Health and Medicine Neuroscience

Ketamine’s Antidepressant Effects Separated from Side Effects


Based on the results of a recent study done with animals, researchers believe that the antidepressant effects of ketamine can be separated from its potential side effects.

At a recent meeting of the American College of Neuropsychopharmacology, investigators presented new preclinical evidence suggesting that a metabolite of ketamine can produce antidepressant like effects for depression. Mice were used for the study. When ketamine is broken down in the body, the metabolite is produced. This result may lead to additional research to understand ketamine’s effectiveness in depression and its potential side effects better.

Ketamine is used as an anesthetic in both veterinary and human medicine. The findings show that it has fast and powerful antidepressant effects in humans, even in those resistant to the positive effects of more traditional antidepressants. For those suffering from the debilitating symptoms of depression, this result has raised hope that ketamine may represent a new treatment option. Ketamine does however have euphoric effects that have been associated with abuse, although these typically come into play at much higher doses than are used to treat depression. Ketamine is also known to induce perceptual changes and dream-like states. This has triggered a race to understand how ketamine may contribute to anti-depressant effects, while at the same time determining whether its beneficial antidepressant effects can be separated from potential side effects.

Ketamine’s structure

Ketamine is made up of two different isomers, S-ketamine and R-ketamine, which are mirror images of each other. These components are converted in the body into S- and R-metabolites that can potentially have different actions. Dr. Kenji Hashimoto showed in his presentation that in rodents, the antidepressant like behavioral effects of ketamine might be related to the actions of R-ketamine and ketamine metabolites. One of these metabolites, S-norketamine, showed the antidepressant like effects in the absence of the motor stimulation effects. This is normally seen after ketamine treatment or recreational use. Dr. Irving Wainer showed that hydroxynorketamine (HNK), another ketamine metabolite, also has powerful antidepressant effects but without motor stimulation effects. As the observations were done in animal studies, these are not necessarily reproducible in humans. Additional studies in humans are required to understand the effectiveness and safety of S-norketamine, R-ketamine and other ketamine metabolites in humans better.

Clinical data from a phase 2 study with intranasal S-ketamine was presented by Dr Jaz Singh. The date showed a dose response in depressed humans who had not responded to conventional antidepressant drugs. The effectiveness persisted for up to 8 weeks after the last dose. Dissociative effects that began shortly after the start of dosing resolved in less than 2 hours and significantly attenuated with multiple dosing. These results were dose dependent.

Hydroxynorketamine’s structure

New insights into how ketamine may act in the brain to exert antidepressant effects was provided by Dr. Lisa Monteggia. She showed that the production of new proteins in nerve cells was activated by ketamine and that these proteins play a role in encoding new memories and other information by brain cells. This suggests that ketamine might improve the function of brain circuits that are involved in mood regulation.

These findings suggest that HNK, R-norketamine and other related drugs could have antidepressant effects like those of ketamine without its negative side effects. Drugs that modify the ability of brain cells to produce new proteins could therefore represent an entirely new class of antidepressant drugs.