Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disease of the
central nervous system and, after trauma, is the most common cause of disability in young
adults, affecting more than 400,000 individuals in the US. Of all the symptoms that can occur
with MS, chronic fatigue is the most common and disabling, reported by at least 75% of
patients at some point. Fatigue limits patients' daily activities, and challenges employment,
resulting in substantial socioeconomic consequences. Despite this negative impact, fatigue
treatments have been inconsistently studied, in part due to poorly understood underlying
pathophysiological mechanisms. Yet to be defined biological processes and lack of clear
treatment targets have also hampered the development of drugs for fatigue. As a result, there
are no medications approved by the Food and Drug Administration (FDA) for the treatment of MS
fatigue.
The investigators recently reported that riluzole, a medication with anti-glutamatergic
effects, increased the fatigue severity in patients with relapsing MS who had participated in
a clinical trial evaluating potential neuroprotective effects of riluzole versus placebo.
Three other clinic trials which examined memantine effects on cognition in patient with MS
also reported worsening fatigue as a major side effect. Memantine main mechanism of action is
blocking the N-methyl D-aspartate (NMDA) glutamate receptor. These observations prompted the
investigators that glutamatergic transmission probably plays an important role in fatigue
pathogenesis and modulating these pathways could have potential therapeutic effect on
MS-related fatigue. A recent paper reported that ketamine, an NMDA receptor blocker with
different kinetics compared to memantine, had a strong and prolonged effect in reducing
fatigue in bipolar patients who participated in a clinical trial, evaluating anti-depressive
effects of ketamine versus placebo. Interestingly, the effect of ketamine on fatigue was
independent of its antidepressant effects.
The primary objective of this study is to determine if modulating glutamatergic transmission
with ketamine is safe and efficacious in improving MS-related fatigue. These objectives will
be answered in a proof of concept, randomized controlled trial of ketamine versus an active
placebo (midazolam) in patients with relapsing or progressive MS who have clinically
significant fatigue.
18 patients with MS and reported fatigue, will be randomized 2:1 to one infusion of ketamine
0.5 mg/kg over 40 minutes versus one infusion of midazolam 0.05 mg/kg over 40 minutes.
Midazolam is chosen as an active placebo to keep the participants blinded to participants'
medication assignment. Primary outcome of the study will be Daily Fatigue Severity measured
daily from day one through day seven post-infusion.
Secondary outcomes of the study include other fatigue questionnaires, depression and
sleepiness. The length of study will be around 28 days.