Rigorous Translational Models Are Key to Studying Ketamine’s Antidepressant Mechanism: Response to Wang and Kaplin

To the Editor: We thank Mr. Wang and Dr. Kaplin for elaborating in detail an interesting signaling mechanism that we briefly referenced in our article, one that could account for the involvement of both opioid and N-methyl-d-aspartate (NMDA) receptors in mediating ketamine’s antidepressant effect. We fully agree that our data do not distinguish whether ketamine acts directly at opioid receptors, or indirectly, perhaps via enhanced release of endogenous opioids or by intracellular signaling crosstalk between opioid and NMDA receptors in the manner described by Mr. Wang and Dr. Kaplin.

We would stress the importance of testing the key predictions of animal studies in humans. The mechanism described by Mr. Wang and Dr. Kaplin predicts that enhancing mammalian target of rapamycin (mTOR) signaling should also enhance ketamine’s antidepressant effect. This prediction has recently been tested in patients with major depression. Abdallah and colleagues (1) pretreated these patients with rapamycin, an mTOR inhibitor, prior to a ketamine infusion. Remarkably, this combination potentiated, rather than blocked, ketamine’s antidepressant effect. This result does not at all preclude the possibility of opioid–NMDA receptor crosstalk. Rather, it highlights the need for animal models that recapitulate the mechanistic features of ketamine’s antidepressant effect observed in humans.