Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression

Abstract

A single, subanesthetic dose of (R,S)-ketamine (ketamine) exerts rapid and robust antidepressant effects. Several groups previously reported that (2S,6S;2R,6R)-hydroxynorketamine (HNK) had antidepressant effects in rodents, and that (2R,6R)-HNK increased cortical electroencephalographic gamma power. This exploratory study examined the relationship between ketamine metabolites, clinical response, psychotomimetic symptoms, and gamma power changes in 34 individuals (ages 18-65) with treatment-resistant depression (TRD) who received a single ketamine infusion (0.5 mg/kg) over 40 min. Plasma concentrations of ketamine, norketamine, and HNKs were measured at 40, 80, 120, and 230 min and at 1, 2, and 3 days post-infusion. Linear mixed models evaluated ketamine metabolites as mediators of antidepressant and psychotomimetic effects and their relationship to resting-state whole-brain magnetoencephalography (MEG) gamma power 6-9 h post-infusion. Three salient findings emerged. First, ketamine concentration positively predicted distal antidepressant response at Day 11 post-infusion, and an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at 3 and 7 days post-infusion. Norketamine concentration was not associated with antidepressant response. Second, ketamine, norketamine, and (2S,6S;2R,6R)-HNK concentrations at 40 min were positively associated with contemporaneous psychotomimetic symptoms; post-hoc analysis revealed that ketamine was the predominant contributor. Third, increased (2S,6S;2R,6R)-HNK maximum observed concentration (C_max) was associated with increased MEG gamma power. While contrary to preclinical observations and our a priori hypotheses, these exploratory results replicate those of a recently published study documenting a relationship between higher (2S,6S;2R,6R)-HNK concentrations and weaker antidepressant response in humans and provide further rationale for studying gamma power changes as potential biomarkers of antidepressant response.

Fig. 1. Relationship between pharmacokinetic parameter value and treatment effects.

The figure plots the results of specific contrasts testing the parameter*drug interaction at each timepoint; slopes are multiplied by the standard deviation of the parameter to yield change in treatment effect associated with a one standard deviation increase in pharmacokinetic parameter. K ketamine, NK norketamine, HNK (2S,6S;2R,6R)-hydroxynorketamine, AUC area under the curve from 0 to 1440 min, CMAX maximum concentration, HL half-life.

Fig. 2. Relationship between (2S,6S;2R,6R)-hydroxynorketamine (HNK) C_max and antidepressant response to ketamine.

The figure plots the difference in MADRS total score between ketamine and placebo arms (response; placebo minus ketamine) by (2S,6S;2R,6R)-HNK Cmax, at each timepoint. The slope for each relationship (with 95% confidence interval) is provided (see also Supplementary Table S2). Increased (2S,6S;2R,6R)-HNK maximum concentration was associated with less clinical response, but this relationship was most robust at later timepoints. MADRS: Montgomery-Asberg Depression Rating Scale.

Fig. 3. Associations between gamma power and (2S,6S;2R,6R)-hydroxynorketamine (HNK) and norketamine (NK) C_max values.

Images of normalized, root mean square gamma power (30–50 Hz) estimates associated with (a) (2S,6S;2R,6R)-HNK C_max levels and (b) NK C_max levels. Images are superimposed on a high-resolution structural scan and thresholded at pFDR < 0.05. Reddish colors represent regions where metabolite levels were positively associated with gamma power, while bluish colors represent regions where metabolite levels were negatively associated with gamma power.