Glutamate is the brain's main excitatory neurotransmitter, the chemical signal that tells the next nerve cell to fire. Roughly 80 to 90 percent of synapses in the cortex use it. It is also an amino acid found in food, but dietary glutamate does not cross into the brain in meaningful amounts, so what you eat does not change brain levels. Within the nervous system, glutamate is released by one neuron, binds to receptors on the next, including the NMDA and AMPA receptors, and is then rapidly cleared by supporting cells so that signaling stays precise.
Glutamate has become central to understanding depression and its newer treatments. For decades, antidepressant research focused on serotonin, norepinephrine and dopamine. Imaging and post-mortem studies then showed that people with long-standing depression have fewer synapses in the prefrontal cortex and altered glutamate signaling. Ketamine and esketamine act on this system directly. By briefly blocking NMDA receptors they cause a burst of glutamate release that activates AMPA receptors and growth pathways, producing new synaptic connections within a day. This is thought to explain why esketamine, sold as Spravato, can relieve symptoms within hours rather than weeks. Too much glutamate activity can be harmful, which is one reason these medications are given in controlled doses under supervision. Lamotrigine, a mood stabilizer, also works partly by reducing excess glutamate release.