A systematic review of studies investigating the acute effects of N-methyl-D-aspartate receptor antagonists on behavioural despair in normal animals suggests poor predictive validity

Abstract

The ability of the N-methyl- D-aspartate receptor antagonist ketamine to induce a rapid and sustained antidepressant effect has led to a surge in pre-clinical studies investigating underlying mechanisms and seeking novel treatments. Animal models are key to this research as they can provide a behavioural readout linking underlying mechanisms to clinical benefits. However, quantifying depression-related behaviours in rodents represents a major challenge with the validity of traditional methods such as models of behavioural despair (forced swim test and tail suspension test) a topic of debate. While there is good evidence to support the value of using these behavioural readouts to study the effects of stress, these approaches have largely failed to detect reliable phenotypic effects in other disease models. In this systematic review, we identified publications which had tested N-methyl- D-aspartate receptor antagonists in normal animals using either the forced swim test or tail suspension test. We compared findings for different doses and time points and also drugs with different clinical profiles to investigate how well the outcomes in the rodent model predicted their effects in the clinic. Despite clear evidence that N-methyl- D-aspartate receptor antagonists reduce immobility time and hence exhibit an antidepressant profile in these tasks, we found similar effects with both clinically effective drugs as well as those which have failed to show efficacy in clinical trials. These findings suggest that behavioural despair tests in normal animals do not provide a good method to predict clinical efficacy of N-methyl- D-aspartate receptor antagonists.

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

“…As suggested by Jefsen et al (2019) [ 63 ], the forced swim test, while effective in evaluating the properties of more “traditional” compounds, might not be suitable for assessing the antidepressant effect of psychedelics. Moreover, our studies were conducted on naive animals; a recent article by Viktorov et al (2022) [ 64 ] suggests that the effect of NMDA antagonists is limited when used on animals who are not subjected to any model of depression. On the other hand, our behavioral tests were performed 24 h after the administration of the drugs, and while that is enough to eliminate their acute effects, it might not be enough for the long-lasting effects to manifest fully, as Hibicke et al (2020) [ 26 ] reported an antidepressant effect observed 7 days post psilocybin administration.…”

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors

“…A 20x20 cm center square was defined as the inside zone. The tail suspension test has also been used to examine the ketamine effects on depression-like behavior in animals ( Fukumoto et al, 2017 ; Yang et al, 2018b ; Ouyang et al, 2021 ; Rawat et al, 2022 ; Viktorov et al, 2022 ). Studies suggest that the forced swim test and the tail suspension test are based on the same principle: measurement of the duration of immobility when rodents are exposed to an inescapable situation ( Castagné et al, 2011 ).…”

Assessment of commonly used tests in experimental depression studies according to behavioral patterns of rodents

“…Behavioral despair tests, such as the forced swim test and the tail suspension test, do not provide a good method for predicting the clinical efficacy of a pharmacological agent in normal animals [ 30 ]. In some studies, it is pointed out that testing antidepressants in animals without any stress model may yield conflicting results [ 22 , 31 ].…”