Low-Dose Ketamine Infusion for the Treatment of Multiple Sclerosis Fatigue
Abstract
Multiple sclerosis (MS) is the leading cause, after trauma, of disability in young adults. In MS, inflammation damages the covering sheets of nerves (called myelin) and can eventually damage and destroy nerve cells. Fatigue is the most common and one of the most disabling symptoms of MS. Unlike healthy individuals, many people with MS feel exhausted all the time (even without or with minimal physical or mental exertion) and require prolonged rests and frequent naps. Fatigue negatively affects their quality of life and is a significant cause of disability and unemployment. Neurologists frequently prescribe a wide range of medications to people with MS to improve their fatigue. However, we recently completed a large clinical trial and showed that none of these medications help with MS fatigue better than a placebo (an inactive substance). Based on this finding, there is an urgent need to develop new treatments for this common and disabling symptom of MS. One of the important chemicals in the brain is glutamate. It is an amino acid that has a significant role in communication between nerve cells. We previously reported that a medication that blocks glutamate action in the brain might worsen the fatigue in people MS. Based on these observations, we hypothesized that glutamate is an important chemical in regard to MS fatigue. Ketamine is a medication that indirectly increases the release of glutamate in the brain. Although it was approved for human anesthesia several decades ago, researchers found that a low dose of ketamine has a solid and rapid anti-depressant effect. In a trial of ketamine in patients with mood disorders, investigators reported major and long-lasting effects of this medication on fatigue severity. This report and our prior observation regarding the possible role of glutamate in MS fatigue motivated us to perform a small (pilot) randomized trial of low-dose ketamine in people with MS fatigue. We showed that compared to patients who received a placebo, the patient-reported fatigue on day 28 after one single infusion of ketamine was significantly improved. This study was carefully designed to reduce the risk of bias (error); however, it was small (18 participants), and we could not draw a firm conclusion regarding the effects of ketamine in MS fatigue. In the proposed study, we aim to show the effect of ketamine in a larger number of people with MS. We also aim to find out if repeated infusions of ketamine are better than one in alleviating fatigue and whether the effects of ketamine last longer than 28 days. To achieve these goals, we will perform a randomized, double-blind, placebo-controlled clinical trial. We will recruit 110 patients with MS fatigue. After signing up for the study, subjects will be measured for fatigue, sleepiness, depression, and pain with standardized questionnaires. We will use midazolam for comparison to keep the research participants and researchers unaware of what medication each participant is receiving (to avoid skewing the results). Midazolam is a medication with no effect on fatigue but some sedative effects to mimic ketamine effects. One-third of participants will receive two infusions of ketamine, four weeks apart, 1/3 will receive one infusion of ketamine, followed by one infusion of midazolam, and 1/3 will receive an infusion of midazolam, followed by an infusion of ketamine. Aside from screening and infusion visits, all other evaluations will be done remotely (through phone, text, and email). Participants will be followed for eight weeks after the first infusion. Fatigue, sleepiness, depression, and pain will be measured by standardized questionnaires throughout these eight weeks. We will use a smartphone app to more frequently measure fatigue and its fluctuations and the amount of physical activity. With this study design, we will be able to answer the study questions (whether ketamine is better than a placebo in improving fatigue, if repea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210729
Entities
People
- Bardia Nourbakhsh
Organizations
- Johns Hopkins University
- United States Army