In vivo Investigation of KOR availability in hoarding disorder and clinically meaningful endophenotypic correlates

The purpose of this mentored career development award is to provide the candidate with rigorous and comprehensive training in preparation for an independent academic research career in molecular neuroimaging. Specifically, the completion of individualized training activities and proposed research over the course of the five-year award term will allow the candidate to develop the requisite expertise for a research career utilizing positron emission tomography (PET) in individuals with severe compulsive and impulsive behaviors, such as hoarding disorder (HD). The three career goals outlined in this training program include intensive, focused training in 1) Neurobiology and pathology of compulsive behaviors (emphasizing HD and relationships to functional outcomes and risk); 2) Intensive training in PET methodology and data acquisition; and 3) Advanced training in biostatistics for integration of PET and behavioral data. Integral to these goals is essential training in responsible conduct of research. The training plan will be executed with oversight from experts in neurobiology, molecular imaging, and psychiatry and performed in a rich academic environment (Yale School of Medicine), offering optimal resources and facilities for the proposed training and research. The proposed research consists of an innovative PET study in individuals diagnosed with DSM-5 HD. HD is a devastating and understudied psychiatric condition characterized by severe and compulsive difficulties with discarding and excessive acquisition, resulting in debilitating levels of clutter. HD is associated with profound personal and public health issues, including medical and psychiatric comorbidity, vast functional impairment, and increased risk for suicide. Alarmingly, studies report that fewer than one-third of patients achieve clinically significant change in treatment due in part to factors such as attrition and low treatment motivation. Currently, no FDA-approved pharmacological therapies for HD are available. Research into novel treatments is necessary to provide symptom relief, reduce risk, and improve quality of life. Moreover, pharmacological interventions addressing acute distress and increasing treatment retention may be needed to impart long-term behavior change. Evidence implicates kappa opioid receptors (KOR) in motivation, emotion regulation, compulsive behaviors, and in pre-clinical models of hoarding. Our promising pilot data show significantly lower KOR availability in subjects with hoarding behaviors (n=5) relative to healthy controls (HC). Here, we aim to extend these exciting findings by examining 1) KOR availability in-vivo using [11C]EKAP PET in individuals with HD relative to demographically matched HC; 2) relationships between KOR availability and clinically meaningful endophenotypes of HD; and 3) associations between KOR and functional outcomes in individuals with HD. Results have potential to significantly impact HD treatment development. Completion of the proposed training plan and research study will optimally position the candidate for a successful career conducting impactful research in psychiatric populations with severe compulsive behaviors. Project Number: 1K08MH141526-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Emily Weiss | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $191,449 | Activity Code: K08 | Study Section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11213327