For decades, major depressive disorder (MDD) has been framed as a disorder of neurotransmitters—primarily serotonin, norepinephrine, and dopamine. This model enabled meaningful therapeutic progress, but its limits are increasingly clear. A large proportion of patients do not achieve sustained remission. Treatment resistance remains common, and relapse rates are high even among responders. These realities suggest that incremental adjustments to synaptic signaling have reached a practical ceiling in their ability to reshape long-term outcomes.