Pharmacological mechanism trials should evaluate candidate compounds with astrocytic or metabolic targets (e.g., modulators of glycogenolysis, purinergic signaling, or glutamate clearance), with biomarker-based stratification and outcomes encompassing PSG-derived sleep continuity, sleep quality, depression severity (MADRS/HAM-D), inflammatory cytokines, BDNF, and imaging changes. Here, BDNF is linked to major depressive disorder.