Temporal Immune Effects of Oral Ketamine on Ptsd: Transcriptomic Evidence of Short-Term Inflammation Suppression and Long-Term Immune Remodelling

Background Ketamine has emerged as a promising rapid-acting treatment for post-traumatic stress disorder (PTSD), offering swift symptom relief. However, the molecular mechanisms underpinning its long-term therapeutic effects remain poorly understood. Aims & Objectives This study aimed to investigate the short- and long-term gene expression changes following oral ketamine treatment in individuals with PTSD. It was hypothesised that ketamine would induce time-dependent transcriptional changes, shifting from acute immune suppression to long-term immune modulation and tissue repair. Method Twenty-three individuals with PTSD (9 males, 14 females) participated in a six-week trial involving subanesthetic doses of oral ketamine. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, one week (short-term), and four weeks (long-term) post-treatment. RNA sequencing and transcriptome-wide analysis were conducted to assess differential gene expression and pathway activity across timepoints. Results Analysis identified 533 up-regulated and 621 down-regulated genes across timepoints. A 37% increase in gene expression changes was observed from short- to long-term, along with a 6.5-fold increase in expression magnitude and an 8.8-fold rise in pathway activation. Key modulated pathways included interferon alpha/beta signalling (z = 4), IL-17 signalling (z = 3.36), cytokine storm (z = 4.26), neutrophil degranulation (z = 6.0), and antimicrobial peptide signalling (z = 1.63). Notable gene-level regulators included IL-6, IL-1β, IFI27, CXCL8, SOCS1/3, IL-10, and CAMP. Discussion & Conclusions Findings demonstrate that ketamine induces distinct temporal molecular changes, transitioning from short-term inflammation suppression and antimicrobial responses to long-term immune remodulation and tissue repair. These results provide critical insight into the prolonged therapeutic mechanisms of ketamine in PTSD and support the development of personalised maintenance strategies to sustain clinical benefit and prevent relapse.