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

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.