Differences in how NMDA antagonists modulate negative affective biases in male rats may serve as a predictor of clinical efficacy in major depressive disorder.
Justyna K. Hinchcliffe, Katie Kamenish, Julia M. Bartlett, Roberto Arban, Bastian Hengerer, Emma Robinson
Translational Psychiatry May 29, 2026 DOI: 10.1038/s41398-026-04133-z (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats (affective bias model) |
| Interventions | Lanicemine Memantine CP101 606 Phencyclidine Ephenidine HNK (2R 6R)-hydroxynorketamine |
| Duration | Acute (<60 min) and ~24 h post-treatment |
| Topics | Depression Ketamine |
| Keywords | Animals Rats, sprague-dawley Disease models, animal Memantine Receptors, n-methyl-d-aspartate Antidepressive agents Behavior, animal Affect Male |
| Key points | In a rat model of affective bias, phencyclidine, lanicemine, and ephenidine acutely reduced negative bias, but CP101,606 did not; at 24 hours only CP101,606 and ephenidine showed sustained effects, with a trend toward positive bias. Lanicemine persisted only at high doses, phencyclidine and memantine had no effect, and HNK resembled ketamine only at supraphysiological doses. The authors propose that sustained affective bias modulation, particularly with positive re-learning, correlates with antidepressant efficacy, and that ion-trapping properties may explain differences among NMDA antagonists. |
Abstract
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 h 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 h, 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 those 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.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.