Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression

Abstract

The antidepressant effects of ketamine are thought to depend on brain-derived neurotrophic factor (BDNF) genotype and dose. The purpose of this study was to characterize the dose-related antidepressant effects of ketamine in patients with treatment-resistant depression drawn from a Chinese population predominately possessing lower activity BDNF genotypes (Val/Met, Met/Met). We conducted a double-blind, randomized, parallel-group, placebo-controlled trial of a single ketamine infusion (saline, 0.2 mg/kg, 0.5 mg/kg). Patients (N=71; BDNF genotype: Val/Val (N=12, 17%), Val/Met (N=40, 56.3%), and Met/Met (N=19, 26.8%)) received mood ratings before infusion, after infusion, and for the subsequent 14 days. Plasma ketamine levels and BDNF genotypes were assessed. This study found a significant dose-related ketamine effect on scores on the Hamilton Depression Rating Scale (HAMD). The responder analysis (>50% reduction from baseline HAMD on at least 2 days between days 2 and 5) also revealed a significant dose-related effect (saline: 12.5%, 0.2 mg/kg: 39.1%; 0.5 mg/kg: 45.8%). This is the first report to our knowledge to demonstrate the dose-related efficacy of R/S-ketamine for treatment-resistant depression and the first to characterize ketamine effects in a genotyped Chinese population in which most (83%) patients possessed at least one copy of the lower functioning Met allele of the BDNF gene.

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…This was the first double‐blinded, placebo‐controlled trial showing the rapidly acting antidepressant effects of ketamine in patients with MDD . Subsequent studies replicated the robust antidepressant actions of ketamine in refractory MDD patients . The seminal study of Krystal et al .…”

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

“…More importantly, BDNF is indispensable in anti‐depressant effects. In the BDNF Met gene knock‐in mice, especially Met/Met mice, synaptogenesis was significantly weakened, 95 consisted of depressed patients 96 . Clinical study showed that either 0.5 or 0.2 mg/kg of ketamine injection could reduce suicidal ideation of patients who had the Val allelic genes.…”

“…Clinical study showed that either 0.5 or 0.2 mg/kg of ketamine injection could reduce suicidal ideation of patients who had the Val allelic genes. However, patients with genotype Met/Met only responded at a dose of 0.5 mg/kg ketamine 96 . Sufficient BDNF content regulates synaptic plasticity and participates in reversing depression 97‐99 …”

Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders

“…Nevertheless, it should be noted that in both studies, the more commonly used 0.5-mg/kg dose was at least numerically more efficacious. 6,7 Furthermore, the increased efficacy of the 0.5-mg/kg dose may be more pronounced in patients with severe depression compared with lower doses. 7 However, lower doses do appear to have few associated adverse events.…”

“…6,7 Furthermore, the increased efficacy of the 0.5-mg/kg dose may be more pronounced in patients with severe depression compared with lower doses. 7 However, lower doses do appear to have few associated adverse events. Thus, because of limited data, it is not possible to clarify the relative benefits and risks of doses other than 0.5 mg/kg delivered intravenously over 40 minutes.…”