NIH – Drug Discovery For Nervous System Disorders (R01, R21 Clinical Trial Not Allowed)

January 17, 2019 by

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

Significant advances in neuroscience, genetics, and basic behavioral science, together with technological developments, have provided a rich knowledge base for identifying new molecular targets for drug discovery, and developing rational pharmacotherapies for the treatment of a wide variety of nervous system disorders. With the wealth of potential new drug targets, the opportunity exists to accelerate the process of drug discovery and development to make quantum leaps toward novel and effective treatments for mental disorders and nervous system disorders associated with aging.

Through this Funding Opportunity Announcement (FOA) the National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA) and the National Institute on Aging (NIA) encourage the submission of research grant applications that aim to translate this wealth of basic science findings into the conceptualization, discovery, and preclinical evaluation of innovative therapeutics for mental illnesses and nervous system disorders associated with aging, with the goal of accelerating the development of new treatments for these diseases.

The objective of this FOA is to stimulate research in the discovery, design, and preclinical testing of innovative and effective therapeutics aimed at prevention or treatment of nervous system disorders of primary interest to the NIMH, NIDA and NIA. Projects focused on novel approaches and targets are highly encouraged. Projects designed for target identification or elucidation of disease mechanisms are not covered under this announcement.

Specific Areas of Research Interest

Applications aimed at the discovery of novel agents for ameliorating, modifying, or correcting potential aberrations in brain signaling are encouraged. These agents should be designed to affect fundamental processes associated with disease, such as neuronal dysfunction, abnormalities in cell growth, migration, plasticity, connectivity, and cell death, by targeting molecules and cellular mechanisms such as neurotransmitters, bioactive lipids, neuromodulators, and neurotrophins; receptors and ion channels; second and third messenger systems; protein synthesis, aggregation, and degradation; brain energy utilization; gene expression; neural-glial communication; and oxidative, immunological, and inflammatory mechanisms.

Research projects may include any activities required to identify, optimize, and validate potential therapeutic candidates and may propose studies focused on all stages of the early drug discovery pipeline, from screening to candidate selection.

Examples of these activities may include, but are not limited to:

  • Preliminary identification of candidate therapeutics, using in vitro, ex vivo, or in vivo assays. This may include:
  • High, medium, or low-throughput assays, as well as counter-screening to assess the activity and selectivity of hit and lead compounds.
  • Ligand-based virtual screening and computational hit expansion following high-throughput screening (HTS) campaigns.
  • The isolation, identification, characterization and synthesis of promising naturally occurring products.
  • Design, synthesis, and preclinical testing of compounds directed toward altering, modifying, or regulating aspects of disease processes, as well as disease initiation or progression. This may include:
  • Initial medicinal chemistry to improve activity and selectivity of validated hit compounds against the target of interest.
  • Initial in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) and in vitro toxicity studies of candidate therapeutics. IND-directed toxicology and safety pharmacology studies are outside the scope of this announcement.
  • Later stage lead optimization to improve efficacy and pharmacokinetics.
  • Development of ligands to serve as research tools in support of proof-of-principle preclinical studies and the validation of novel therapeutic targets.
  • Initial DMPK and toxicity studies of candidate therapeutics. This may include in vitro and/or in vivo testing.
  • Development of novel delivery systems to target therapeutics to the brain.

Use of innovative assays for the evaluation of the potential efficacy or toxicity of candidate therapeutics, such as cell-based or in vivo model systems that recapitulate critical molecular, cellular, or circuit/systems level features of a specific nervous system disorder, are encouraged.  Preclinical assays should be directed toward assessing CNS effects rather than elucidating disease mechanisms. The choice of assays should be well-justified and appropriate for the stage of therapeutic development. While non-selective behavioral assays of CNS effects may be appropriate for initial in vivo preclinical screening to establish pharmacodynamics, later stage in vivo assays used for candidate prioritization should incorporate measures of circuits and brain processes linked to disorders.

The above-mentioned areas of investigation are representative and not meant to be exhaustive.

