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Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

Abstract

Purpose of Review

Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.

Recent Findings

Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity.

Summary

Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.

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Acknowledgements

The authors acknowledge support from the US Department of Veterans Affairs through its support for the National Center for PTSD and it support, with the US Department of Defense, of the Consortium to Alleviate PTSD. We also recognize the National Center for Advancing Translational Science for its support of the Yale Center for Clinical Investigation (UL1RR024139). In addition, the authors acknowledge the support of the US National Institute on Alcohol Abuse and Alcoholism (P50AA12870, JHK), the State of Connecticut for the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center (GS, RSD). 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 was licensed by Biohaven Medical Sciences. He has stock or stock options in Biohaven Medical Sciences, ARett Pharmaceuticals, Blackthorn Therapeutics, and Luc Therapeutics. 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. He has fiduciary responsibility for the International College of Neuropsychopharmacology as president of this organization.

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Correspondence to John H. Krystal.

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Benjamin Kelmendi declares no conflict of interest.

John H. Krystal has received grants from the Department of Veterans Affairs and has received consultancy fees from Biogen, Idec, MA, Biomedisyn Corporation, Forum Pharmaceuticals, Janssen Research and Development, L.E.K. Consulting, Otsuka America Pharmaceuticals, Inc., S K Life Science, Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd., Naurex Pharmaceuticals, and Pfizer Pharmaceuticals. Dr. Krystal owns stock in ArRETT Neuroscience, Inc., Biohaven Pharmaceuticals Medical Sciences, Blackthorn Therapeutics, Inc., Luc Therapeutics, Inc., and Spring Care, Inc.

Chadi G. Abdallah has received consultancy fees from Genentech and Janssen.

Lynette A. Averill has received grants from the Department of Veterans Affairs and the Brain and Behavior Foundation.

Ilan Harpaz-Rotem has received a grant from the Brain and Behavior Foundation.

Gerard Sanacora has received consultancy fees from Allergan, Alkermes, BioHaven Pharmaceuticals Holding Company, Janssen, Merck, Sage, Taisho Pharmaceuticals, Takeda, and Vistagen Therapeutics. Dr. Sanacora has also received grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Johnson and Johnson, Hoffman La-Roche, Merck, Naurex, and Servier and has received payment from Alkermes for developing educational Disease Education non-promotional material. Dr. Sanacora owns stock in BioHaven Holding Company.

Steven M. Southwick has received grants from the National Center for PSTD.

Ronald S. Duman has received consultancy fees from Johnson and Johnson and Taisho and grants from Taisho, Navitor, Relmada, Allergan, Johnson and Johnson. Dr. Duman has also received honoraria payments from Johnson and Johnson and Navitor.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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This article is part of the Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

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Krystal, J.H., Abdallah, C.G., Averill, L.A. et al. Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic. Curr Psychiatry Rep 19, 74 (2017). https://doi.org/10.1007/s11920-017-0829-z

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  • DOI: https://doi.org/10.1007/s11920-017-0829-z

Keywords

  • PTSD
  • Synapse
  • Glutamate
  • NMDA
  • Ketamine
  • Plasticity
  • Connectivity