Ketamine treatment lowered epigenetic age markers in patients with depression and PTSD

Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are tied to cardiovascular and metabolic disease, reduced healthspan and premature mortality, outcomes that resemble accelerated aging. Epigenetic clocks, which read DNA methylation patterns to estimate biological age, have repeatedly shown advanced age in people with these conditions. This raises a question: can an effective, rapid-acting antidepressant also shift aging biomarkers? Ketamine, an NMDA receptor antagonist, offers a test case, yet its effects on epigenetic aging had not been well studied in patients with moderate-to-severe symptoms.

The researchers enrolled 20 outpatients at a Kentucky clinic (NCT05294835). All had MDD (PHQ-9 of 15 or higher) or PTSD (PCL-5 of 33 or higher) and had not remitted after at least one adequate standard medication trial. Participants received six subanesthetic infusions (0.5 mg/kg) over two to three weeks. Blood was drawn at baseline and ten days after treatment, yielding 40 samples. DNA methylation was measured on the Illumina EPIC array, and clinical labs covering about 60 tests were available for 16 participants.

Symptom scores fell after treatment on both the PHQ-9 and PCL-5, as expected. On the aging side, epigenetic age acceleration decreased in three second-generation clocks: OMICmAge, GrimAge V2 and PhenoAge. Age acceleration was calculated as the residual after regressing epigenetic age on chronological age, adjusted for batch-related control-probe principal components. Changes were tested with Wilcoxon signed-rank tests, with each participant serving as his or her own baseline. The excerpt available for this summary does not include the full results tables, so exact effect sizes are not reported here.

To understand what drove the clock changes, the team examined epigenetic biomarker proxies, which are methylation-based surrogates for clinical measures, metabolites and proteins. They also examined Marioni EpiScore protein estimates and immune cell composition. Significant changes were reported after multiple-testing correction based on independent degrees of freedom, and the authors say these changes are consistent with prior literature on ketamine's biological effects. They also correlated clock changes with clinical lab and questionnaire changes and ran mixed-effects models to test whether shifts in leukocyte composition explained the results.

The findings suggest that effective treatment of severe depression and PTSD may be accompanied by measurable changes in aging-related methylation signatures. They also suggest that GrimAge V2, PhenoAge and OMICmAge capture signals tied to clinical biomarkers. For clinicians and patients, the work hints that aging biomarkers could eventually serve as secondary readouts of treatment response. That remains speculative.

Important caveats apply. There was no control group, so placebo effects, symptom recovery, time-of-day variation in blood draws and regression to the mean cannot be separated from a ketamine effect. The sample was small and predominantly Caucasian. One participant stopped treatment after an adverse event that led to an emergency room visit. Follow-up was only ten days, so durability is unknown. Several authors are affiliated with TruDiagnostic, which performed the methylation analysis, and with the clinics involved.