Examining Mu Opioid Mechanisms of Ketamine's Rapid Effects in OCD

PROJECT SUMMARY Obsessive-compulsive disorder (OCD) typically starts in childhood, leads to lifelong morbidity, and costs the economy $2.1 billion (direct costs) and $6.2 billion (indirect costs such as lost productivity) annually. OCD often responds inadequately to serotonin reuptake inhibitors (SRIs). Moreover, the typical SRI response is only partial and is delayed by 2-3 months. Given the dysfunction OCD imposes on millions of U.S. adults, exploring whether SRI non-responders are helped by adding drugs with different mechanisms of action is urgently needed. Emerging data support ketamine’s rapid and sustained anti-obsessional effects in OCD. We seek to understand the mechanisms underlying ketamine’s rapid OCD effect and thereby to speed development of more effective agents for OCD. For several reasons, this proposal focuses on ketamine’s action on the mu-opioid system and OCD neural circuits. First, our prior work found that the mu-opioid receptor antagonist naltrexone blocks ketamine’s acute, dramatic antidepressant effects. Second, naltrexone also worsens OCD symptoms, while morphine (a mu-opioid receptor agonist) diminishes OCD symptoms. Third, in major depression, attempts to develop follow- on agents that work via NMDA antagonism have not been successful. One possible explanation is that NMDA antagonism may not fully explain ketamine’s rapid and enduring antidepressant effects. To assess the neural targets modulated by mu-opioid receptor antagonism, we focus on fronto-striatal cognitive control circuits which neuroimaging studies show are directly influenced by the mu-opioid system. Indeed, mu-opioid receptors are distributed throughout the fronto-striatal circuits associated with OCD. Drawing on this rationale, the proposed mechanistic trial would be the first to probe the role of ketamine’s opioid properties in modulating fronto-striatal circuitry and bringing about anti-obsessional effects in OCD. We will test, by administering pre-treatment with naltrexone, whether opioid receptor antagonism blocks ketamine’s effects on control and reward circuits and circuit connectivity. Low-cost markers of opioid system engagement that predict anti-obsessional response are needed. We will therefore explore two promising, low- cost markers of opioid system engagement in humans. The proposed projects combine experimental medication and neuroimaging approaches in order to open a new avenue for therapeutics to transform psychiatric treatments.