Effects of Adjunctive Ketamine Intravenous Infusion in Taiwanese Patients with Treatment-Resistant Depression: Antidepression, Antisuicidality, BDNF Val66Met, and Brain Imaging

Abstract

About 21% of Taiwanese patients with major depression developed treatment-resistant depression (TRD) during 1-year follow-up in Taiwan. TRD was commonly coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behaviors, and a high relapse rate. From 2012 and 2015, we had conducted the first randomized, double-blind, placebo control trial in Asian countries to examine the therapeutic efficacy of a single low-dose ketamine infusion in Taiwanese patients with TRD. Seventy one subjects were evenly distributed in three dose groups with 0.5 mg/kg, 0.2 mg/kg, and placebo, respectively. Responder was identified by response (≥50% reduction of mood ratings) at any two daily HAMD measures during the period of 24–96 h (day 2–5) post-ketamine infusion. There was a significant difference in the response rate across the three groups (0.5 mg/kg: 45.8%; 0.2 mg/kg: 39.1%; placebo: 12.5%; p = 0.03), which is much lower than that in the Caucasians (70%). Two factors might be related: lower serum ketamine levels and lower Val/Val allele percentage in BDNF Val66Met genotyping found in the Taiwanese patients. In addition to the rapid antidepressant effect of ketamine, a greater antisuicidal effect (59%) was also identified. The former may only account for 52.7% of the latter, indicating that the antisuicidality may be independent from antidepressiveness. Single dose of ketamine only resulted in short-lived psychedelic/dissociation adverse effect, which was resolved within 2 h post-infusion. Up to present, no long-term side effects were identified, given a single-dose administration. Using 18F-FDG-PET scanning and 24 h post-ketamine infusion, glucose metabolism of the prefrontal cortex (PFC), supplementary motor area (SMA), and dorsal anterior cingulate cortex (dACC) were activated immediately (40 min post-infusion), and activation of SMA and dACC could sustain for 1 day, which may contribute to the persistent antidepressant effect of ketamine beyond its half-life, suggesting that a short activation in the PFC engendered by ketamine infusion may be a kindler, facilitating the persistent increase in glucose metabolism in the SMA and dACC; therefore, the PFC may be still considered to play a key role in improving TRD. These findings were also supported by a simple wearable forehead EEG monitoring from baseline to 40 min post-infusion, revealing that ketamine may increase the theta and low alpha power and decrease asymmetry in the PFC. Finally, a maintenance trial in a double-blind, randomized fashion using a partial NMDA agonist, d-cycloserine (DCS) vs. placebo, was conducted in the ketamine responders. This DCS augmentation treatment was not superior to placebo in maintaining the initial antidepressant response to ketamine infusion, but DCS did appear to maintain the antisuicidal effect during the 6-week follow-up study.