Foundation-supported scientists have just solved an important mystery. They have determined how ketamine, a drug approved long ago as an anesthetic but used recently on an experimental basis in treating major depression, exerts its beneficial antidepressant effect.

Low doses of the drug rapidly alleviate symptoms of depression, including major depression that has resisted other forms of treatment. Studies have found patients with depression experience dramatic improvement within hours of treatment with ketamine, whereas traditional antidepressants can take weeks to take effect. But serious side effects, including hallucinations and the feeling of being outside one’s own body (dissociation), as well as a potential for abuse, have limited ketamine’s potential for clinical use in treating depression.

The new research suggests it may be possible to separate ketamine’s benefits from its unwanted effects. Inside the body, ketamine is broken down, forming several new compounds, called metabolites. The team discovered that one of these metabolites—a molecule called hydroxynorketamine (HNK)—is responsible for ketamine’s antidepressant effects. In mice, HNK reduces depression-associated behaviors as well as ketamine, but does not cause ketamine’s side effects. The findings were reported May 4 in the journal Nature.

Further studies will be needed to determine whether HNK has the same effect in patients. But the researchers, led by Todd Denton Gould, M.D., a NARSAD 2013 Independent Investigator and 2004, 2010 Young Investigator at the University of Maryland School of Medicine, and including the Brain & Behavior Research Foundation Award for Bipolar Mood Disorder Research 2011, NARSAD 2005 Independent Investigator and 1996 Young Investigator Carlos A. Zarate, M.D., at the National Institute of Mental Health, say their discovery has already provided a new understanding of how ketamine acts on the brain to exert its antidepressant effects.

Unlike commonly used “SSRI”-class antidepressants (such as Paxil, Lexapro, Celexa, Prozac), ketamine’s mechanism of action does not primarily rely on altering brain levels of the neurotransmitters serotonin or norepinephrine. It does, however, block signaling from a nerve cell receptor called the NMDA receptor—this is how it acts as an anesthetic, and also why it causes its most significant side effects. Researchers had thought ketamine’s antidepressant effects might also be due to inhibition of the NMDA receptor, but the team’s studies of HNK showed this is not the case.

Dr. Gould and his colleagues found that HNK reduces depression-like behaviors in mice without inhibiting NMDA receptors, instead activating molecules called AMPA receptors. The finding could help researchers design a new generation of antidepressants.