Combining DNA methylation features and clinical characteristics predicts ketamine treatment response for PTSD.
Amir Valizadeh, John D Roache, Xinyu Zhang, Ying Hu, Ralitza Gueorguieva, Lynnette A. Averill, Mohini Ranganathan, Zuoheng Wang, Douglas E Williamson, Paulo R Shiroma, Matthew J. Girgenti, Ismene L. Petrakis, Argelio L López-roca, Stacey Young-McCaughan, Terence M Keane, Alan L Peterson, Chadi G. Abdallah, John H. Krystal, Ke Xu
iScience January 16, 2026 DOI: 10.1016/j.isci.2025.114445 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Population | Participants in the CAP-ketamine trial with PTSD |
| Intervention | Ketamine |
| Topics | Esketamine Ketamine PTSD |
| Keywords | Mental state Precision medicine |
| Citations | 2 |
| Key findings | Peripheral DNA methylation patterns can identify individuals likely to benefit from ketamine for PTSD, with a methylation-derived score achieving 92.9% accuracy in distinguishing responders. |
Abstract
Post-traumatic stress disorder (PTSD) exhibits extensive clinical and biological variability, making treatment challenging. The Consortium to Alleviate PTSD (CAP)-ketamine trial, the largest randomized study of ketamine for PTSD, found no overall benefit of ketamine over placebo, underscoring the necessity to identify responsive subgroups. Using pre-treatment blood DNA methylation profiles and clinical measures from the CAP-ketamine trial, we applied machine learning to predict treatment response. A model based on 1,208 methylation sites achieved higher predictive accuracy than models using clinical variables alone, and combining both data types further improved performance. The methylation-derived score distinguished responders with 92.9% accuracy. The predictive CpGs were enriched near genes involved in glutamatergic signaling and immune regulation, as well as established PTSD risk loci. These findings suggest that peripheral DNA methylation patterns can identify individuals likely to benefit from ketamine, advancing precision approaches to PTSD pharmacotherapy.
Comparable studies
Other randomized controlled trials on ketamine for PTSD, most cited first.
Citations in the library
Cites 21
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry 2018
- Do the dissociative side effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders February 18, 2014
- A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. American Journal of Psychiatry January 5, 2021
and 16 more in the library