Metabolic reprogramming in PTSD: GLP-1 receptor agonists and cardiometabolic drug repurposing for precision therapeutics

Post-traumatic stress disorder (PTSD) is increasingly recognized as a systemic disorder closely linked to metabolic dysfunction, including obesity, insulin resistance, type 2 diabetes and cardiovascular disease. These comorbidities are associated with poorer treatment response, yet pharmacological options for PTSD remain limited. Here, we review evidence that PTSD and metabolic disease share convergent mechanisms, including dysregulation of the hypothalamic–pituitary–adrenal axis, glucocorticoid receptor signaling, neuroinflammation, insulin resistance and mitochondrial dysfunction. We evaluate the rationale for repurposing approved cardiometabolic drugs, including glucagon-like peptide-1 receptor agonists, insulin sensitizers, statins, renin–angiotensin system modulators and glial-targeting agents. We critically assess preclinical and clinical evidence, highlight current limitations and propose a biomarker-guided framework to match therapies to dominant biological mechanisms. Finally, we discuss the exceptional burden of PTSD with cardiometabolic disease in war-affected Ukraine as a priority setting for future mechanism-based clinical trials. Drug repurposing represents a promising, but unproven, precision-psychiatry strategy.