A new review published in Regulatory Toxicology and Pharmacology highlights the urgent need for international regulatory bodies to update guidelines on nonclinical efficacy testing for antidepressants. The study, authored by PETA scientists and advocates across the world, including AFSA CEO Rachel Smith, emphasises the shortcomings of traditional animal tests, specifically the forced swim test (FST) and the tail suspension test (TST), which have long been used in the pharmaceutical industry despite growing criticism over their validity.
Depressive disorders, affecting approximately 3.8% of the global population, remain one of the most significant mental health challenges. Traditional medications, including monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs), have proven inadequate for about 30% of patients, leading to a diagnosis of treatment-resistant depression (TRD). Despite new treatments like esketamine and brexanolone, the drug discovery process has stagnated, partly due to reliance on flawed animal testing models.
The review argues that the FST and TST fail to accurately predict human responses to antidepressants. These tests, developed decades ago, measure rodents’ immobility in stressful situations, an approach that lacks both construct and predictive validity for human depressive disorders. The study calls for a shift towards more reliable and ethical testing methods, including human-induced pluripotent stem cell (hiPSC) platforms and other in vitro techniques.
The Forced Swim Test (FST) involves placing rodents in a cylinder filled with water and measuring the time they spend immobile, with the assumption that reduced immobility indicates antidepressant activity. The Tail Suspension Test (TST) suspends mice by their tails and records the duration of their immobility, under the same assumption. Both tests have been criticised for their variability and lack of relevance to human depression.
Several countries, including the UK and Australia, have already begun to phase out the FST, citing its scientific limitations and ethical concerns. Recent examples of the use of these tests include:
- Dr. Willmar Schwabe Pharmaceuticals (Germany): Used the FST on rats to test Silexan, an essential oil from lavender flowers.
- Eli Lilly and Company (USA): Employed both FST and TST on mice to study ammonium salts.
- Gilgamesh Pharmaceuticals (USA): Conducted FST on rats to evaluate GM-1020, a novel NMDA receptor antagonist
The review concludes with a call to action for ICH to form a working group of experts to draft new guidelines, emphasising the importance of harmonising global standards to foster innovation and reduce the reliance on outdated animal models in antidepressant research. The authors liken the current state of regulatory science to a ‘crisis’ stage as described by Thomas Kuhn in “The Structure of Scientific Revolutions,” suggesting that the field is on the brink of a paradigm shift. This shift involves moving from whole animal models to more predictive and humane non-animal methods.