Polyamine stress response in schizophrenia: A translational framework beyond monoamine-centered models

Schizophrenia treatment still relies mainly on dopamine-targeting antipsychotics, yet unmet needs remain in negative symptoms, cognition, and real-world functioning. Here, we propose the Polyamine Stress Response (PSR) as a systems-level program initiated by stress-driven resetting of intracellular polyamine pools, with downstream consequences for oxidative load, glial responses, membrane dynamics, and circuit stability. We further position PSR as a potentially conserved stress-response program across brain disorders, with schizophrenia representing an important context for mechanistic and translational investigation. The arginine-nitric oxide-agmatine-polyamine junction makes key PSR set points visible and actionable. Evidence from human and animal studies suggests that agmatinase may function as a regulatory node shaping agmatine tone. Insights from plant biology suggest that upstream entry steps can be manipulated with irreversible inhibitors, supporting PSR as a controllable checkpoint with measurable outputs. Clinically, infection-mimicking psychoses and the Toxoplasma gondii literature motivate biomarker-stratified subgroup designs. We close with a roadmap that first uses polyamine-flux modulators as pharmacological probes in animal models, then advances toward more selective modulators if signals are consistent.