Re‐evaluating the forced swim test: ethical, scientific, and regulatory drivers for validated alternatives

The forced swim test (FST), a controversial rodent assay developed in the 1970s, measures immobility as “behavioral despair” to screen antidepressants. Despite its utility in identifying monoaminergic drugs, its validity is disputed: immobility may reflect adaptive energy conservation, not depression, whereas ethical concerns include distress, hypothermia, and hypoxia. Regulatory bodies (the UK to India) now restrict FST, citing poor human translatability. Global bans have spurred the adoption of alternatives (e.g., sucrose preference tests, and human iPSC-derived models). However, challenges persist in validation, cost, and regulatory acceptance. Case studies reveal post-ban innovation (e.g., UK universities shifting to AI-driven assays), whereas public advocacy intensifies demand for humane research. Emerging technologies, optogenetics, organ-on-a-chip systems, and biomarker-based AI analytics offer paths to human-relevant depression research without animal distress. This review critiques FST’s scientific limitations, analyzes the ethical-policy shifts driving its phase-out, and evaluates alternatives. We argue for harmonized global standards to incentivize alternative validation, reformed ethical oversight, and collaborative frameworks bridging industry, academia, and regulators. The future of antidepressant screening lies in ethically aligned, human-centric models that transcend the constraints of the FST.