Rethinking zebrafish anxiety models in drug discovery and precision psychiatry

Anxiety disorders are among the most prevalent psychiatric conditions worldwide, yet the development of novel anxiolytic therapies remains limited by poor translational success and the complexity of anxiety neurobiology. Zebrafish (Danio rerio) have emerged as a valuable vertebrate model bridging high-throughput in vitro screening and mammalian preclinical studies by combining whole-organism physiology with scalable phenotypic screening.

This review evaluates advances in zebrafish models for anxiolytic drug discovery, focusing on features supporting their construct and predictive validity. Larval zebrafish enable high-throughput behavioral and imaging-based screening, whereas adults provide more complex behavioral phenotypes and translational validation. Genetically engineered models, automated behavioral tracking, functional imaging, and molecular profiling further support mechanism-based drug discovery. A targeted search of PubMed/MEDLINE, Web of Science, and Scopus identified current and foundational studies on zebrafish anxiety models, neurobiology, behavioral assays, and drug discovery.

Integration of behavioral phenotyping with genetics, multi-omics, functional imaging, and artificial intelligence could transform zebrafish from a screening organism into an integrated platform for precision psychiatry and personalized neuropsychopharmacological drug discovery, and improving translation across experimental scales. Zebrafish are best positioned as an efficient intermediate translational model that accelerates mechanism-based anxiolytic discovery while complementing, rather than replacing, mammalian preclinical studies.