Source: Joshua Gordon, NIMH

Many pharmacologists began to believe that to make significant improvements, new drugs would need to target mechanisms beyond the monoamines. But where to turn? John Krystal, M.D., Ph.D., and Dennis Charney, M.D., at Yale University, made an educated guess: Let’s try glutamate. Glutamate is the major excitatory neurotransmitter in the brain, responsible for activating neurons to turn on the key circuits that drive all forms of behavior. Drs. Krystal and Charney had been studying the effects of altering glutamate neurotransmission in healthy subjects and patients with schizophrenia, testing the hypothesis that changes in glutamate function might underly psychosis. They noticed that a particular glutamate receptor blocker, ketamine, had profound psychological effects on people, inducing psychotic-like symptoms. They were aware of preclinical studies, particularly those of Phil Skolnick, Ph.D., D.Sc., and his colleagues suggesting that antagonists of one of the glutamate receptors, the NMDA receptor, had antidepressant-like properties. They also knew that glutamate has important roles in mood, and in the regulation of monoamines. They wondered, might glutamate play a role in depression? Could ketamine be used to treat depression? In a small group of patients with depression, the scientists at Yale found that low doses of ketamine – lower than those that cause psychosis-like symptoms – dramatically reduced depressive symptoms. Remarkably, while monoaminergic antidepressants take weeks to work, the effects of ketamine on depression occurred within hours.

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