Differences in how NMDA antagonists modulate negative affective biases in male rats may serve as a predictor of clinical efficacy in major depressive disorder

Affective biases shape cognitive and emotional behaviour and are important in major depressive disorder (MDD). Modulation of affective biases by the NMDA antagonist, ketamine, may underlie its antidepressant effects but not all NMDA antagonists are efficacious. Some studies suggest ketamine’s efficacy involves non-NMDA mechanisms e.g. via its active metabolite HNK (2R,6R)-hydroxynorketamine), but an alternative hypothesis is that pharmacodynamic differences relating to ion trapping and/or affinity may be relevant. This study used a rat model of affective biases to investigate how different NMDA antagonists influence retrieval of a negatively biased memory, both acutely (<60 min) and ~24 hours post-treatment. We compared compounds tested clinically (lanicemine, memantine, CP101,606), reference antagonists with different pharmacodynamic profiles (phencyclidine, PCP; ephenidine), and HNK. PCP, lanicemine, and ephenidine but not CP101,606 acutely attenuated negative biases. At 24 hours, these effects were sustained for CP101,606 and ephenidine with a trend towards inducing a positive bias. Lanicemine’s effects were sustained only at high doses and PCP and memantine had no effects. HNK looked like ketamine but only at doses higher than would be achieved through metabolism of the effective ketamine dose. These findings suggest that sustained modulation of affective biases, particularly when the treatment facilitates re-learning with a more positive affective valence, correlates with therapeutic efficacy. Based on preliminary findings using reference NMDA antagonists, differences in antidepressant efficacy may relate to ion trapping properties. Very high or very low ion trapping appear less effective than intermediate compounds like ketamine and ephenidine or subunit-selective antagonists like CP101,606.