title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Institute of Nursing Research, Division of Intramural Research, National Institutes of Health, 31 Center Drive, MSC 2178, Bethesda, MD 209892, USA. Electronic address: saliganl@mail.nih.gov.
authors.forename: Leorey N
authors.initials: LN
authors.lastname: Saligan
authors.affiliation: Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, 10 Center Drive, Rm 4N222, MSC 1381 Bethesda, MD 20892, USA. Electronic address: luckenbd@mail.nih.gov.
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.affiliation: Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, 10 Center Drive, Rm 4N222, MSC 1381 Bethesda, MD 20892, USA. Electronic address: elizabeth.slonena@nih.gov.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Slonena
authors.affiliation: Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, 10 Center Drive, Rm 4N222, MSC 1381 Bethesda, MD 20892, USA. Electronic address: rodrigo.machadovieira@nih.gov.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.affiliation: Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, 10 Center Drive, Rm 4N222, MSC 1381 Bethesda, MD 20892, USA. Electronic address: zaratec@mail.nih.gov.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000188:drug therapy*; D018592:Cross-Over Studies; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004311:Double-Blind Method; D005221:Fatigue / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: Depression; Fatigue; Glutamate; Ketamine; New therapeutics