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

J Affect Disord. 2016 Apr;194:115-9. doi: 10.1016/j.jad.2016.01.009. Epub 2016 Jan 19.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bipolar Disorder / drug therapy*
  • Cross-Over Studies
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Double-Blind Method
  • Fatigue / prevention & control*
  • Female
  • Humans
  • Ketamine / therapeutic use*
  • Male
  • Middle Aged
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Retrospective Studies
  • Treatment Outcome


  • Receptors, N-Methyl-D-Aspartate
  • Ketamine