Ketamine is a Potent Antidepressant, But How Does It Work?

For more than a decade, researchers across the country have been trying to figure out how ketamine produces its rapid antidepressant response. A series of published studies in mice has supported the view that ketamine, a commonly used anesthetic and a club drug, blocks the glutamate receptor N-methyl-D-aspartate (NMDA) on nerve cells, creating the initial strong antidepressant reaction and cascading effects.

“The results of these trials have major implications for millions of depressed patients seeking help, particularly those who have yet to find a medication that works,” said Lisa Monteggia, M.D., a neuroscientist at the O’Donnell Brain Institute at the University of Texas Southwestern Medical Center and author of several ketamine studies. The findings can help scientists identify new drugs to replicate ketamine’s antidepressant effects but without the side effects. They also can help researchers to look back at existing drugs in search of ones that work similarly, she said.

In March 2016, contrary to previously published papers, researchers at the National Institute of Mental Health (NIMH) published a mouse study in Nature whose results supported a new, different view—that a ketamine metabolite (chemical byproduct), known as hydroxynorketamine (HNK), produces the antidepressant effect, not ketamine itself. The researchers also found that HNK’s antidepressant effect required the activation of another glutamine receptor, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Unlike ketamine, HNK does not inhibit NMDA receptors. Thus, HNK does not produce the usual intensified sensory perception and euphoric effects of ketamine.

“The next steps are to confirm if hydroxynorketamine works similarly in humans and if it can be used therapeutically,” said Todd Gould, M.D., principal investigator of Gould Lab at the University of Maryland School of Medicine, who worked on the NIMH study.

University of Texas Southwestern Medical Center scientists responded to the NIMH findings with a short study, “Effects of a Ketamine Metabolite on Synaptic NMDAR Function,” published June 22 in Nature. Their mouse study reaffirmed the findings of previous research involving NMDA receptors, using the same electrophysiological lab techniques as the NIMH study, but administering ketamine to mice at higher doses. The Texas research team again found that ketamine itself triggers the initial antidepressant effects, and the metabolite only extends the duration of the effect.

“Until you have a target, it’s very difficult to think about designing drugs or even knowing what drugs to screen,” said Monteggia.

Gould, who collaborated with Carlos Zarate, M.D., and colleagues in the NIMH study, said that it is not necessary to know exactly how ketamine works to develop new, alternative drugs. He also pointed out that these were mice studies; future human studies may produce different results.

“Clearly, this needs more follow-up behind it,” said Gerard Sanacora, M.D., Ph.D., a professor of psychiatry at Yale University and director of the Yale Depression Research Program. “There may be an additional mechanism that is playing a role other than the blockade of the NMDR receptor. It’s pretty early on, and we can’t get ahead of ourselves with limited preclinical data.”

Ketamine continues to be prescribed off label and administered, usually in low doses intravenously, at specialized ketamine clinics and in academic hospitals across the country to quickly stabilize severely depressed patients (see story below). The high demand for the drug is overriding important questions that remain about ketamine, such as how often should patients get infusions, what is a safe dose, how long do the effects last, and the amount of time they can safely continue to receive this drug, said Monteggia.

Meanwhile, intranasal ketamine has shown strong promise in clinical trials for patients with treatment-resistant major depressive disorder (MDD). Investigators at the Icahn School of Medicine at Mount Sinai in New York City found that intranasal ketamine spray conferred a rapid antidepressant effect within 24 hours, was well tolerated, and had few side effects. Their study was published in April 2014 in Biological Psychiatry. “This could lay the groundwork for using NMDA-targeted treatments for MDD,” according to the researchers. ■