DNA methylation changes in a pharmaco-epigenomic EWAS in depression: comparing fixed and response-guided dosing paradigms for ketamine in the KADS trial

DNA methylation is a dynamic biomarker suited to investigate processes, e.g., treatment response. We investigate DNA methylation changes in different dosing paradigms for ketamine (s.c.) vs. midazolam (s.c.) in treatment resistant depressed patients (the Ketamine for Adult Depression Study – KADS). After a 4-week randomized controlled trial (RCT) DNA methylation data (Illumina Infinium MethylationEPIC 850k BeadChip) were available for 87 patients, with 76 having DNA methylation data at baseline too. Patients received either ketamine or midazolam. Initially dosing was fix, however, following a protocol amendment, newly recruited patients received the clinically more effective response-guided ‘flexible’ dosing. We performed cross-sectional and paired longitudinal DNA methylation analyses, the latter with focus on differentially methylated regions (DMR), comparing treatment with ketamine and midazolam, as well as fixed and flexible dosing. We used R-packages RnBeads and comb-p for quality control and statistical analyses, and DMR identification, respectively. P-values were False-discovery-rate (FDR)-corrected (Benjamini Hochberg). Only the response-guided cohort in the ketamine vs. midazolam comparison returned one epigenome-wide significant CpG (cg15945600; PDCD6; p-valFDR < 0.05). Flexible dosing (midazolam + ketamine) vs. fixed dosing (midazolam + ketamine) returned a suggestive hit (cg20023762, NEDD9; p-valFDR < 0.10). The flexibly dosed ketamine condition returned the only statistically significant DMR in the longitudinal analyses (p-valFDR = 0.0045; CAPS2/GLIPR1L2). The clinically more effective response-guided paradigm has a correlate at the DNA methylation level with most pronounced DNA methylation changes in the flexibly dosed ketamine group. Pharmaco-epigenomics in Psychiatry, as a growing field, facilitates interpretation of DNA-methylation dynamics for treatment response in depression.