Pilot randomized active-placebo controlled double-blind trial of low dose ketamine for the treatment of multiple sclerosis-related fatigue (1642)

Objective: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. Background: Fatigue is a common and disabling symptom of multiple sclerosis (MS). Intravenous administration of low-dose ketamine, a modulator of glutamatergic transmission might improve fatigue in patients with mood disorders. Design/Methods: In this double-blind, randomized, parallel-group, active placebo-controlled trial, 18 subjects with MS and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) over 40 min or midazolam (0.05 mg/kg). The primary outcome measure was change in Daily Fatigue Severity (DFS), a single question asking the participants to rate fatigue severity from zero (no fatigue) to 10 (the most severe fatigue) for seven days post-infusion. Secondary outcomes included fatigue severity scale (FSS), NeuroQoL-Fatigue, Epworth Sleepiness Scale (ESS), and Beck Depression Inventory (BDI-II), measured on days 7 and 14 and modified fatigue impact scale (MFIS) measured on day 28 post-infusion. We analyzed changes in all outcomes using generalized estimating equations. Results: 18 participants (aged: 45.7±11.3y; 61% male) were enrolled; 12 participants received ketamine, and 6 participants received midazolam. Side effects of ketamine were largely transient and included dizziness, numbness, euphoria, impaired concentration, and elevated blood pressure. There was no significant change in the DFS after seven days (difference in the rate of change in DFS score per day between ketamine vs. midazolam: −0.10 point; 95% CI: −0.32, 0.12; p=0.40). We observed a trend in improved FSS scores at 1-week (−6.5 points; 95% CI: −13.4, 0.41; p=0.07) and a significant improvement in MFIS score on day 28 post-infusion (−13.5 point; 95% CI: −23.5, −3.5; p=0.0008). ESS scores improved significantly (−2.2 point; 95% CI: −4.2, −0.2; p=0.04). No changes in Neuro-QoL fatigue or BDI-II were observed (both p>0.05). Conclusions: Ketamine infusions were safe and well-tolerated. Results suggest a potential role for modulators of glutamatergic pathways in the treatment of MS-related fatigue. Disclosure: Dr. Fitzgerald has nothing to disclose. Dr. Morris has nothing to disclose. Dr. Soroosh has nothing to disclose. Dr. Balshi has nothing to disclose. Dr. Kaplin has nothing to disclose. Dr. Nourbakhsh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Jazz Pharmaceutical.