DESCRIPTION (provided by applicant): Obsessive-Compulsive Disorder (OCD) is characterized by a lack of cognitive (effortful) control over repetitive thoughts (obsessions) and behaviors (compulsions) and is associated with dysfunction in fronto- striatal circuits. Treatment of OCD with serotonin reuptake inhibitors (SRIs) results in a long lag time (2-3 months) before clinical benefit that is typically only partially effective. Identification of effective, fast-actig treatments will help prevent OCD morbidity. We found that a single IV infusion of an N-methyl-D-Aspartate (NMDA) receptor antagonist, ketamine, can rapidly reduce OCD severity in the absence of an SRI. Animal studies find fronto-striatal activity modulation is a critical driver of OCD-like repetitive behaviors, with knockout of a gene encoding a postsynaptic scaffolding protein at glutamate synapses leading to altered fronto-striatal activity, OCD-like behavior, and elevated expression of NMDAR subunits. Taken together, these studies support the NMDA receptor as a promising new target for OCD-relevant behaviors. This R01 will test the acute mechanism of ketamine's therapeutic action in adults with OCD at the level of molecules, circuits, and network synchrony. We use a novel approach to simultaneously study both spatial and temporal functional brain changes caused by NMDA receptor antagonism. Current theories posit that the fronto-striatal hyperactivity observed in OCD at baseline is due to dysfunction in inhibitory and excitatory neural networks. Consistent with these theories, we find deficits in the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the medial prefrontal cortex (MPFC) in OCD compared to healthy controls. We also discovered that OCD subjects given a single dose of IV ketamine show a significant increase of MPFC GABA 1 hour post-infusion. In healthy controls, increases in prefrontal GABA are correlated with the induction of gamma oscillations, a potential biomarker for local inhibitory circuits within this region. Based on our findings, we propose a testable working model for how the ketamine may decrease OCD severity that links GABA, functional connectivity in frontal- striatal circuits, and network synchrony. The overall goal of this R01 is to determine how NMDA receptor antagonism modifies disease-specific pathology to relieve repetitive thoughts and behaviors. The proposed projects use a multimodal imaging approach across multiple units of analysis (molecules, circuits, and network synchrony) in order to open a new avenue for rapid acting therapeutics (with NMDAR antagonism as a first new target) to transform psychiatric treatments.

PUBLIC HEALTH RELEVANCE: Obsessive-Compulsive Disorder (OCD) is a chronic and disabling disorder that costs the economy over $2 billion annually and represents a significant public health problem. This R01 builds on our discovery that a potent NMDA receptor antagonist, ketamine, has rapid (in hours) and robust therapeutic effects in OCD. The proposed projects test the acute mechanism of action of ketamine at the level of molecules, circuits, and network synchrony to determine how NMDA receptor antagonism modifies the underlying pathology of OCD to relieve repetitive thoughts and behaviors.