Ketamine's immediate effects on PTSD involve changes in GABA, glutamate, and glutamine levels that trigger re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95, along with other molecular influences. Sustained therapeutic effects arise from neurotransmitter remodulations and prolonged changes in gene expression, including mTOR-mediated BDNF expression and epigenetic modifications. These molecular changes promote long-term synaptic stability and re-regulation in key brain regions. Understanding these sustained mechanisms is critical for developing safe and effective personalised treatments.
People with post-traumatic stress disorder who had a sustained clinical response to oral ketamine showed distinct baseline differences in DNA methylation and gene expression across 112 genes compared with non-responders. Key biomarkers included DENND5B, ZFY, PDGFRA, CPT1A, AHRR, and others involved in metabolism, cell signaling, neuronal development, immune response, and synaptic plasticity. Non-responders had persistent dysregulation in these pathways, suggesting biological barriers to treatment. Clinically, sustained responders had more severe PTSD at baseline and responded at lower ketamine doses. The findings point toward molecular profiling that could help personalize ketamine therapy for PTSD.
A six-week course of oral ketamine produced substantial and persistent changes in gene expression in 23 people with PTSD. Short-term effects included suppression of inflammation and antimicrobial activity; long-term effects shifted toward sustained immune regulation, inflammation remodulation, and tissue repair. Over four weeks, the number of genes whose activity changed rose by 37%, the magnitude of expression changes increased 6.5-fold, and pathway activity strengthened 8.8-fold. Key immune and inflammatory pathways modulated included interferon alpha/beta signaling, IL-17 signaling, cytokine storm signaling, neutrophil degranulation, and antimicrobial peptide signaling. Central regulators such as IL-6, IL-1β, IFI27, IL-10, CXCL8, SOCS1/3, and CAMP were implicated. These molecular changes point to mechanisms underlying ketamine's long-term therapeutic effects and suggest avenues for personalized maintenance therapy to prevent relapse.