Trauma-focused therapies like Prolonged Exposure (PE) are recommended over medication for PTSD, but 30% to 50% of military and veteran patients do not show meaningful symptom improvement. Ketamine, an anesthetic that affects glutamate signaling, has shown in preclinical studies to improve extinction learning and reduce fear renewal. A planned randomized controlled trial will compare three ketamine infusions to an active placebo (midazolam) given alongside PE therapy in veterans with PTSD. Infusions occur 24 hours before PE sessions for the first three weeks. Out of 100 veterans, 80 are expected to reach the primary outcome assessment. Secondary outcomes include depression, anxiety, safety, cognition, and dropout rates. Results may clarify which components are essential and which patients benefit most.
Post-traumatic stress disorder varies greatly in its clinical and biological features, making treatment difficult. The largest randomized trial of ketamine for PTSD found no overall benefit over placebo, highlighting the need to identify which patients might respond. Using pre-treatment blood DNA methylation profiles and clinical data from that trial, machine learning models predicted treatment response. A model based on 1,208 methylation sites outperformed models using only clinical variables, and combining both data types improved accuracy further. The methylation-derived score identified responders with 92.9% accuracy. Predictive methylation sites were near genes involved in glutamatergic signaling, immune regulation, and known PTSD risk loci, suggesting peripheral DNA methylation patterns can guide precision pharmacotherapy for PTSD.