The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [11C]CURB λk3, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [11C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [11C]CURB λk3 were observed between MDD participants and controls (F1,27 = 0.32; p = 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [11C]CURB λk3 binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F1,11 = 6.75; p = 0.02). Depressive severity and anxiety did not have a significant relationship to [11C]CURB λk3 binding. The relationship of greater fronto-limbic [11C]CURB λk3 to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.
© 2025. The Author(s).