Ketamine Improves MDD and PTSD while Slowing Aging

Objective & Rationale

Study Goal and Scientific Context: The study was designed to assess shifts in epigenetic aging, DNA methylation, and immune cell composition following ketamine treatment in patients with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD). Researchers hypothesized that ketamine could reduce premature and/or accelerated biological aging and affect associated morbidities. The study addressed the gap in understanding ketamine's molecular mechanisms beyond symptom relief, given that MDD and PTSD mimic non-pathological aging, increasing risks for chronic diseases like cardiovascular and metabolic disorders. The epigenetic clocks used in this research help analyze mortality and healthspan impacts of the intervention, indicating that a rapid ketamine intervention could improve outcomes in treatment-resistant cases while also positively affecting non-neurologic symptomology.

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Methodology

Design: Pilot, single-arm, longitudinal interventional study with pre- and post-treatment assessments (designed for subjects to serve as their own controls).‍

Population: Outpatients with treatment-resistant MDD and/or PTSD, an illness duration ≥2 weeks (MDD) or ≥4 weeks (PTSD), and a mean age ~39 years; exclusions included severe comorbidities or contraindications to ketamine.‍

Intervention: Six intravenous subanesthetic ketamine infusions administered over 2-3 weeks.

‍Duration: 2-3 weeks for the intervention phase, with blood samples collected at baseline and ~10 days after the final infusion.

‍Epigenetic Measurements: DNA methylation profiled using Infinium MethylationEPIC 850k BeadChip; epigenetic clocks included OMICmAge, GrimAge V2, PhenoAge, DNAmPhenoAge, DunedinPACE, SystemsAge, and DNAmTL; epigenetic biomarker proxies (EBPs) measured proteins, metabolites, and clinical traits; Marioni EpiScores analyzed proteins; immune cell deconvolution occurred via EpiDISH; epigenome-wide association studies (EWAS) were carried out for differentially methylated CpGs with Gene Ontology enrichment.

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Key Findings

Results: An interventional course of sub-anesthetic ketamine infusions significantly alleviated MDD and PTSD symptoms but did not cause notable changes as measured by standard clinical lab tests. Epigenetic analyses revealed significant reductions in biological age as measured by the OMICmAge clock, which is uniquely able to capture biomarker proxies’ ability to detect associations with depression, PTSD, and, possibly, other psychiatric conditions. Other clocks showed trends toward reductions and indicated inflammation linked with increased morbidities. Post-intervention, shifts in metabolic pathways and circadian sleep regulation were respectively correlated with biomarkers of clinical improvement and improved sleep patterns. Overall, findings suggest ketamine's rapid effects extend to epigenetic reversal of aging in MDD/PTSD, potentially via neuroimmune, metabolic, and circadian mechanisms, though the small sample and lack of control group warrant larger confirmatory studies.

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‍Standard Metrics: % change in biological age, direction of effect, significance OMICmAge: Δ = -1.81 years; GrimAge V2; PhenoAge; DunedinPACE and SystemsAge: non-significant trends toward decrease; DNAmTL: no significant change.

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‍Academic Significance: Using longitudinal measurements allowed subjects to serve as their own controls over time, while the use of multiple biological clocks and epigenetic analyses yielded a more nuanced picture of interventional effects.

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‍Clinical Significance: Though a longer study period could be required to capture the full effects of the intervention, results showed significant reductions in self-reported MDD and PTSD symptoms, coupled with indications of arrested aging (i.e., a slowing of the accelerated aging patterns associated with MDD and PTSD and a return toward healthier aging rates) and improved sleep and digestion patterns. The study also shows that epigenetic methylation patterns could be more clinically informative than standard laboratory tests in capturing functional, symptom-related outcomes of interest.