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.