Investigators are highly encouraged to explore novel approaches for identifying potential therapeutic agents. While such projects involve higher risk, they also offer the potential for high impact.  It is anticipated that investigators will balance risk, innovation, and impact and that applications that involve higher risk may focus on a shorter term, proof of concept effort.

This FOA uses the R01 grant mechanism while PAR-19-063 uses the R21 mechanism. High risk/high payoff projects that lack preliminary data may be most appropriate for the R21 mechanism, while applicants with preliminary data may wish to apply using the R01 mechanism.

Points to consider relevant to this announcement:

  • Applications should be relevant to mental illnesses and/or nervous system disorders relevant to aging.
  • The main emphasis of projects submitted under this FOA should be on therapeutic discovery rather than target identification or elucidation of disease mechanisms.
  • Applications seeking extensive studies required for the clinical development of candidate therapeutics, such as IND-enabling studies (e.g. lead compound directed absorption, distribution, metabolism, and excretion [ADME] toxicity) and GMP (Good Manufacturing Practices) synthesis are outside the scope of this initiative and should consider other programs and resources available to investigators for these efforts, including the NIH Blueprint Neurotherapeutics Network program ( In addition, the NIH Bridging Interventional Development Gaps (BrIDGs) Program ( might be considered.

Institute Interests

Projects proposing to develop compounds for targets that have significant prior or current investment may be of lower programmatic interest to participating ICs, unless applicants provide a compelling case that there are significant advantages to their approach.

Applicants are strongly advised to contact the Scientific/Research contacts listed in this announcement for NIMH and NIA prior to submission of an application.


NIMH supports neuroscience research to discover the causes of mental illness and to develop more effective and safer treatments.  Specifically, the NIMH is interested in the discovery of novel molecules to explore innovative targets for treatment development to address key deficits within and across  mental illnesses, especially schizophrenia (cognitive and affective components), autism spectrum disorder (ASD), treatment-resistant depression, bipolar disorder, post-traumatic stress disorder (PTSD), and HIV-induced CNS dysfunction (see From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses). Therapeutic approaches aimed at addressing brain defects downstream of genomic mutations must be based on adequately powered clinical studies as detailed by the NIMH Report of the National Advisory Mental Health Council Workgroup on Genomics.

NIMH is particularly interested in applications that address specific go/no-go criteria based on reliable and quantitative assay measures that assess whether the compound has: 1) sufficient activity at the appropriate molecular target or brain region, and 2) effects on specific neurophysiological systems or functional domains that are potentially impacted in mental disorders (see Research Domains Criteria (RDoC)).

Projects aimed at the discovery of in vitro or in vivo chemical probes should consider applying to PAR-17-335 or PAR-17-336. Projects spanning broader goals including development and testing of novel assays or biomarkers of drug effects, initial GLP (Good Laboratory Practice) and GMP, to first in human studies should consider the National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-18-231 (U19) and PAR-18-230 (U01). Projects at the development stage proposed by small businesses should consider applying to the NIMH SBIR/STTR Programs

Scientific rigor and transparency in conducting biomedical research is key to the successful application of knowledge toward improving health outcomes.  In support of this important goal, investigators must follow NIH Guidance on addressing rigor and reproducibility in grant applications (

Further information on NIMH research priorities can be found on the NIH/NIMH Therapeutics Discovery Research website and in the NIMH Strategic PlanStrategic Research Priorities, and Interventions Workgroup Report. Applicants are strongly encouraged to discuss applications with NIMH staff listed in Section VII – Agency Contact(s) Scientific/Research Contacts.


NIA is interested in the discovery of novel therapeutics including small molecules and biologics aimed at modifying the behavioral symptoms in Alzheimer’s disease (AD), delaying the onset or slowing the progression of AD, mild cognitive impairment (MCI), other dementias of aging and age-related cognitive decline. NIA is not interested in projects aimed at repurposing therapeutics or developing combination therapies.

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.

Deadlines:  standard dates and standard AIDS dates apply


Filed Under: Funding Opportunities