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.

Figure 1

Consort flow diagram.

Figure 2

Least square means for Hamilton Depression Rating Scale-17 (HAMD) total scores by baseline HAMD severity level: low (a, top figure), average (b, middle figure), and high (c, bottom figure). The presented least square means are based on the model fit to the entire sample and hence the sample in each figure is the same. (a) Estimated least square means for HAMD scores by group at ‘low’ baseline depression severity, ie, HAMD scores=1 SD below the mean (baseline HAMD score=18). There were no significant differences between ketamine groups. (b) Estimated least square means for HAMD scores by group at ‘average’ baseline depression severity, ie, baseline HAMD score=23. (c) Estimated least square means for HAMD scores by group at ‘high’ baseline depression severity, ie, baseline HAMD scores=1 SD above the mean (baseline HAMD score=28). Significant differences between ketamine groups, *p<0.05, ⁺p<0.1 (total n=71). PBO, saline placebo.

Figure 3

Least square means for Hamilton Depression Rating Scale-17 (HAMD) emotional cluster (somatic anxiety, psychological anxiety, guilt and delusions, loss of interest, depressed mood) symptom scores by baseline emotional cluster severity level: low (a, top figure), average (b, middle figure), and high (c, bottom figure). The presented least square means are based on the model fit to the entire sample and hence the sample in each figure is the same. (a) Estimated least square means for HAMD emotional cluster scores by group at ‘low’ baseline emotional cluster severity, ie, baseline emotional cluster scores=1 SD below the mean. There were no significant differences between ketamine groups. (b) Estimated least square means for HAMD emotional cluster scores by group at ‘average’ baseline emotional cluster severity. (c) Estimated least square means for HAMD emotional cluster scores by group at ‘high’ baseline emotional cluster severity, ie, baseline scores=1 SD above the mean. Significant differences between ketamine groups, *p<0.05, ⁺p<0.1 (total n=71). PBO, saline placebo.

Figure 4

Least square means for Hamilton Depression Rating Scale-17 (HAMD) atypical symptom cluster (reduced libido, psychomotor slowing, suicidality, psychomotor agitation, hypochondriasis) scores by baseline atypical cluster severity level: low (a, top figure), average (b, middle figure), and high (c, bottom figure). The presented least square means are based on the model fit to the entire sample and hence the sample in each figure is the same. (a) Estimated least square means for HAMD atypical symptom cluster scores by group at ‘low’ baseline atypical cluster severity, ie, scores=1 SD below the mean. There were no significant differences between groups (total n=71). (b) Estimated least square means for HAMD atypical symptom cluster scores by group at ‘average’ baseline symptom cluster severity. (c) Estimated least square means for scores by group at ‘high’ baseline symptom cluster severity, ie, scores=1 SD above the mean. Significant differences between ketamine groups, *p<0.05, ⁺p<0.1 (total n=71). PBO, saline placebo.

Figure 5

Plasma levels of ketamine (a, top figure) and norketamine (b, bottom figure) by dose for patients in this study. Plasma levels are presented as nM/ml and as mean±SE.