Translating the immediate effects of S-Ketamine using hippocampal subfield analysis in healthy subjects-results of a randomized controlled trial

Anna Höflich,Christoph Kraus,Carlos A. Zarate,Siegfried Kasper,Dietmar Winkler,Rupert Lanzenberger,Rene Seiger,Dan Rujescu,Ruth M. Pfeiffer

doi:10.1038/s41398-021-01318-6

Abstract

Antidepressant doses of ketamine rapidly facilitate synaptic plasticity and modify neuronal function within prefrontal and hippocampal circuits. However, most studies have demonstrated these effects in animal models and translational studies in humans are scarce. A recent animal study showed that ketamine restored dendritic spines in the hippocampal CA1 region within 1 h of administration. To translate these results to humans, this randomized, double-blind, placebo-controlled, crossover magnetic resonance imaging (MRI) study assessed ketamine’s rapid neuroplastic effects on hippocampal subfield measurements in healthy volunteers. S-Ketamine vs. placebo data were analyzed, and data were also grouped by brain-derived neurotrophic factor (BDNF) genotype. Linear mixed models showed that overall hippocampal subfield volumes were significantly larger (p = 0.009) post ketamine than post placebo (LS means difference=0.008, standard error=0.003). Post-hoc tests did not attribute effects to specific subfields (all p > 0.05). Trend-wise volumetric increases were observed within the left hippocampal CA1 region (p = 0.076), and trend-wise volumetric reductions were obtained in the right hippocampal—amygdaloid transition region (HATA) (p = 0.067). Neither genotype nor a genotype–drug interaction significantly affected the results (all p > 0.7). The study provides evidence that ketamine has short-term effects on hippocampal subfield volumes in humans. The results translate previous findings from animal models of depression showing that ketamine has pro-neuroplastic effects on hippocampal structures and underscore the importance of the hippocampus as a key region in ketamine’s mechanism of action.

Highlights

Ketamine has emerged as a potent and rapid-acting treatment for patients with difficult-to-treat depression and acute suicidal ideation, leading to a major interest in its mechanism of action[1,2]
The linear mixed effects model (LMM) adjusted for sex, age, and total intracranial volume (TIV) showed that ketamine led to significantly larger hippocampal subfield volumes than placebo at 65 min post infusion
The results were generally similar when the model was adjusted for total hippocampal volume (THV) instead of TIV, with a slightly stronger main effect observed for drug (p = 0.008)

Summary

Introduction

Ketamine has emerged as a potent and rapid-acting treatment for patients with difficult-to-treat depression and acute suicidal ideation, leading to a major interest in its mechanism of action[1,2]. One of its several major mechanisms of antidepressant action is the restoration of synaptic plasticity deficits, which is in line with evidence of decreased dendrites in animal models of depression as well as in depressed patients[6]. Höflich et al Translational Psychiatry (2021)11:200 ketamine triggered the release of brain-derived neurotrophic factor (BDNF)/TrkB, with downstream effects on the mechanistic target of rapamycin (mTOR) via αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and L-type voltage-dependent Ca2+channels[7]. NMDA receptor blockade by ketamine has been reported to deactivate eukaryotic elongation factor-2 (eEF2 kinase), reducing eEF2 phosphorylation and increasing BDNF translation[11]

Methods

Results

Conclusion