Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments
Ronald S Duman, Gerard Sanacora, John H Krystal, Ronald S Duman, Gerard Sanacora, John H Krystal
Abstract
The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.
Conflict of interest statement
Declaration of Interests
Dr. Duman has received consulting fees from Janssen, Taisho, Naurex, and Aptinyx, and has received research support from Lilly, Taisho, Allergan, Janssen, Naurex, Aptynix, Navitor, and Relmada. He is also listed as a co-inventor with Drs. Abdallah, Krystal, and Sanacora on Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 047162–7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. Dr. Sanacora has received consulting fees from Allergan, Alkermes, AstraZeneca, Avanier, Axsome Therapeutics, Pharmaceuticals, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, Epiodyne, Intra-Cellular Therapies, Janssen, Merck & Co., Naurex, Navitor, NeruoRx, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, and Vistagen therapeutics over the last 36 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, and Servier over the last 36 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), and a U.S. Provisional Patent Application No. 047162–7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01.
Dr. Krystal has received consulting fees from_AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia) Boehringer Ingelheim International, Concert Pharmaceuticals, Inc., Epiodyne, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, L.E.K. Consulting, Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries,Taisho Pharmaceutical Co., Ltd. He is listed on the Scientific Advisory Boards of Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Broad Institute of MIT and Harvard, Cadent Therapeutics, Lohocla Research Corporation, Stanley Center for Psychiatric Research at the Broad Institute. Dr. Krystal holds stock in ArRETT Neuroscience, Inc., BlackThorn Therapeutics, Inc., Biohaven Pharmaceuticals Medical Sciences Spring Care, Inc., Sage Pharmaceuticals; Stock Options in Biohaven Pharmaceuticals Medical Sciences, Storm Biosciences, Inc. He receives Income Greater than $10,000 as Editor of Biological Psychiatry. He has Patents and Inventions in 1) Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #5,447,948. September 5, 1995. 2) 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: July 15, 2014. US Patent Application No. 15/695,164: Filing Date: 09/05/2017 3) 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 March 5, 2014; United States application or Patent Cooperation Treaty (PCT) International application No. 14/306,382 filed on June 17, 2014 4) Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Department of Veterans Affairs “Methods for Treating Suicidal Ideation”, Patent Application No. 14/197.767 filed on March 5, 2014 by Yale University Office of Cooperative Research. 5) Arias A, Petrakis I, Krystal JH. – Composition and methods to treat addiction. Provisional Use Patent Application no.61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research. 6) Chekroud, A., Gueorguieva, R., & Krystal, JH. “Treatment Selection for Major Depressive Disorder” [filing date 3rd June 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University. 7) Gihyun, Yoon, Petrakis I, Krystal JH – Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. U. S. Provisional Patent Application No. 62/444,552, filed on January10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01. 8) Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 047162–7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. He has NON Federal Research Support AstraZeneca Pharmaceuticals provides the drug, Saracatinib and Novartis provides maveglurant for research related to NIAAA grant “Center for Translational Neuroscience of Alcoholism [CTNA-4].
Copyright © 2019 Elsevier Inc. All rights reserved.
Figures
Source: PubMed