Treatment-resistant depression (TRD) challenges standard approaches, prompting a shift toward non-monoaminergic interventions like neuromodulation and glutamatergic agents. This narrative review examines the endocannabinoid system (ECS) as a potential common pathway for these treatments. Evidence indicates that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) increase endocannabinoids anandamide and 2-arachidonoylglycerol, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors, while psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions. These findings suggest ECS modulation may unify diverse antidepressant mechanisms in TRD, offering a promising target for novel therapies.
In a rat model of treatment-resistant depression (Wistar-Kyoto rats exposed to chronic mild stress), brain scans revealed metabolic and structural changes distinct from non-depressed controls. Magnetic resonance spectroscopy showed reduced glutamate, glutamine, and taurine in the prefrontal cortex and decreased glutamine and choline compounds in the hippocampus, along with increased myo-inositol in the prefrontal cortex. Diffusion tensor imaging indicated higher mean diffusivity in both regions, consistent with demyelination or axonal loss, and lower fractional anisotropy in the hippocampus, suggesting compromised white-matter integrity. These findings mirror depression- and stress-related brain changes in humans, supporting the model's use for testing novel treatments like rTMS and psychedelics.