Ketamine Metabolites and Clinical Response in Treatment-Resistant Major Depression

Young female psychiatrist talking with despair patient
The investigators sought to evaluate the relationship of the primary metabolites of ketamine to antidepressant and psychotomimetic effects, along with their impact on gamma oscillation.

Among individuals with treatment-resistant depression (TRD), a relationship has been shown between ketamine metabolites and clinical response, psychotomimetic symptoms, and gamma power changes. An exploratory analysis was performed among a group of inpatients who participated in a randomized, placebo-controlled, crossover trial of ketamine ( identifier: NCT00088699) conducted in the Mood Disorders Research Unit of the National Institutes of Health in Bethesda, Maryland, between 2011 and 2017. Results of the study were published in the Neuropsychopharmacology.

The investigators sought to evaluate the relationship of the primary metabolites of ketamine to antidepressant and psychotomimetic effects, along with their impact on gamma oscillation. Their primary hypothesis was that increased ketamine and (R,S)-norketamine (NK) plasma concentrations would be preferentially associated with improved acute response (ie, at

230 minutes), whereas increased (2S,6S;2R,6R)-hydroxynorketamine (HNK) concentrations would be linked to an improved extended response (i.e., at day 7). They also explored the relationship between ketamine concentration and the concentrations of its metabolites to increases in magnetoencephalography gamma power.

The study enrolled a total of 34 participants with TRD and 23 healthy controls, and researchers obtained plasma levels of ketamine and its metabolites as part of an earlier study. All of the participants were free of psychotropic medications for ≥2 weeks prior to randomization and remained medication free for the duration of the study. In this 2-arm, 2-period, exploratory crossover study, 40-minute intravenous infusions of ketamine hydrochloride 0.5 mg/kg or saline were administered 2 weeks apart in an inpatient setting.

The average antidepressant response to ketamine vs placebo on day 1 was –7.11 (95% CI, –11.04 to –3.19) points on the Montgomery Asberg Depression Rating Scale (MADRS) total score. Although ketamine concentration did not mediate the antidepressant response at the acute timepoints, it was positively related to antidepressant response at day 11 postinfusion (P =.009), with higher ketamine concentrations actually associated with improved antidepressant responses. No meaningful relationship to response was reported for NK concentration, nor for (S)-NK or (R)-NK.

Furthermore, lower (2S,6S;2R,6R)-HNK concentrations were associated with better antidepressant response, whereas higher (2S,6S;2R,6R)-HNK concentrations were linked to an attenuated response. These associations were strongest at the middle timepoints (i.e. days 3 and 7), but were not observed at day 11.

A major limitation of the current study is the fact that ketamine metabolism is dynamic, since the agent is extensively metabolized to several pharmacologically active metabolites. Thus, the correlating antidepressant response to any individual metabolite may not offer an accurate window into the effects of ketamine.

The investigators concluded that the results provide additional support for exploring gamma power changes as potential biomarkers of antidepressant response. Additional research is warranted, in order to better characterize the antidepressant side effect profiles of (2S,6S;2R,6R)-HNK concentrations, especially with respect to central nervous system levels of the metabolite and their relationship to changes relative to drug administration.


Farmer CA, Gilbert JR, Moaddel R, et al. Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression [published online April 6, 2020]. Neuropsychopharmacology. doi:10.1038/s41386-020-0663-6.