An assessment of the anti-fatigue effects of ketamine from a double-blind, placebo-controlled, crossover study in bipolar disorder

Abstract

Background: Fatigue is a multidimensional condition that is difficult to treat with standard monoaminergic antidepressants. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist produces rapid and robust improvements in depressive symptoms in treatment-resistant depression. However, there is a dearth of literature examining the anti-fatigue effects of ketamine. We hypothesize that ketamine will rapidly improve fatigue symptoms in treatment-resistant depressed patients.

Methods: This is an exploratory analysis of data obtained from two double-blind, randomized, placebo-controlled, crossover trials. A total of 36 participants with treatment-resistant bipolar I or II disorder in a depressive episode (maintained on therapeutic levels of lithium or valproate) received a single infusion of ketamine hydrochloride intravenously (0.5 mg/kg over 40 min) or placebo. A post-hoc analysis compared fatigue scores on ketamine vs. placebo at 10 time points from baseline through 14 days post-treatment using the National Institute of Health-Brief Fatigue Inventory.

Results: A linear mixed model showed that ketamine significantly lowered fatigue scores compared to placebo from 40 min post-treatment to Day 14 with the exception of Day 7. The largest difference in anti-fatigue effects between placebo and ketamine was at day 2 (d=0.58, p<0.05). The effect remained significant after controlling for changes in non-fatigue depressive symptoms.

Limitation: The retrospective nature and a small sample size are study limitations.

Conclusions: Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders.

Keywords: Depression; Fatigue; Glutamate; Ketamine; New therapeutics.

Published by Elsevier B.V.

Figures

Figure 1

Mean fatigue scores with ketamine and placebo. Fatigue was measured by the National Institutes of Health – Brief Fatigue Inventory. Fatigue significantly decreased 40 minutes post treatment until the end of the study (Day 14) with the exception of day 7.

Figure 2

Study responders. Participants who had >50% reduction in fatigue score compared to baseline with placebo or ketamine infusion. Fatigue measured by the National Institutes of Health – Brief Fatigue Inventory.

Figure 3

Potential Anti-fatigue effects of ketamine. Ketamine increases extracellular glutamate release favoring AMPA receptors over NMDA receptors. Post-synaptically, administration of ketamine leads to upregulation of BDNF levels by inhibiting eEF2 kinase. In addition, activation of the mTOR-dependent protein synthesis leads to enhancement of synaptogenesis. We hypothesize that aberrant glutamate signaling plays a role in fatigue pathogenesis by affecting functional brain connectivity and altering neurobehavioral plasticity. Ketamine alleviate fatigue symptoms by targeting these aberrant glutamate signaling pathways.