Pharmacological treatments in disorders of consciousness

Abstract Disorders of consciousness (DoC) are among the most severe and devastating neurological conditions. The poorly understood underlying pathophysiology of DoC renders the search for adequate treatment options particularly difficult. The aim of this narrative review is to provide an overview of currently available pharmacological treatments, report the limitations of current research, and discuss future directions, notably potential new treatments, advances in modelling approaches, potential mechanisms of action, and the development of a standardised registry. We review pharmacological treatments that promote the recovery of consciousness in patients with DoC acting on dopaminergic (amantadine, levodopa, apomorphine, methylphenidate, bromocriptine, modafinil, selegiline) and GABAergic (zolpidem, baclofen, midazolam) pathways, as well as other pharmacological treatments (tricyclic antidepressants, anticonvulsants, simvastatin) and the combination of different drugs. The literature includes a limited number of randomised controlled trials (RCTs) alongside a large body of retrospective studies and case reports, which are classified as class IV evidence. Reported improvements in arousal or functional responsiveness are inconsistent, reflecting marked heterogeneity in patient populations, dosing regimens, and outcome measures. Risk of bias assessment indicated that 12 of 22 RCTs (∼60%) exhibit some or high risk of bias. Multiple correspondence analysis (MCA) yielded a descriptive mapping of RCT characteristics, demonstrating how pharmacological trials in DoC are grouped. Although mechanistic hypotheses converge on dopaminergic, GABAergic, and thalamocortical modulation, the current literature on pharmacological treatments in DoC remains poorly reproducible. Given the significant methodological variability (e.g., study design, patient characteristics, outcome measures) across studies, current evidence does not allow firm conclusions regarding the most effective consciousness-enhancing pharmacological treatments in DoC. To make informed decisions in terms of pharmacological treatments and move towards personalised care for patients with DoC, rigorously designed multicentre controlled trials with harmonised outcome measures conducted with mechanistic and computational approaches are required. This can be achieved through an international registry to standardise data collection and improve replicability and reproducibility.