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Preprint VersionCC BY V4.0, Open Access
Ketamine’s rapid acting symptom relief make it a promising intervention for PTSD.
However, the mechanisms driving its long-term efficacy over weeks and months
remain poorly understood. This study investigated the short- and long-term impacts
on gene expression of a six-week subanesthetic oral ketamine trial in 23 PTSD
participants (9 males, 14 females). Peripheral Blood Mononuclear Cells (PBMCs)
were collected at baseline, one week (short-term), and four weeks (long-term) post
oral ketamine for RNA sequencing and transcriptome analysis. Differential
expression analysis identified substantial and persistent transcriptomic changes over
time, with 533 genes upregulated and 621 downregulated across timepoints.
Notably, there was a 37% increase in differential gene expression between the shortand
long-term responses, accompanied by a 6.5-fold rise in expression magnitude
and an 8.8-fold enhancement in pathway activity. Pathway analysis emphasised
critical immune and inflammatory pathways that appear to be modulated by
ketamine, including interferon alpha/beta signalling (z = 4), IL-17 signalling pathway
(z = 3.36), and cytokine storm signalling (z = 4.26), neutrophil degranulation (z = 6.0)
and antimicrobial peptide signalling (z = 1.63) which differed across timepoints. The
findings suggest a transition from short-term inflammation suppression and
antimicrobial activity to long-term sustained immune regulation, inflammation
remodulation and tissue repair. Key cytokines, chemokines, interferons and
antimicrobial peptides included, IL-6, IL-1β, IFI27, IL-10 signalling, CXCL8, SOCS1/3
and CAMP which represent central regulators of immune and inflammatory
pathways. These molecular changes offer novel insights into the short- and longterm
therapeutic potential of ketamine for PTSD and highlight avenues for precision
psychiatry and individualised maintenance therapy to prevent relapse.