Background: Major depression has the highest rate of prevalence and incidence of morbidity among all mental disoders. The limited efficacies of current antidepressant treatments necessitate the development of alternative pharmacotherapies. Recent preclinical findings suggesting that cannabinoid CB(1) receptor agonists and endocannabinoid enhancers possess antidepressant-like properties, and clinical evidence that the CB(1) antagonist rimonabant increases the risk of depression and suicidality, support the notion that the endocannabinoid system represents a novel target in the treatment of mood disorders.
Objective/methods: To compare the mechanism of endocannabinoid enhancers and CB(1) agonists with current antidepressants and provide a rationale for a role of the endocannabinoid system in the pathology and treatment of mood disorders.
Results/conclusion: CB(1) agonists and fatty acid amide hdyrolase (FAAH) inhibitors share mechanisms with other antidepressants: the ability to enhance central serotonergic and noradrenergic transmission and promote neurogenesis in the hippocampus. FAAH inhibitors, compared with direct CB(1) agonists, exhibit distinct pharmacological properties that quell adverse cannabinoid effects and widen the therapeutic window. Since the endocannabinoid system also plays a role in peripheral functions, side effects need to be addressed.