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Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression

Molecular Psychiatry volume 23, pages 824–832 (2018)Cite this article

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Abstract

The mechanisms of action of the rapid antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, have not been fully elucidated. This study examined the effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and 13 MDD nonsmokers participated in two [11C]ABP688 positron emission tomography (PET) scans on the same day—before and during intravenous ketamine administration—and a third scan 1 day later. At baseline, significantly lower [11C]ABP688 binding was detected in the MDD as compared with the control group. We observed a significant ketamine-induced reduction in mGluR5 availability (that is, [11C]ABP688 binding) in both MDD and control subjects (average of 14±9% and 19±22%, respectively; P<0.01 for both), which persisted 24 h later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (P=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (P<0.001), which was associated with the change in binding (P<0.04) immediately after ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.

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Acknowledgements

We thank Ms Samantha Rossano for her contributions to the data analysis and manuscript development. We also thank the Yale University Positron Emission Tomography Center staff for their aid with radiotracer syntheses, related analyses and subject imaging. We acknowledge the biostatistical consultation and support from the Biostatistical Consulting Core at the School of Medicine, Stony Brook University. Support was provided by K01MH092681 (to IE), VA National Center for PTSD (to IE, JHK, RHP, CGA), K01MH091354 (to CD) and R01MH104512 (to CD).

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Authors and Affiliations

  1. Department of Psychiatry, Yale University, New Haven, CT, USA

    I Esterlis, N DellaGioia, R H Pietrzak, D Matuskey, C G Abdallah, C Pittenger, G Sanacora & J H Krystal

  2. U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA

    I Esterlis, R H Pietrzak, C G Abdallah & J H Krystal

  3. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

    D Matuskey, N Nabulsi & R E Carson

  4. Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA

    J Yang

  5. Department of Neuroscience, Yale University, New Haven, CT, USA

    J H Krystal

  6. Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA

    R V Parsey & C DeLorenzo

  7. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA

    R V Parsey & C DeLorenzo

  8. Department of Radiology, Stony Brook University, Stony Brook, NY, USA

    R V Parsey

  9. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    R E Carson

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  1. I Esterlis
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Correspondence to I Esterlis.

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JHK: (1) Vladimir, Coric, Krystal, John H, Sanacora, Gerard—Glutamate Modulating Agents in the Treatment of Mental Disorders US Patent No. 8,778,979 B2 Patent Issue Date: 15 July 2014. (2) Charney D, Krystal JH, Manji H, Matthew S, Zarate C—Intranasal Administration of Ketamine to Treat Depression United States Application No. 14/197,767 filed on 5 March 2014; United States application or PCT International application No. 14/306,382 filed on 17 June 2014. He was also on consultant/advisory board for: AMGEN, AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Forum Pharmaceuticals, Janssen Research & Development, Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd, Biohaven Pharmaceuticals, Blackthorn Therapeutics, Inc., Lohocla Research Corporation, Luc Therapeutics, Inc., Pfizer Pharmaceuticals, and TRImaran Pharma. GS has received consulting fees form Allergan, Alkermes, AstraZeneca, BioHaven Pharmaceuticals, Hoffman La-Roche, Janssen, Merck, Naurex, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valenant pharmaceutical North America and Vistagen therapeutics over the past 24 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Johnson & Johnson, Hoffman La-Roche, Merck & Co., Naurex and Servier over the past 24 months. Free medication was provided to GS for an NIH sponsored study by Sanofi-Aventis. In addition, he holds shares in BioHaven Pharmaceuticals Holding Company and is a co-inventor on a patent ‘Glutamate agents in the treatment of mental disorders’ Patent number: 8778979. RHP: Scientific Consultant to Cogstate, Ltd. CGA served on advisory boards for Genentech. REC received research support from Astra-Zeneca, Astellas, BMS, Pfizer, Siemens, Taisho and UCB. The other authors declare no conflict of interest.

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Esterlis, I., DellaGioia, N., Pietrzak, R. et al. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Mol Psychiatry 23, 824–832 (2018). https://doi.org/10.1038/mp.2017.58

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