The Endocannabinoidome in Major Depressive Disorder: From Gene Expression and Neuroinflammation to Potential Novel Therapeutics

Abstract

Major depressive disorder (MDD) affects approximately 5% of adults worldwide, causing substantial personal and societal costs. Current treatments like selective serotonin reuptake inhibitors (SSRIs) show limited effectiveness, with only 20% of patients demonstrating meaningful improvement over non-pharmacological interventions. The complex pathophysiology of depression involves multiple interconnected mechanisms, including monoamine dysfunction, neurotransmitter dysregulation, oxidative stress, and chronic inflammation. The endocannabinoidome (eCBome), a complex lipid signalling system, regulates many of these pathways, yet its role in depression remains poorly understood. Through systematic post-mortem human brain analysis, animal studies, and cellular and plant characterisation work, this thesis investigated eCBome alterations in MDD and explored novel therapeutic approaches targeting this system.</p