Intravenous methylphenidate for acute traumatic disorders of consciousness: A phase 1 dose-finding and target engagement study
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Background
There are currently no therapies proven to accelerate recovery of consciousness for patients with acute severe traumatic brain injury (TBI) in the intensive care unit (ICU). Dopaminergic stimulation is a candidate strategy for reactivating subcortical networks that underly consciousness.
Methods
We performed an open-label, Phase 1 safety and dose-finding study of intravenous methylphenidate (IV MPH) in ICU patients with acute disorders of consciousness (DoC) caused by severe TBI. IV MPH, a potent and rapid-acting dopamine reuptake inhibitor, was administered in daily doses of 0.5, 1.0, and 2.0 mg/kg. The primary outcome measure was the number of adverse events (AEs) at each dose. IV MPH pharmacokinetics were measured for 24 hours after each dose. Pharmacodynamic target engagement – the effect of IV MPH on brain networks – was measured using EEG and resting-state functional MRI (rs-fMRI). A pharmacodynamic response was defined by change-point analysis of EEG and rs-fMRI time-series data. Behavioral responses were assessed using the Coma Recovery Scale-Revised (CRS-R).
Results
Between August 24, 2020, and April 1, 2024, we screened 488 ICU patients with TBI and enrolled 9 males (age 23-79 years) with acute traumatic DoC: coma (n=3), vegetative state/unresponsive wakefulness syndrome (n=3), and minimally conscious state (n=3). There were no serious AEs at any dose. Mild-moderate AEs observed at 1.0 mg/kg or 2.0 mg/kg included insomnia, emesis, paroxysmal sympathetic hyperactivity, and transaminitis. Maximum plasma MPH concentration ranged from mean (SD) 312.7 (100.6) ng/mL to 1319.5 (433.8) ng/mL and occurred within a median of 7-14 minutes across doses. Pharmacodynamic responses were observed via EEG in 7/8 participants who received 0.5 mg/kg (1/9 did not undergo EEG), 6/9 who received 1.0 mg/kg, and 4/6 who received 2.0 mg/kg. One of two patients who completed rs-fMRI showed a pharmacodynamic response. CRS-R level of arousal increased within 15 min of the IV MPH bolus for 6/9 participants at 0.5 mg/kg, 5/9 at 1.0 mg/kg, and 0/6 at 2.0 mg/kg.
Conclusions
For patients with acute severe TBI, IV MPH may be safe at daily doses of 0.5-2.0 mg/kg. EEG and rs-fMRI evidence of target engagement, accompanied by rapid behavioral increases in arousal, provides proof-of-principle that IV MPH reactivates subcortical networks underlying arousal, a prerequisite of consciousness. These findings support further evaluation of IV MPH in controlled trials.
