Beyond the Serotonin Hypothesis A Systems-Level Perspective on Depression via Gut–Brain and HPA Axis Dysregulation

This preprint presents a systems-level perspective on depression that moves beyond the classical serotonin deficiency hypothesis. Drawing on evidence from psychiatry, neuroimmunology, endocrinology, and gut microbiome research, the paper synthesizes current findings into a conceptual framework centered on gut–brain axis signaling and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Rather than rejecting serotonergic mechanisms, the model repositions serotonin as a downstream modulatory process embedded within broader stress-regulation systems involving inflammation, metabolic signaling, and endocrine feedback. Particular attention is given to chronic low-grade inflammation, altered tryptophan metabolism, glucocorticoid receptor resistance, and self-reinforcing feedback loops linking gut dysbiosis and HPA overactivation. This work is intended as a conceptual synthesis / perspective paper, not as a definitive causal model or a source of clinical guidance. It aims to provide a coherent post-serotonin framework that may help explain heterogeneity, chronicity, and treatment resistance in depressive disorders, and to support further empirical and theoretical research in systems psychiatry.