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

This double-blind, randomized, parallel-group, placebo-controlled trial study (n=71) examines adjunctive ketamine’s dose-related effects (14-35mg) in Taiwanese patients with treatment-resistant depression (TRD). This first such report showing the dose-related efficacy of ketamine for TRD, and characterized ketamine effects in a genotyped Chinese group in which 83% of patients had at least one copy of the BDNF gene’s lower functioning Met allele.

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.“

Authors: Tung-Ping Su, Mu-Hong Chen, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ralitza Gueorguieva, Pei-Chi Tu, Ya-Mei Bai, Chih-Ming Cheng & John H. Krystal

Summary

INTRODUCTION

Ketamine is a rapid and robust antidepressant that produces clinical response in 50 – 75% of patients and remission in 30% of patients 24 h following a single 0.5 mg/kg dose.

Ketamine, a drug used to treat depression, has never been rigorously tested for its antidepressant effects. It is possible that lower doses of ketamine could retain efficacy while having lower side effects.

Ketamine has not been studied in diverse races or ethnicities and the presence of a less functional Met allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene may influence the antidepressant response to ketamine. However, a small study in Chinese patients found evidence of efficacy.

In a double-blind, randomized, parallel-group, placebo-controlled study, 0.5 mg/kg of R/S-ketamine was found to be effective in treating treatment-resistant depression in genotyped Taiwanese patients.

Screening Process and Patient Selection

Patients with major depressive disorder (MDD) recurrent without psychotic features, who had failed to respond to more than two adequate antidepressant trials, were recruited at the outpatient clinic of Taipei Veterans General Hospital (TVGH) from 2012 to 2015 and provided written informed consent before study entry.

Study Design and Procedures

Patients completed a 40 min intravenous infusion test day and were randomized to receive saline or R/S-ketamine hydrochloride at doses of 0.2 or 0.5 mg/kg. Blood pressure, heart rate, and digit pulse oximetry were monitored repeatedly preinfusion and 10, 20, 30, 40, 80, 120, and 240 min following the initiation of test infusions. For ketamine infusion test days, assessments were evaluated in relation to baseline. Subsequent assessments were based on the prior 24 h, and patients were discharged from testing 240 min after infusion.

Laboratory Procedures

Genomic DNA was extracted from EDTA-containing venous blood samples and amplified using PCR with the primers 5′-ACTCTGGAGAGCGTGAAT-3′ and 5′-AT ACTGTCACACACGCTC-3′. The Val66Met polymorphism was differentiated with the NlaIII restriction enzyme and the genotyping was processed blinded to clinical data.

Plasma levels of ketamine and norketamine were measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the extraction procedure consisting of protein precipitation of serum samples with 10% trichloroacetic acid (TCA) and subsequent centrifugation. The limits of detection and limits of quantification were set at 10 ng/ml for K and NK, respectively.

Statistical Analyses

A mixed effects regression model was used to assess ketamine effects on HAMD during the treatment period. A baseline HAMD score was used as a between-subject predictor.

Ketamine effects on features of depression were evaluated separately using the same model as for the overall score. The results showed that ketamine decreased scores in all three symptom clusters.

To evaluate the effects of BDNF genotype on depression severity, genotype and baseline severity and time were added to a mixed model.

Responder status was identified by 50% reduction of mood ratings on two daily HAMD measures. Ketamine and norketamine levels were compared between groups, across time points, and by responder status.

Study Subjects

Patients were predominately female between 40 and 50 years of age, and not obese. The rate of moderate-to-severe suicidality was greater in the patients receiving 0.5 mg/kg of ketamine than in those receiving 0.2 mg/kg of ketamine and placebo.

HAMD Score

Ketamine effects on depression severity differed by group, time, and baseline severity. We assessed group differences overall and by time point, and reported the results at different levels of baseline depression severity.

The 0.5 mg/kg dose of ketamine was statistically significantly better than placebo, but the 0.2 mg/kg dose was not. The 0.5 mg/kg dose was more effective than the 0.2 mg/kg dose at high baseline depression severity.

HAMD Factor Scores

There were significant interactions between ketamine dose and baseline severity for emotional symptom cluster scores and between group, time, and baseline atypical severity for atypical symptom cluster scores.

The 0.5 mg/kg ketamine group was significantly different from the 0.2 mg/kg and placebo groups at high baseline depressive severity, but not from the 0.2 mg/kg group at mean baseline severity. The three groups were not different from each other at low baseline severity.

Response Rate

The response rate was higher in the 0.5 mg/kg group than the 0.2 mg/kg group and the placebo group than the 0.5 mg/kg group.

Response Rate by BDNF Val66Met Genotype

In this Chinese study, the distribution of BDNF genotypes was not significantly different between subjects with the Val66Met BDNF polymorphism and those with the Met allele. The BDNF genotype was not a significant predictor of ketamine response.

Ketamine and Norketamine Levels and Clinical Outcome

Plasma ketamine and norketamine levels were dose related and varied by time point, but there were no significant differences by responder status.

Hemodynamic Effect of Ketamine

There were statistically significant dose-related ketamine effects on systolic blood pressure (SBP) and diastolic blood pressure (DBP) with largest increases occurring at the 40 min time point. However, by the 2 h time point, the levels were back to baseline.

Heart rate increased in a dose-related manner in the 0.5 mg/kg and 0.2 mg/kg groups, and then trended down in the placebo group.

Tolerability and Safety

Ketamine had no unexpected clinically significant adverse events, and no significant doserelated psychosis was observed. Nausea occurred in 6 patients, and one patient had a transient behavioral effect.

DISCUSSION

This study found that ketamine had doserelated antidepressant effects and was most effective at 0.5 mg/kg. The lower 0.2 mg/kg dose was not significantly better than placebo in reducing HAMD scores, suggesting that any tolerability benefits provided by this lower dose are offset by reduced efficacy.

Ketamine treated depression symptoms to varying degrees and for varying durations, suggesting differential modulation of brain circuits underlying these symptoms. Ketamine did not reduce the insomnia-related cluster of depression symptoms, but daytime fatigue was reported to respond to ketamine in another trial.

The results of the current study suggest that R/S-ketamine is less potent than S-ketamine, and that the difference in efficacy between 0.2 mg/kg R/S-ketamine and 0.2 mg/kg S-ketamine may be due to the higher occupancy of NMDA-R by S-ketamine.

Ketamine showed significant efficacy in patients with more severe depression, but not mild depression. The inclusion of patients with relatively mild depression complicates the interpretation of their data.

This study found no evidence that the Met allele of the Val66Met polymorphism in the BDNF gene is associated with reduced ketamine efficacy in patients with treatment-resistant unipolar depression. The response to ketamine within dose group did not correlate with the plasma blood level.

Ketamine has dose-related antidepressant effects that are moderated by baseline depression severity, and it is effective in a Chinese population. Further research is needed to determine whether higher ketamine doses would result in higher response rates.

FUNDING AND DISCLOSURE

The authors declare no conflict of interest, but Dr Krystal has financial interests in several pharmaceutical companies. He receives over $5000 in income from the Society of Biological Psychiatry for editing the journal Biological Psychiatry.

ACKNOWLEDGMENTS

We thank Jennifer Vessicchio for her assistance with the preparation of this manuscript, all patients who kindly participated in this study, the research assistants, physicians, pharmacists, and nursing staffs at D020 Unit of Taipei Veterans General Hospital, and Dr Guang Cheng for his excellent opinions.