For people struggling with severe depression, antidepressants have the potential to provide much-needed relief, but they often take weeks to work. That’s why there is growing excitement about reports that the anesthetic drug ketamine, when delivered intravenously in very low doses, can lift depression and suicidal thoughts within a matter of hours. Still, there has been reluctance to consider ketamine for widespread treatment of depression because, even at low doses, it can produce very distressing side effects, such as dissociation—a sense of disconnection from one’s own thoughts, feelings, and sense of identity. Now, new findings suggest there may be a way to tap into ketamine’s depression-fighting benefits without the side effects.
In a mouse study published in the journal Nature, an NIH-funded research team found that the antidepressant effects of ketamine are produced not by the drug itself, but by one of its metabolites—a substance formed as the body breaks ketamine down. What’s more, the work demonstrates that this beneficial metabolite does not cause the risky dissociation effects associated with ketamine. While further development and subsequent clinical trials are needed, the findings are a promising step toward the development of a new generation of rapid-acting antidepressant drugs.
Ketamine belongs to a class of drugs that block neurochemical receptors found on nerve cells called NMDA receptors, or NMDARs. These receptors respond to the chemical messenger known as glutamate, helping to form and maintain neural connections and play a role in memory. It wasn’t clear, however, that this action of ketamine could explain its effects on depression, since clinical trials of other drugs targeting NMDARs failed to show the same antidepressant effects.
Those findings prompted Carlos Zarate of the NIH’s National Institute of Mental Health to reach out to Todd Gould at the University of Maryland School of Medicine, Baltimore, who is an expert in conducting studies of the neuro-behavioral effects of drugs on mice, to figure out how ketamine works as an antidepressant. They knew that ketamine comes in two structural forms that are mirror images of each other. They also knew that one of those forms blocks NMDARs much more effectively, suggesting it should have stronger antidepressant actions. In fact, the researchers discovered the opposite is the case. While both have antidepressant actions, the form of ketamine that is the weaker NMDAR blocker is actually more effective at reducing depression-like symptoms in mice.
The team got another clue that something unexpected might be going on when Gould and Zarate, in collaboration with their colleagues at the NIH’s National Institute on Aging, discovered that a metabolite of ketamine known as hydroxynorketamine (HNK) is pharmacologically active and reaches levels that are three times higher in female mice than in male mice. Because female mice were also known to respond more effectively to the antidepressant effects of ketamine than males, the discovery suggested that differences in HNK might provide an explanation.
With the help of chemists at the NIH’s National Center for Advancing Translational Sciences who were able to develop a form of ketamine that is not readily metabolized, the team went on to show that the drug’s antidepressant effects indeed require its break down into HNK. The researchers also found that mice treated with a single dose of HNK showed improvements in their symptoms that lasted for days.
Adding to the encouraging news, HNK appears to come without the side effects of ketamine. After receiving HNK, mice didn’t show changes in their physical activity, coordination, or sensory perception, as is normally seen after a dose of ketamine. HNK also doesn’t appear to have the same potential for abuse either. When given the option, mice will choose to self-administer ketamine, but not HNK.
The new evidence confirms that HNK doesn’t block NMDA receptors like ketamine does. While there’s more to discover about how HNK works, the evidence reveals an important role for AMPA receptors, another type of glutamate receptor in the brain.
More research is needed, but Gould says the team is “cautiously optimistic” about the prospects for a new drug based on HNK. Working with NIH, they now have a plan in place to move toward human testing. First, toxicology tests must be done; if those go well, the researchers hope to proceed with clinical trials to test the safety and efficacy of HNK in people with depression.
The study should come as encouraging news for the 20 percent of the world’s population that will suffer from a severe depressive disorder at one time in their life or another. It’s also a reminder of the importance of researchers with diverse expertise, working together across disciplines, in efforts to bring promising new treatments to the people who most need them.
NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KSS, Fang Y, Huang X-P, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate Jr CA, Gould TD. Nature. 2016 May 4. [Epub ahead of print]
Depression (National Institute of Mental Health/NIH)
Video: Ketamine and Depression:From Despair to Hope in Hours (NIMH/NIH)
Gould Lab (University of Maryland, Baltimore)
Carlos Zarate Jr. (NIMH/NIH)
NIH Support: National Institute of Mental Health; National Institute on Aging; National Center for Advancing Translational Sciences