LETTER LETTER REPLY TO HASHIMOTO: is not an but requires opioid system for actions

Roberto Malinowa,b and Matthew E. Kleinc,1

We agree with Hashimoto (1) that the molecular mech- respond to clinical antidepressant treatment (predictive anisms underlying the psychiatric properties of (R,S)- validity), and their behavioral performance is correlated ketamine remain active areas of investigation. Race- with cellular hyperactivity of the lateral habenula (LHb) mic ketamine as well as [(S)-ketamine] are (construct validity), a brain nucleus implicated in de- potent N-methyl-D-aspartate receptor (NMDAR) an- pression (8, 9). We observed that in cLH animals ket- tagonists and have displayed acute antidepressant amine treatment acutely diminishes LHb hyperactivity and antisuicidal effects in multiple clinical studies (2, and improves helplessness performance, as well as 3). However, these compounds display activity, albeit chronically improves performance in a task measuring with lower affinity, on a number of receptors, including motivation. Our pharmacological results are consistent μ-opioid receptors (MORs), complicating the issue of with MOR being necessary but not sufficient for the . Clinical studies arguing for (4) behavioral and cellular effects of ketamine (10). These and against (5) a role for MORs in the antidepressive results suggest MOR is not the direct target of ket- effects of ketamine are both small (n = 7 and 5 patients, amine, but MOR may play a permissive role. Other stud- respectively), and thus larger studies will be required. ies have demonstrated a physical complex between While the recent clinical data from the ketamine MOR and NMDARs that can gate NMDAR biophysical (R)- and metabolites are intriguing, we properties, consistent with our results (11). Further stud- agree with Hashimoto that further studies are ies are needed to determine whether the antidepres- needed before we can rule out NMDAR inhibition sant effects of ketamine employ such a mechanism. in the antidepressant effects of ketamine (6). We note In conclusion, a mechanistic understanding of that while some NMDAR antagonists have not shown the antidepressant effects of ketamine will require clinical benefit for , other NMDAR antag- more studies with results that are replicated across onists unrelated to ketamine have shown efficacy different experimental model systems. Correlating [i.e., (7)], although again target biophysical, cellular, and behavioral results in pre- specificity clouds the underlying mechanism. clinical studies may help guide future clinical As Hashimoto notes, there has been variability in studies. preclinical studies concerning the effects of different ketamine-related compounds, possibly due to the Acknowledgments particular animal and stress model used. We chose This work was supported by the National Institute of Mental congenital helpless (cLH) rats for our model as they Health (R.M., R01MH091119; M.E.K., R25MH101072 [principal display depressive-like symptoms (face validity), investigator, Neal Swerdlow]).

1 K. Hashimoto, Are NMDA and opioid receptors involved in the antidepressant actions of ketamine? Proc. Natl. Acad. Sci. U.S.A. 117, 11200–11201 (2020). 2 S. T. Wilkinson et al., The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. Am. J. Psychiatry 175,150–158 (2018). 3 P. Zanos et al., Ketamine and ketamine metabolite pharmacology: Insights into therapeutic mechanisms. Pharmacol. Rev. 70, 621– 660 (2018). 4 N. R. Williams et al., Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am. J. Psychiatry 175,1205– 1215 (2018).

aDepartment of Neurosciences, University of California San Diego, La Jolla, CA 92093; bSection of Neurobiology, Division of Biology, University of California San Diego, La Jolla, CA 92093; and cDepartment of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA 92093 Author contributions: R.M. and M.E.K. designed research; M.E.K. performed research; R.M. and M.E.K. analyzed data; and R.M. and M.E.K. wrote the paper. The authors declare no competing interest. Published under the PNAS license. 1To whom correspondence may be addressed. Email: [email protected]. First published May 19, 2020.

11202–11203 | PNAS | May 26, 2020 | vol. 117 | no. 21 www.pnas.org/cgi/doi/10.1073/pnas.2002739117 Downloaded by guest on September 30, 2021 5 G. Yoon, I. L. Petrakis, J. H. Krystal, Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and use disorder. JAMA Psychiatry 76, 337–338 (2019). 6 G. C. Leal et al., Intravenous arketamine for treatment-resistant depression: Open-label pilot study. Eur. Arch. Psychiatry Clin. Neurosci., 10.1007/s00406-020- 01110-5 (2020). 7 S. M. Stahl, Dextromethorphan/: A novel oral NMDA (N-methyl-D-aspartate) with multimodal activity. CNS Spectr. 24,461–466 (2019). 8 C. D. Proulx, O. Hikosaka, R. Malinow, Reward processing by the lateral habenula in normal and depressive behaviors. Nat. Neurosci. 17, 1146–1152 (2014). 9 C. Winter, B. Vollmayr, A. Djodari-Irani, J. Klein, A. Sartorius, Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav. Brain Res. 216, 463–465 (2011). 10 M. E. Klein, J. Chandra, S. Sheriff, R. Malinow, Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents. Proc. Natl. Acad. Sci. U.S.A. 117, 2656–2662 (2020). 11 M. Rodr´ıguez-Mu~noz et al., The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor-glutamate NMDA receptor cross-regulation. Cell. Mol. Life Sci. 68, 2933–2949 (2011).

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