Evidence of ketamine’s power to alleviate treatment resistant depression in adults continues to mount, with clinical studies showing the drug’s efficacy even as Janssen’s FDA-approved ketamine-based nasal spray Spravato enters the market. But surprising findings in a new study suggest the common anesthetic and sometimes club drug may help adolescents with depression too, and might even make teens more resilient to stress-induced depression after treatment.
The results are preclinical and require further study, but it’s a first step toward determining whether ketamine could be an appropriate and effective treatment for adolescent depression. “One of the striking things about adolescent depression is that they tend to be treatment resistant,” said Eric Parise, a postdoctoral fellow in the Nestler lab at the Icahn School of Medicine and first author on the study that was published in the journal Biological Psychiatry.
Parise and his fellow researchers administered 10 milligrams of ketamine per kilogram of bodyweight — a dose that approximates that used in human treatments for depression — to adolescent mice every day for 15 days, and then allowed a week for any ketamine in their systems to wash out. Control mice were given saline injections over the same time period.
Both the saline controls and ketamine-treated mice were then subjected to “chronic social defeat stress,” where they were placed in a cage with a larger, more aggressive mouse that would dominate them for 10 minutes a day, for 10 days. Researchers intervened to prevent any injuries, but Parise notes that this kind of social stress is more relevant and a better model for human depression, as such interactions are natural in rodent societies. “Rodents fight,” he said, “and they develop social hierarchies based on who is victorious in these fights.”
After allowing 24 hours to pass after the last social defeat stressor, researchers assessed the mice using a social interaction test, a measure of how much the rodents interact with each other, and the forced swim test, which is a standard rodent model for measuring the antidepressant effects of interventions. In each test, the control mice showed signs of depression, while the ketamine-treated mice did not. Importantly, the ketamine-treated mice showed resilience to stress without any ketamine in their systems, recapitulating a sometimes naturally occurring “stress-resistant phenotype” in mice.
“There’s a subset of those mice that do not succumb to that stress after 10 days,” Parise said. “In that case, you would sort of expect that when you look at them from a molecular standpoint, that they would almost be identical to a control animal who has not received any exposure to stress. But it turns out that’s not true.”
Resistance to stress-induced depression, the researchers found, is instead an active process depending on molecular and DNA transcriptional changes that occur naturally in some mice, and are induced by repeated ketamine exposure in others.
The result was surprising, Parise said because typically adolescent drug exposure leads to negative outcomes in older animals. “We tested a lot of other drugs over the years and they almost overwhelmingly did not result in positive findings,” Parise said. In tests of adolescent rodent exposure to nicotine, methamphetamine, cocaine and methylphenidate (Ritalin), “all of them produced stress-sensitive phenotypes in adulthood. These animals would be hypersensitive to the effects of anxiety and stress in general.”
Their results are not the first to show ketamine protects against social defeat stress in rodents, Parise said, but they are the first to show this effect extends to adolescents. So the effect appears robust, but more work is required to ensure against any risks specific to human adolescents. “I think the next steps need to be our sort of ironing out what are the true addictive liability aspects of [ketamine] exposure during adolescence.”
At the same time, Parise said, there is always a trade-off between risks and benefits in medicine, noting that Ritalin is still widely prescribed to children despite evidence it can make them more prone to abuse stimulants as adults. In cases of treatment-resistant depression with suicidal ideation, the risks of ketamine may be outweighed by the positives. “Technically speaking, it is FDA-approved and can be prescribed off-label, so there’s no rule stating that a psychiatrist can’t administer it to an adolescent,” Parise said. “You just have to find one who’s willing to put themselves out there and do it.”