Imaging Alterations in Endocannabinoid Metabolism in Depression and Suicide

Project Summary Strong epidemiological evidence linking cannabis use to depression and suicide suggests that the endocannabinoid (eCB) system plays a key role in its pathophysiology. Understanding the neurobiology of depression and suicide in young people is critically needed to identify new therapeutic targets for prevention

and treatment. Fatty acid amide hydrolase (FAAH) is the enzyme responsible for the metabolism of eCBs such as anandamide setting the tone of the eCB. In humans (periphery and postmortem) previous studies have shown some evidence of altered eCB in depression. We present preliminary clinical data showing

relationships between FAAH and mood symptoms/guilt/resentment/impulsivity and aggression and trauma (below age 6) and significant sex effects (higher FAAH in females). Preliminary postmortem data suggesting a potential increase in FAAH protein expression in MDD who died by suicide (intermediate response in MDD) in

prefrontal Cortex (PFC), consistent with recent reports of reduction anandamide levels (likely high FAAH) in suicide attempters. In addition, FAAH inhibition and the elevation of anandamide has been proposed as treatment for depression/anxiety. Furthermore, anandamide can inhibit synaptic reuptake of neurotransmitters

implicated in depression. However, no study has investigated brain FAAH, the eCB gatekeeping enzyme, in-vivo in brain in depression with and without suicide attempts, compared to healthy controls. Our team has synthesized [11C]CURB and demonstrated its excellent properties for selective and reliable

PET brain imaging of FAAH (72). We also established the safety, validation and dosimetry of [11C]CURB as well as its reproducible quantification (75, 76). Thus, the overall aim of our proposal is to use a novel and validated radiotracer, [11C]CURB, to quantify the eCB rate limiting enzyme FAAH using Positron Emission

Tomography (PET) with a high-resolution research tomograph (HRRT) in young adults with current unipolar (non-psychotic) major depression with a recent suicide attempt within the last 6 months with a lethality score of at least 3 (D+SA), compared with similar age/sex matched depressed patients without life history of a suicide attempt

(D-SA) and age/sex matched Healthy Volunteers (HV). Our study will be the first to investigate the contribution of the eCB (FAAH) in depression and suicidal behaviors, perhaps usable as a novel molecular target amenable for more physiological intervention (i.e. FAAH) to regulate eCB in depression and suicide.

The PI and her colleagues have a considerable track record of performing complex molecular PET imaging studies in vulnerable youth (34, 73-82). The high-resolution PET scanner, well characterized radiotracer and the infrastructure for neurobiological research in depression and suicide are novel aspects of the

project that will provide a fundamental basis for future studies of pharmacologic interventions in depression and suicidal behavior focused on the eCB.