For decades, psychiatry has framed major depressive disorder (MDD) as a disorder of chemistry, an imbalance of serotonin, norepinephrine, or dopamine. That model produced meaningful therapeutic advances, yet it has not consistently delivered durable remission for a substantial proportion of patients. Roughly one-third remain treatment resistant, and among responders, relapse is common. Incremental modulation of synaptic signaling alone appears to have reached a ceiling in its ability to transform long-term outcomes at scale.