A Hypothesis of How the Glutamate Surge Treats Depression: Orchestrating Synaptogenesis and Neuroplasticity

John J. Miller, MD, reviews the glutamate surge, which ultimately agonizes postsynaptic AMPA-glutamate receptors and triggers production of brain-derived neurotrophic factor. This orchestrates synaptogenesis and neuroplasticity, as further explained in Miller’s February 2026 Editorial, “Glutamate and GABA: The Yin and Yang of the Human Brain.”¹

This cascade of events is believed to be responsible for the observed increase in global brain connectivity in the prefrontal cortex of individuals with MDD within 24 hours of a single ketamine infusion and imaged with functional connectivity MRI.^2,3 This putative mechanism for a rapid antidepressant effect demonstrates the complex interdependence of the glutamate and GABA circuitry in the human brain.

Glutamate and GABA, while they are oppositional in their neurophysiology, are intimately integrated in the human brain through their parallel distribution, interdependent metabolism via astrocytes, and codependent role in maximizing the accuracy and efficiency of the location, timing, and degree of synaptic output for the shared outcome of EIB and homeostasis, shared Miller.

References

1. Miller JJ. Glutamate and GABA: the yin and yang of the human brain. Psychiatric Times. 2026;43(2).

2. Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42(6):1210-1219.
3. Abdallah CG, Dutta A, Averill CL, et al. Ketamine, but not the NMDAR antagonist lanicemine, increases prefrontal global connectivity in depressed patients. Chronic Stress (Thousand Oaks). 2018;2:2470547018796102.