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Imaging the effect of ketamine on synaptic density (SV2A) in the living brain

Abstract

The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J—a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine’s therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine’s therapeutic effects.

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Fig. 1: Dissociative and antidepressant effects of ketamine.
Fig. 2: Effect of ketamine administration on SV2A density 24 h after administration in HC and clinical groups.
Fig. 3: Ketamine-induced increase in SV2A density following ketamine in ‘SV2A deficit’’ group (post-hoc analysis).
Fig. 4: No effect of ketamine or HNK administration on SV2A density in non-human primates.

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Acknowledgements

The authors dedicate this work to the late Ronald S. Duman—a colleague, mentor, and friend whose pioneering research has made seminal contributions to the neuroscience of depression and PTSD, and to understanding the mechanisms underlying ketamine’s therapeutic effects. We thank the staff at Yale PET Center and the West Haven National Center for PTSD, and all the individuals who took part in this study. Funding support was provided by the Veterans Affairs National Center for PTSD (RSD, JHK, and IE), the National Center for Advancing Translational Science (SEH: UL1TR001863), the Nancy Taylor Foundation (IE), and the NARSAD Young Investigator Award (SJF).

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Contributions

IE, RSD, JHK, and GS conceived and designed the experiments. SEH analyzed the PET data with input from REC, SJF, and MN. The manuscript was written by SEH with feedback from co-authors. Non-human primate imaging was conducted by DH and KF. Radiochemistry was performed by JR, PE, YY, and NN. Recruitment was overseen by ND and MD. GS assisted with the referral of clinical participants and interpretation of findings. DM and GAA provided medical oversight. All authors helped shape the research, analysis, and manuscript.

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Correspondence to Sophie E. Holmes or Irina Esterlis.

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Competing interests

Dr. Krystal acknowledges the following relevant financial interests. He is a co-sponsor of a patent for the intranasal administration of ketamine for the treatment of depression that was licensed by Janssen Pharmaceuticals, the maker of s-ketamine. He has a patent related to the use of riluzole to treat anxiety disorders that were licensed by Biohaven Pharmaceuticals Medical Sciences. He has stock or stock options in Biohaven Pharmaceuticals Medical Sciences, Sage Pharmaceuticals, Spring Care Inc., EpiVario Inc., Neumora Therapeutics Inc., Terran Biosciences Inc., and Tempero Bio, Inc. He consults broadly to the pharmaceutical industry, but his annual income over the past year did not exceed $5000 for any organization. He receives over $5000 in income from the Society of Biological Psychiatry for editing the journal Biological Psychiatry. Dr. Gerard Sanacora has served as consultant to Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Cowen, EMA Wellness, Engrail Therapeutics, Clexio, Denovo Biopharma, Gilgamesh, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Levo, Lundbeck, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, Vistagen Therapeutics, and XW Labs; and received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Naurex, and Usona over the past 36 months. Dr. Sanacora holds equity in BioHaven Pharmaceuticals and is a co-inventor on a US patent (#8778979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University has a financial relationship with Janssen Pharmaceuticals and may in the future receive financial benefits from this relationship. The University has put multiple measures in place to mitigate this institutional conflict of interest. Questions about the details of these measures should be directed to Yale University’s Conflict of Interest office. Dr. Sjoerd Finnema is an employee and shareholder of Abbvie. None of the authors declare any conflicts of interest.

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Holmes, S.E., Finnema, S.J., Naganawa, M. et al. Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Mol Psychiatry 27, 2273–2281 (2022). https://doi.org/10.1038/s41380-022-01465-2

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