Effect of Ketamine on Fatigue Following Cancer Therapy

Although the underlying mechanisms of fatigue have been studied in several disease conditions (Bower et al., 2002; Brola et al., 2007), the etiology, mechanisms, and risk factors remain elusive, and this symptom remains poorly managed. Fatigue is conceptualized as a multidimensional symptom which incorporates temporal, sensory, cognitive/mental, affective/emotional, behavioral, and physiological dimensions (Voss, et al., 2006). We recently observed increased levels of neutrophic factors (brain-derived neurotrophic factor (BDNF)), glial-cell line derived neurotrophic factor (GDNF) and synaptosomal-associated protein (SNAP) from the serum samples of fatigued prostate cancer men receiving external beam radiation therapy, suggesting that fatigue may be a component of depression and the N-methyl-D-aspartate (NMDA) receptors may be involved in fatigue intensification during cancer therapy. Ketamine is an NMDA receptor antagonist and has been reported to treat acute depression (Berman et al., 2000; Prommer, 2012; Aan Het Rot et al., 2012). Depression and cancer-related fatigue (CRF) are highly correlated during cancer therapy (Portenoy and Itri, 1999; Roscoe et al., 2002, Servaes et al., 2002, Aan Het Rot et al., 2012).

This double-blind, placebo-controlled, cross-over study will explore the effect of a single, intravenous dose of ketamine in providing immediate reduction of fatigue following radiation therapy. The primary objective of the study is to determine the immediate effect of a single intravenous dose of ketamine in reducing clinically-significant worsening of fatigue following radiation therapy. The secondary objectives of this study are to investigate the levels of cytokines (i.e., tumor necrosis factor-alpha (TNFalpha), insulin-like growth factor 1 (IGF-I), interleukin (IL)-6, IL-8, transforming growth factors (TGF)alpha and beta), neurotrophic factors (i.e., BDNF, GDNF, SNAP), metabolic (i.e., apoliprotein, arginine, arginase), and mitochondrial (i.e., oxygen consumption rate, glycolysis rate) markers from peripheral blood before and after treatment with ketamine or placebo and relate these levels to self-reported fatigue, depression, and health-related quality of life (HRQOL) scores. This study also aims to measure cognitive function and skeletal muscle strength of patients before and after treatment with ketamine or placebo and relate these findings with self-reported fatigue, depression, and HRQOL scores.

We will enroll 40 subjects who completed radiation therapy for cancer within at least 3 months. The primary outcome measure of the study is the change in self-reported fatigue score after receiving a single intravenous dose (0.5 mg/kg) of ketamine or placebo. The secondary outcomes of this study include: the cytokine profile (e.g. TNFalpha, IGF-I, IL-6, IL-8, TGFalpha and TGFbeta), neurotrophic factors (e.g. BDNF, GDNF), metabolic (i.e., apoliprotein, arginine, arginase), and mitochondrial markers (i.e., Complex I-V, manganese superoxide dismutase (MnSOD), oxygen consumption rate, glycolysis rate) from blood samples; cognitive function test scores; depression scores; HRQOL scores; and skeletal muscle strength of study participants before and after a dose of ketamine or placebo.