Despite advancements in the neuroscience of consciousness, no new effective medications for disorders of consciousness (DOC), such as coma or vegetative state, have been discovered in over a decade. Repurposing existing FDA-approved drugs for DOC is crucial for improving clinical management and patient outcomes.
To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from April 2012 to April 2024 tested the model’s predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 3,879 coma patients.
Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. Incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, were linked to higher coma recovery rates compared to non-incretin-based diabetes medications, after matching patients by age, gender, initial GCS score, coma etiology, and glycemic status (95% confidence interval of 0.63–12.02%, p = 0.0013). Preclinical studies identified several pathways through which saxagliptin may aid awakening from DOC: restoring neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-beta, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage.
Our findings suggest saxagliptin as a potential novel therapeutic agent for DOC. Further prospective clinical trials are needed to confirm its efficacy and safety in DOC.