Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments
- PMID: 30946828
- PMCID: PMC6450409
- DOI: 10.1016/j.neuron.2019.03.013
Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments
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.
Copyright © 2019 Elsevier Inc. All rights reserved.
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),
Dr. Krystal has received consulting fees from
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