Researchers found that mice more consistently experience antidepressant effects from ketamine when administered by men and not women. The corresponding study was published in Nature Neuroscience.
Those who work with mice often report that their behavior depends on who is handling them. Anecdotal reports and some scientific reports even suggest that while mice tend to be more uptight or fearful around men, they are more comfortable and relaxed around women. Whether this affects experimental results, however, is unknown.
The current study was inspired by anecdotal evidence of ketamine consistently producing antidepressant effects when administered by male and not female researchers. To understand why this may be the case, the researchers began by observing mice's preference for t-shirts, and cotton swabs rubbed on the wrists, elbows, or behind the ears of women compared to men.
To understand the mechanisms behind the preference, the researchers used a chemical block to disable their sense of smell. With this in place, they noted that mice no longer preferred women's cotton swabs or T-shirts over men's. This, they noted, may be as mice have a more keenly developed sense of smell than humans and, therefore, a higher sensitivity to pheromones.
From further experiments, the researchers found that the smell of men, and not women, activated corticotropin-releasing factor (CRF) neurons in the hippocampus, which are responsible for learning and memory and have previously been linked to depression.
To see if activation of these neurons could explain the difference in treatment outcomes among mice treated by men or women, the researchers had women administer ketamine alongside CRF to mice. In doing so, they found that mice who received ketamine alongside CRF experienced antidepressant effects, almost as if men treated them.
"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, Ph.D., a former postdoctoral fellow in Dr. Gould's laboratory, who led the project.
"Alternatively, we typically see the antidepressant effects of ketamine lasting 1-3 days, but with CRF administration, it is possible that we may be able to extend the effects to last longer with CRF," she added.
The researchers concluded that a better understanding of how the sex of human experimenters affects treatment outcomes among rodents could improve replicability between studies. They noted that it could also reveal biological and pharmacological mechanisms that could be used to improve treatment outcomes.