Molecular Mechanisms Underlying Ketamine’s Rapid Antidepressant Action

Byproduct of ketamine metabolism underlies the antidepressant-like activity of the agent in mice.

Depression has become the top cause of disability worldwide, now affecting approximately 350 million individuals of all ages, and it has been linked with a range of problems pertaining to personal and public health.1 People with depression have a significantly higher risk of death from suicide, cardiovascular disease, and stroke, and the economic costs related to missed work and lost productivity have been estimated to exceed $36 billion in the United States alone.2

Though effective psychological and pharmaceutical treatment options exist, less than half of individuals with depression receive them due to barriers such as lack of resources, stigma surrounding mental illness, and inaccurate assessment.1 Even when antidepressant medications are appropriately prescribed, there is a high nonresponse rate, and for patients who do respond to treatment, it may be weeks or months before clinical improvement is evident.

Ketamine, a noncompetitive glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist that is commonly used as an anesthetic agent, has “demonstrated rapid and robust efficacy as an antidepressant by improving core depressive symptoms including depressed mood, anhedonia, and suicidal thoughts” when administered in subanesthetic doses in patients with treatment-refractory unipolar and bipolar depression, wrote the authors of a new study on the topic.3 These effects are evident within hours of administration and persist for an average of 1 week. There are disadvantages associated with the drug, however, including its potential for abuse and addiction, as well as the temporary dissociative symptoms it causes. These are some of the undesirable adverse effects that have prevented the widespread adoption of ketamine as a treatment option for depression despite its demonstrated effectiveness.

How the drug exerts its antidepressant effect is also unclear, though it has been assumed to result from direct NMDAR inhibition. Data from human trials, however, show that other NMDAR antagonists do not have the same antidepressant effects as ketamine, and the new findings indicate an NMDAR inhibition-independent mechanism of the drug’s antidepressant action in mice. To test the NMDAR-inhibition hypothesis, scientists from the University of Maryland and the National Institutes of Health evaluated the effects of the (S)- and (R)-ketamine enantiomers (molecules that are mirror images of each other) in 3 tests designed to assess antidepressant-like activity in rodent models of depression.

“While the NMDAR hypothesis of ketamine action would predict greater efficacy of (S)-ketamine since it is an approximately 3- to 4-fold more potent inhibitor of the NMDAR than (R)-ketamine,” the results instead show greater potency of (R)-ketamine in all 3 tests, consistent with findings of another recent study, the authors reported. The results further demonstrate that a byproduct of ketamine metabolism underlies the antidepressant activity of the agent; specifically that the “metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological, and cellular antidepressant-related actions in mice,” according to the paper.  The authors also found that the (2R,6R)-HNK metabolite did not result in dissociative and addictive adverse effects like those associated with ketamine itself. These findings have promising implications for the development of novel, fast-acting antidepressant medications that will be eventually be explored in human trials.


1. World Health Organization. Depression fact sheet. Available at: Accessed May 9, 2016.

2. Lépine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. 2011; 7(Suppl 1): 3-7.

3. Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016; May 4. doi: 10.1038/nature17998.

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