Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants

Sub-anesthetic doses of ketamine and its S-enantiomer, esketamine, rapidly reduce depression symptoms in patients with treatment-resistant major depressive disorder. A pharmacometabolomics approach mapped global metabolic effects in 33 patients receiving ketamine and 20 receiving esketamine, with esketamine retested after a second infusion four days later. Both drugs altered metabolites related to tryptophan metabolism (e.g., indole-3-acetate and methionine) and the urea cycle (e.g., citrulline, arginine, and ornithine) two hours post-infusion. Changes in glutamate and circulating phospholipids were significantly associated with decreases in depression severity. These findings provide new insights into the mechanisms underlying the rapid antidepressant effects of these therapies.

Study at a glance

Abstract

Ketamine, at sub-anesthetic doses, is reported to rapidly decrease depression symptoms in patients with treatment-resistant major depressive disorder (MDD). Many patients do not respond to currently available antidepressants, (for example, serotonin reuptake inhibitors), making ketamine and its enantiomer, esketamine, potentially attractive options for treatment-resistant MDD. Although mechanisms by which ketamine/esketamine may produce antidepressant effects have been hypothesized on the basis of preclinical data, the neurobiological correlates of the rapid therapeutic response observed in patients receiving treatment have not been established. Here we use a pharmacometabolomics approach to map global metabolic effects of these compounds in treatment-refractory MDD patients upon 2 h from infusion with ketamine (n=33) or its S-enantiomer, esketamine (n=20). The effects of esketamine on metabolism were retested in the same subjects following a second exposure administered 4 days later. Two complementary metabolomics platforms were used to provide broad biochemical coverage. In addition, we investigated whether changes in particular metabolites correlated with treatment outcome. Both drugs altered metabolites related to tryptophan metabolism (for example, indole-3-acetate and methionine) and/or the urea cycle (for example, citrulline, arginine and ornithine) at 2 h post infusion (q<0.25). In addition, we observed changes in glutamate and circulating phospholipids that were significantly associated with decreases in depression severity. These data provide new insights into the mechanism underlying the rapid antidepressant effects of ketamine and esketamine, and constitute some of the first detailed metabolomics mapping for these promising therapies.