Contemporary psychiatric models are increasingly incorporating systems biology approaches to supplement symptom-based nosology. While localized neurotransmitter hypotheses remain foundational, they may be insufficient to fully capture the non-linear, multisystemic dysfunctions associated with severe mental illnesses. This study proposes a theoretical framework and corresponding computational model conceptualizing anxiety disorders and Major Depressive Disorder (MDD) as potential emergent properties of systemic bioenergetic instability. The model parameterizes peripheral somatic irritation—specifically mucosal inflammation and vagal afferent excitation associated with Gastroesophageal Reflux Disease (GERD)—as a persistent allostatic load generator. Based on the Allostatic Triage Model of Psychopathology (ATP Model), we hypothesize that this stressor, transduced via the vagal-neural network, may contribute to the depletion of astrocytic mitochondrial energy capacity. The methodology involves the derivation of Coupled Ordinary Differential Equations (ODEs) to model astrocytic bioenergetic equilibrium through ATP-dependent Michaelis-Menten kinetics. Utilizing Jacobian matrix stability criteria, the framework identifies a Saddle-Node Bifurcation as a mathematical boundary representing critical metabolic instability. To evaluate this dynamical system, the study integrates bidirectional Mendelian Randomization (MR) causal inference and an empirically parameterized Pan-Ancestry in silico simulation (N=30,000). The simulation suggests a potential Gene-Environment (GxE) interaction, estimating a 78.4% incidence of simulated bioenergetic collapse in East Asian (EAS) cohorts under parameterized borderline environmental stress conditions. This computational finding suggests that diagnostic thresholds derived predominantly from European-ancestry populations may underestimate metabolic vulnerability in EAS populations. These in silico findings are intended to inform future precision psychiatry frameworks and generate testable hypotheses requiring prospective empirical validation using in vivo neurometabolic imaging.
Cefiyana Cefiyana (Thu,) studied this question.