Pharmacotherapy in Disorders of Consciousness: A Mechanism-Based Review

Disorders of consciousness pose major therapeutic challenges owing to the complexity of underlying brain dysfunctions. Current pharmacological interventions explored in disorders of consciousness target distinct molecular systems, including dopaminergic modulators (amantadine, levodopa, apomorphine, bromocriptine, selegiline, methylphenidate, and modafinil), GABAergic agents (zolpidem and baclofen), and other neuromodulatory compounds acting on glutamatergic, opioid, or serotonergic receptors (ketamine, remifentanil, and psilocin). These treatments aim to modulate disrupted neural circuits, including the mesocircuit, a thalamocortical-striatal network critically involved in consciousness and motor control. This review explores the pathophysiological mechanisms underlying disorders of consciousness and the pharmacological profile of these agents. It summarizes reported clinical improvements and discusses determinants of therapeutic response, highlighting the role of biomarkers derived from neurophysiological and neuroimaging assessments. Safety profiles associated with these treatments are also critically evaluated to guide clinical decision making. By integrating current knowledge on pharmacological modulation of key neural systems, including dopaminergic and GABAergic pathways, this article provides a comprehensive framework for understanding treatment strategies in disorders of consciousness.