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

Back to table of contents Previous article Next article Letters to the EditorFull AccessRigorous Translational Models Are Key to Studying Ketamine’s Antidepressant Mechanism: Response to Wang and KaplinBoris D. Heifets, M.D., Ph.D., Nolan R. Williams, M.D., Christine Blasey, Ph.D., Keith Sudheimer, Ph.D., Carolyn I. Rodriguez, M.D., Ph.D., Alan F. Schatzberg, M.D.Boris D. HeifetsSearch for more papers by this author, M.D., Ph.D., Nolan R. WilliamsSearch for more papers by this author, M.D., Christine BlaseySearch for more papers by this author, Ph.D., Keith SudheimerSearch for more papers by this author, Ph.D., Carolyn I. RodriguezSearch for more papers by this author, M.D., Ph.D., Alan F. SchatzbergSearch for more papers by this author, M.D.Published Online:1 May 2019https://doi.org/10.1176/appi.ajp.2019.19010044rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail 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.Department of Psychiatry and Behavioral Sciences (Williams, Blasey, Sudheimer, Rodriguez, Schatzberg) and Department of Anesthesiology, Perioperative, and Pain Medicine (Heifets), Stanford University, Stanford, Calif.Send correspondence to Dr. Heifets ([email protected]) and Dr. Williams ([email protected]).Drs. Heifets and Williams share first authorship.The authors’ disclosures accompany the original article.Reference1 Abdallah C, Averill LA, Gueorgueiva R, et al.: Rapamycin, an immunosuppressant and mTORC1 inhibitor, triples the antidepressant response rate of ketamine at 2 weeks following treatment: a double-blind, placebo-controlled, cross-over, randomized clinical trial. bioRxiv 2018; 10.1101/500959Crossref, Google Scholar FiguresReferencesCited byDetailsCited byCNS Spectrums, Vol. 24, No. 5 Volume 176Issue 5 May 01, 2019Pages 412-412 Metrics KeywordsAntidepressantsDrug InteractionsKetamineOpioidNaltrexoneDepressionPDF download History Accepted 4 March 2019 Published online 1 May 2019 Published in print 1 May 2019