reward responsiveness, reward learning, reward valuation, or reward anticipation), or as a clinically meaningful symptom-relevant construct that maps onto positive affect and reward function. Examples mentioned in the opportunity include anhedonia (including particular subtypes), decision-making about immediate versus future rewards, and the capacity to generate "reasons for living" when imagining or anticipating positive experiences. In practice, this pushes applicants to be precise about what aspect of positive functioning they believe is impaired or protective in suicidal individuals, rather than treating "positive affect" as a broad, undefined concept.

Beyond defining the construct, the FOA highlights three major aims that strong applications should address. First, a project should clearly specify the construct and justify why it matters for suicide risk. Second, it should demonstrate that measures of that construct are reliable and reproducible and that they engage relevant brain subsystems tied to positive affect and reward processing. This means the grant is not just about collecting self-report mood data; it is also about building confidence that the measurements are stable, interpretable, and biologically grounded, often through neuroimaging, electrophysiology, or other neuroscience-informed approaches. Third, applicants are encouraged to test whether the targeted system can actually be modified. The FOA explicitly invites studies that attempt to change the relevant brain system and the associated behavioral measures through interventions such as behavioral training paradigms, non-invasive neuromodulation approaches, pharmacological probes, or psychosocial therapeutic probes. The intent is to move beyond description toward identifying actionable targets that could become the basis for novel prevention or treatment approaches.

In terms of methods, the NIH encourages the use of both established and innovative behavioral tasks that assess PVS components, including reward sensitivity, reward valuation, and reward learning, as well as tasks that probe hedonic capacity and closely related subconstructs. The opportunity also places special value on measuring dynamic changes in positive affect, not just static averages. This emphasis suggests interest in capturing how positive emotions fluctuate over time, how quickly they recover after stress, how they respond to rewarding experiences, and how these shifts may co-occur with other suicide risk factors and with changes in suicidal thinking or behavior. Designs that can track within-person variability (for example, repeated assessments, ecological momentary assessment, or time-sensitive laboratory paradigms) would fit well with this priority.

Administratively, this is a discretionary NIH grant mechanism under the health funding category (CFDA 93.242). The funding instrument is a grant, and the activity mechanism is R21, which typically supports exploratory, high-impact studies that generate preliminary evidence rather than large definitive clinical trials. The FOA is labeled "Clinical Trial Optional," meaning applicants may propose studies that meet the NIH definition of a clinical trial, but they are not required to do so. The original closing date listed is October 16, 2021, and the FOA was created on April 16, 2021; applicants would need to verify current availability or any reissued versions if planning to apply now.

Eligibility is broad and includes many types of organizations: state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; tribal organizations that are not federally recognized; public housing authorities and Indian housing authorities; nonprofit organizations (both 501(c)(3) and non-501(c)(3)); for-profit organizations (other than small businesses) and small businesses; and other eligible entities. The FOA also explicitly highlights additional eligible applicant categories, including Alaska Native and Native Hawaiian Serving Institutions, AANAPISISs, Hispanic-serving institutions, Historically Black Colleges and Universities, Tribally Controlled Colleges and Universities, faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, and even non-U.S. (foreign) entities and regional organizations. This wide eligibility signals an interest in supporting diverse research settings and partnerships, including those embedded in communities disproportionately affected by suicide risk and barriers to mental health care.

Overall, this opportunity is aimed at accelerating suicide prevention science by focusing on a somewhat underdeveloped area in traditional suicide research: the mechanisms of positive emotion, reward, and motivation. The NIH is looking for projects that can pinpoint measurable PVS-related targets in high-risk individuals, demonstrate those targets are meaningfully captured with reliable tools tied to relevant neural systems, and show early evidence that the targets can be modified in ways that could eventually translate into practical interventions for suicide prevention.

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