Re: concerns about the antidepressant-like effects of high-dose ketamine in mice

Abstract

In our recent paper titled “CD-1 and Balb/cJ mice do not show enduring antidepressant-like effects of ketamine in tests of acute antidepressant efficacy,” we explored the effects of a wide range of ketamine doses to investigate the lasting antidepressant effects of ketamine in mice. Yang et al. expressed concern about the use of high doses of ketamine in such studies. Like many groups, we recognize the importance of the finding that ketamine produces sustained antidepressant effects in humans. We sought to model this effect in mice so that we could design studies to examine its neurobiology. We were surprised by the lack of antidepressant-like effects within what we considered to be a broad and extremely thorough range of doses, from low to high doses. Of course, dose response curves may be different across species, and we wanted to test all possibilities. Therefore, we included doses that we considered very high to determine whether there are any conditions under which ketamine can produce in mice effects that resemble the therapeutic effects seen in humans. During our studies we remained mindful of a concern shared by many depression researchers: that current animal models may only identify standard antidepressant medications and may not be sensitive to drugs that work via truly novel mechanisms.