Ketamine, an anesthetic drug that has been found in experimental studies to rapidly alleviate symptoms of depression, causes a rapid surge in two important neurotransmitters—glutamate and GABA—in the brains of people with major depressive disorder, a new study has found.

The study, reported August 18 in the journal Molecular Psychiatry, suggests that changes in glutamate and GABA neurotransmitter systems may account, at least in part, for ketamine's antidepressant effects. Interestingly, glutamate is the most common of the brain’s “excitatory” neurotransmitters, while GABA has an opposite, inhibitory, role.

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Ketamine has been used as an anesthetic since 1970, and has also long been abused as a “recreational drug.” But in recent years, researchers have discovered that low doses of ketamine can rapidly relieve the symptoms of severe depression. Unlike traditional antidepressants, which can take weeks to benefit patients, ketamine dramatically reduces depression symptoms within hours – notably, even in some patients who have not responded to other antidepressant medications.

Ongoing research will determine whether ketamine is safe and effective for widespread treatment for treatment-resistant depression. Understanding how the drug exerts its effects could also guide the development of related molecules with fewer potential side-effects as new fast-acting therapies for depression.

In the current study, a team of scientists led by BBRF Scientific Council member J. John Mann, M.D., a 2008 NARSAD Distinguished Investigator at Columbia University Medical Center, used brain scans to measure the levels of glutamate, a related precursor molecule called glutamine, and GABA in the medial prefrontal cortex region of the brain before, during, and after treatment with a single dose of ketamine. All 11 participants in their study had major depressive disorder.

Other recipients of NARSAD grants were involved in the work: Lawrence S. Kegeles, M.D., Ph.D., a 2010 Independent Investigator who received Young Investigator grants in 1995 and 1997; Carolyn I. Rodriguez, M.D., Ph.D., who received Young Investigator grants in 2009 and 2014; and John G. Keilp, Ph.D., who received Young Investigator grants in 1996 and 1998.

The treatment effectively reduced patients' symptoms, as expected. Ten of the 11 patients experienced remission of their depression within four hours of receiving ketamine. The researchers also found that both glutamate and glutamine (measured together as “glutamatergic compounds”) and GABA rose rapidly in the brain's medial prefrontal cortex. The levels of these molecules peaked 26 minutes after treatment had begun, when they were about 40 percent higher than pre-treatment levels.

The rise in glutamatergic compounds in the patients' brains was consistent with what other researchers had previously observed in animal studies of ketamine's effects, whereas the drug's effects on GABA had not previously been recognized. Disruptions of both neurotransmitter systems have been found in people with major depression.

Read the abstract.