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

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2020-07, Vol.45 (8), p.1398-1404
• Main Authors: Farmer, Cristan A, Gilbert, Jessica R, Moaddel, Ruin, George, Jomy, Adeojo, Lilian, Lovett, Jacqueline, Nugent, Allison C, Kadriu, Bashkim, Yuan, Peixiong, Gould, Todd D, Park, Lawrence T, Zarate, Jr, Carlos A
• Format: Article
• Language: English
• Subjects: Antidepressants; Antidepressive Agents - therapeutic use; Cross-Over Studies; Depression; Depressive Disorder, Major - drug therapy; EEG; Humans; Ketamine; Magnetoencephalography; Mental depression; Metabolites; Placebos
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-020-0663-6

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 ) 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.