The underlying neural mechanisms identified may help clinicians better understand ketamine response in human patients.
Does a health care provider’s sex impact how well active agents perform? The answer appears to be a “yes,” according to a new study that examined the antidepressant response to ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine when the drug was administered to mice by men compared to women.
Todd Gould, MD, study coauthor and professor of psychiatry at the University of Maryland School of Medicine, and colleagues decided to study the relationship between mouse response to ketamine and the sex of the ketamine administrator when they noticed anecdotally that mice only seemed to respond consistently to ketamine when it was administered by a male researcher. When they reached out to other labs that were studying mouse response to ketamine, they learned that other labs had noticed the same thing, but had not systematically documented the phenomena or investigated potential causes.1
So, the authors tested the phenomena by having both men and women rub cotton swabs and T-shirts on a wrist or elbow or behind an ear, and then placing the swabs and shirts among the mice to see which scent the mice preferred to be around. They noted that the mice preferred to be around the swabs and shirts that came from women—however, when they incorporated a chemical to block the smell of the mice, the mice no longer showed a preference for the women’s swabs or shirts.1
After verifying these findings in a large systematic experiment, the authors investigated the mechanism that causes this behavior in mice.
They determined that the scent aversion and stress susceptibility in the mice was mediated by the activation of corticotropin-releasing factor (CRF) neurons within the entorhinal cortex that project into the hippocampal area CAI2—the region of the brain responsible for memory and learning that had been previously associated with depression.
When the authors had female researchers administer the ketamine with an injection of CRF, the mice began responding to the antidepressant effects of the ketamine.1
“Our findings in mice suggest that activating a specific stress circuit in the brain may be a way to improve ketamine treatment,” Gould said in a press release. “Our thought is that you may be able to provide a more robust antidepressant effect if you combine the ketamine with activation of this brain region, either a drug that spurs this process in the brain or even some sort of specific stressor.”
Although these findings are not directly relevant to the human response to ketamine, the authors stated that the underlying brain mechanism may be useful in determining why some patients do not respond well to ketamine therapy and potentially in helping clinicians adjust the therapy for greater effectiveness in these patients.1
“We think that some people may have higher or lower levels of CRF, and we believe that people who do not respond well to ketamine antidepressant therapy might respond if we could administer the treatment with some CRF-related chemical that could induce ketamine’s effects,” said Polymnia Georgiou, PhD, study leader and former postdoctoral fellow in Gould’s lab, in a press release. “Alternatively, we typically see the antidepressant effects of ketamine lasting 1 to 3 days, but with CRF administration, it is possible that we may be able to extend the effects to last longer with CRF.”
1. Drug effects of ketamine in mice can depend on the sex of the human experimenter. University of Maryland School of Medicine. News release. August 30, 2022. September 13, 2022. https://www.newswise.com/articles/drugs-effects-of-ketamine-in-mice-can-depend-on-the-sex-of-the-human-experimenter
2. Georgiou P, Zanos P, Mou TM, et al. Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nat Neurosci. 2022;25:1191-1200.