Dynorphin/Kappa Opioid Receptor Signaling Role in Ketamine’s Anti-Suicidal Ideation Effect

The overall goal of this novel proposal is to investigate the role of the kappa opioid receptor (KOR) in the brain and stress reactivity in ketamine’s rapid and robust attenuation of suicidal thoughts. Stressful life events are a potent predictor of suicidal ideation. However, the mechanisms linking stress to suicidal ideation and the transition to suicidal behavior are not fully understood. Current measures of suicidal ideation do not assess sensitivity to stress, which is critical to understanding how stress triggers suicidal ideation and how to intervene before transition to suicidal behavior. The use of smartphone-based Ecological Momentary Assessment (EMA) allows for real-time tracking of suicidal ideation in relation to naturalistic stressors occurring throughout the day, over the course of one week, providing insights into how stress influences suicidal ideation on a moment-to-moment basis. Ketamine has been shown to improve suicidal ideation in depressed patients, and animal studies suggest it dampens the response to stressors. Specifically, in rodents, prophylactic ketamine protects against stress-induced depression-like behavior and activation of KOR by its endogenous agonist, dynorphin, has been shown to mediate the link between stress and depression. Therefore, dynorphin/KOR signaling may be a biological mechanism for ketamine’s rapid suicidal ideation attenuation effects that acts by boosting stress resiliency. This innovative study will probe the dynorphin/KOR system with in vivo positron emission tomography (PET) brain imaging using the novel tracer [11C]EKAP in participants with major depressive disorder. We will administer a single intravenous dose of ketamine and perform a second, post-treatment [11C]EKAP scan in half of the depressed participants (n=6) from Dr. Bartlett’s NIMH-funded K01 (n=12), where they will have already received baseline [11C]EKAP scans. Unique to this study, in both pre- and post-ketamine PET scans, a laboratory stressor will be administered, allowing us to measure the location and magnitude of stress-induced endogenous dynorphin release in the brain. Smartphone-administered ecological momentary assessment (EMA) will allow us to track suicidal ideation in response to naturally occurring life stressors both pre- and post-ketamine. We hypothesize that ketamine treatment will induce stress resiliency, as measured by decreased post-treatment dynorphin release and decreased suicidal ideation severity due to life stressors. This study’s novelty and innovation lies in: (1) utilizing a new PET tracer with high specificity and selectivity to target dynorphin/KOR signaling, (2) administering an experimental stressor during the PET scans to quantify real-time endogenous dynorphin release, and (3) quantifying suicidal ideation response to naturalistic stressors with EMA. This proposal will generate pilot data for future large grants to uncover the biological mechanism of ketamine’s rapid attenuation of suicidal thinking, with a specific focus on the dynorphin/KOR system and prophylactic ketamine treatment to block the stress-induced genesis of suicidal behavior. Investigating dynorphin/KOR stress sensitivity, coupled with EMA-measured patterns in suicidal ideation fluctuations will advance the American Foundation for Suicide Prevention’s mission by offering potential biomarkers and strategies for detecting risk/resiliency for suicidal behavior and options for timely intervention with rapid, effective treatments to prevent suicidal behavior.