This technology includes the identification and use of a ketamine metabolite, (2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone (HNK), for the treatment of depression. Ketamine is an NMDA receptor antagonist that exerts a rapid and sustained antidepressant and anti-suicidal effect. However, even low doses of ketamine has addictive and psychomimetic effects. The downstream metabolite, (2R,6R)-HNK, does not inhibit the NMDA receptor but recapitulates the antidepressant and anti-suicidal effect of ketamine. Further clinical work could establish a ketamine metabolite, such as (2R,6R)-HNK, for the treatment of depression.
While ketamine has already been demonstrated as a robust and acute antidepressant, its use is limited due to multiple liabilities, including its addictive potential. The use of ketamine metabolites, including (2R,6R)-HNK, retains all of the antidepressant effects of ketamine without the associated liabilities.