Models of depression for preclinical drug discovery and development: an update of the literature

Depression is a heterogeneous and multifactorial condition with substantial unmet therapeutic need. Despite significant research, current pharmacotherapies remain limited in efficacy and onset, reflecting an incomplete understanding of underlying pathophysiology. Animal models have therefore been central to dissecting biological mechanisms and enabling antidepressant drug discovery.

This review provides a synthesis of animal models of depression, including stress paradigms, developmental and genetic models, neuroendocrine manipulations, immune-based, metabolic and hormone-related models. PubMed was searched from database inception to March 2026 using depression-, species-, and model-specific terms. Each paradigm is evaluated in terms of face, construct, and predictive validity, with emphasis on relevance to drug discovery. Converging evidence across models highlights shared pathophysiological domains, including HPA axis dysregulation, neuroinflammation, monoaminergic and glutamatergic imbalance, and impaired neuroplasticity.

No single model captures the complexity of depression; thus, reliance on isolated paradigms may contribute to translational failure. Future progress will depend on multimodal and endophenotype-driven approaches that align biological mechanisms with defined subtypes (e.g. inflammation-associated, hormone-sensitive, or stress-related depression). Integration of animal models with human-relevant data and sex-informed experimental design will advance precision psychiatry, improving predictive validity of preclinical antidepressant discovery.