The Disordered Mind: What Unusual Brains Tell Us About Ourselves

by Eric R. Kandel

Ketamine works differently from traditional antidepressants. To begin with, it targets glutamate, not serotonin. To understand why this is important, we must first know that neurotransmitters fall into two categories: mediating and modulatory. Mediating neurotransmitters are released by a neuron at the synapse and act directly on the target cell, either exciting the target cell or inhibiting it. Glutamate is the most common excitatory transmitter, and GABA (gamma aminobutyric acid) is the most common inhibitory transmitter. Modulatory neurotransmitters, on the other hand, fine-tune the action of excitatory and inhibitory neurotransmitters. Dopamine and serotonin are modulatory neurotransmitters. Because ketamine acts on the excitatory neurotransmitter glutamate, which directly affects the target cell, the drug reduces depression more quickly than drugs that act on the modulatory transmitter serotonin. In addition, ketamine prevents the transmission of glutamate from one neuron to the next by blocking a particular glutamate receptor on the target cell. Since a receptor blocked by ketamine can’t bind glutamate, the neurotransmitter can’t affect the target cell. The demonstration of the antidepressant effect of ketamine profoundly changed the way we think about depression.