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.

Keywords: N-methyl-D-aspartate; Rapid-acting antidepressant; behavioural despair; forced swim test; mice; predictive validity; tail suspension test.

Figure 1.

Flowchart of study selection process for meta-analysis.

Figure 2.

Ketamine reduces immobility time in the FST and TST in mice following acute administration and testing up 60-min post-treatment. Data are divided into studies using the FST or TST and Hedge’s G is plotted for the dose inducing the maximum effect size out of all the doses reported. The full-dose range available is indicated in the study name column and the dose illustrated in the graph is given in the second column. The n number for the study, pre-treatment time and statistical findings are also included. Negative Hedge’s G-value indicate increased immobility time following administration of drug compared to vehicle while positive values indicate decreased immobility time.

Figure 3.

Non-ketamine NMDAR antagonists reduce immobility time in the FST and TST in mice following acute administration and testing up 60-min post-treatment. Data are divided into studies using the FST or TST and Hedge’s G is plotted for the dose inducing the maximum effect size out of all the doses tested and reported in this article. The full-dose range available is indicated in the study name column and the dose illustrated in the graph is given in the second column. The n number for the study, pre-treatment time and statistical findings are also included. Negative Hedge’s G value indicate increased immobility time following administration of drug compared to vehicle while positive values indicate decreased immobility time.

Figure 4.

Ketamine and other NMDAR antagonists reduce immobility time in the FST and TST 24 h post-treatment. Data are divided into studies using the FST or TST and Hedge’s G is plotted for the dose inducing the maximum effect size out of all the doses tested and reported in this article. The full-dose range available is indicated in the study name column and the actual dose illustrated in the graph is given in the second column. The n number for the study, pre-treatment time and statistical findings are also included. Negative Hedge’s G value indicate increased immobility time following administration of drug compared to vehicle while positive values indicate decreased immobility time.

Figure 5.

Ketamine and other NMDAR antagonists reduce immobility time in the FST and TST greater than 24-h post-treatment. Data are divided into studies using the FST or TST and Hedge’s G is plotted for the dose inducing the maximum effect size out of all the doses tested and reported in this article. The full-dose range available is indicated in the study name column and the actual dose illustrated in the graph is given in the second column. The n number for the study, pre-treatment time and statistical findings are also included. Negative Hedge’s G value indicate increased immobility time following administration of drug compared to vehicle while positive values indicate decreased immobility time.

Figure 6.

Locomotor effects of treatment in the FST/TST and measures of study quality. (a) Pie chart showing the number of studies reporting locomotor outcomes following treatment with NMDAR antagonists in the FST or TST. (b) Summary of study quality according to the SYRCLE reporting guidelines (Hooijmans et al., 2014) showing the percentage of included studies that either complied with each item or did not report.