Rodent ketamine depression-related research: Finding patterns in a literature of variability

Discovering that the anesthetic drug ketamine has rapidly acting antidepressant effects in many individuals with major depression is one of the most important findings in clinical psychopharmacology in recent decades. The initial report of these effects in human subjects was based on a foundation of rodent preclinical studies carried out in the 1990s, and subsequent investigation has included both further studies in individuals with depression, as well as reverse translational experiments in animal models, especially rodents. While there is general agreement in the rodent literature that ketamine has rapidly-acting, and generally sustained, antidepressant-like properties, there are also points of contention across studies, including the precise mechanism of action of this drug. In this review, we briefly summarize prominent yet variable findings regarding the mechanism of action. We also discuss a combination of similarities and variances in the rodent literature in the antidepressant-like effects of ketamine as a function of dose, species and strain, test, stressor, and presumably sex of the experimenter. We then present previously unpublished mouse strain comparison data suggesting that subanesthetic ketamine does not have robust antidepressant-like properties in unstressed animals, and may actually promote depression-like behavior, in contrast to widely reported findings. We conclude that the data best support the notion of ketamine action principally via NMDA receptor antagonism, transiently boosting glutamatergic (and possibly other) signaling in diverse brain circuits. We also suggest that future studies should address in greater detail the extent to which antidepressant-like properties of this drug are stress-sensitive, in an effort to better model major depression present in humans.