An Overview of Depression Pathogenesis: Prevailing Hypotheses and Associated Neurobiological Underpinnings Primarily Evidenced by Rodent Studies

Abstract

Depression has emerged as a globally prevalent mental disorder that severely compromises both physiological and psychological well‐being. Its widespread prevalence constitutes a pressing public health concern that necessitates intensified attention and targeted therapeutic interventions. Clinical studies primarily delineate core symptomatology of depression and validate the therapeutic efficacy of candidate antidepressants in clinical cohorts. Complementarily, preclinical animal studies, predominantly utilizing chronic stress‐induced rodent models, decipher the sophisticated molecular underpinnings of depression, and enable primary screening for high‐potency antidepressants and innovative therapeutic regimens. Decades of clinical and preclinical research have substantially facilitated the establishment of diverse pathogenic hypotheses and development of first‐line antidepressant therapies. To date, prevailing mechanistic hypotheses include classic theories regarding hypothalamic–pituitary–adrenal (HPA) axis dysregulation and monoamine deficiency, intermediate mechanisms centered on glutamate excitotoxicity and brain‐derived neurotrophic factor dysregulation (BDNF), and emerging theories of neuroinflammation, oxidative stress, and microbiota–gut–brain (MGB) axis dysfunction. Currently available antidepressant regimens primarily comprise conventional monoamine‐targeted agents and novel glutamate‐modulating drugs (e.g., tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOIs], selective serotonin reuptake inhibitors [SSRIs], and esketamine), which, however, are plagued by inherent limitations and undesirable adverse reactions. Despite substantial advances achieved to date, further in‐depth mechanistic investigations are still warranted to develop novel, safe, and efficacious antidepressants and optimize current therapeutic regimens. This review systematically recapitulates the prevailing pathogenic hypotheses and dissects associated multifaceted neurobiological underpinnings, with key evidence predominantly obtained from preclinical chronic stress rodent models. We outline the defining features of each mainstream hypothesis, and the intricate crosstalk and bidirectional regulatory networks among distinct mechanistic pathways, with a particular focus on underlying molecular signaling cascades, thereby constructing a holistic landscape of depression pathogenesis.