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.

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].

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Figures

Figure 1.. Stress and depression decrease both glutamate and GABA neurotransmitter systems in cortical and limbic brain regions: Reversal by ketamine.

SST interneurons innervated dendrites of principle neurons and gate synaptic input while PV interneuron subtypes innervate the soma (basket cells) and initial axon (chandelier cells) of principle neurons and gate output. Under normal nonstressed conditions, GABA and glutamate transmission is balanced and optimized to provide high signal to noise ratio and integrity of signal transfer. Clinical and preclinical studies report that depression and chronic stress cause deficits of both GABA and glutamate systems. Clinical studies demonstrate reductions in the volume of prefrontal cortex (PFC) and hippocampus, reductions in synaptic markers, decreased SST interneuron markers, as well as decreased levels of glutamatic acid decarboxylase (GAD). There is less consistent evidence for deficits of PV interneurons. Preclinical studies demonstrate that chronic stress exposure causes atrophy of pyramidal neuron dendrites in PFC and hippocampus, reductions of synapse number and proteins (PSD95, GluA1), and decreased levels of the vesicular glutamate transporter (VGLUT); chronic stress also causes reductions of GABA neuronal markers, notably SST, the vesicular GABA transporter (VGAT), GAD, and gephyrin. Reductions in GABA and glutamate neurotransmitter systems would decrease signal to noise ratio and result in degradation of signal integrity in these regions. In contrast, a single dose of ketamine, which causes rapid and efficacious antidepressant actions in depressed patients, rapidly increases both GABA and glutamate systems and reverses the deficits caused by chronic stress exposure. Preclinical studies show that ketamine causes a burst of glutamate via blockade of NMDARs on GABA interneurons. GABA interneurons are more sensitive to ketamine because their tonic firing removes Mg+2 from the channel, allowing ketamine to enter and block the channel. This glutamate burst causes activity dependent release of BDNF and increased synapse number and function in layer 5 pyramidal neurons in the medial prefrontal cortex (mPFC), as well as increased synaptic markers (PSD95, GluA1, VGLUT). Recent studies show that ketamine rapidly increases GABA function in the mPFC including increased levels the VGAT, GAD, and gephyrin. Up-regulation of GABA and glutamate neurotransmitter systems reverses the effects of chronic stress exposure, and thereby increases signal to noise and enhances integrity of signaling in these regions

Figure 2.. Genome and transcriptome overlap between psychiatric disorders.

(A) The psychiatric genomics consortium (PGC) reported common variant risk was significantly correlated for psychiatric illnesses, most notably attention hyperactivity disorder (ADHD), BD, MDD, and schizophrenia (Brainstorm Consortium, 2018). There was little or no overlap with neurological disorders, including Alzheimer’s disease, epilepsy, and migraine. Both psychiatric and neurological disease groups show correlations with neurocognitive quantitative phenotypes. Blue indicates positive, and red negative correlations; solid lines indicate higher degree of correlation. The first panel shows correlations between psychiatric conditions and with quantitative measures of neuroticism, smoking and education. The second panel shows correlations between psychiatric and neurological disorders. (B) A meta-analysis found significant overlap of transcriptome profiles between schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD) and major depressive disorder (MDD) (Gandal et al., 2018). There was no significant overlap with irritable bowel syndrome (IBD) and alcoholism (AAD).

Figure 3.. Chronic stress and depression decrease and rapid acting antidepressants increase glutamate and GABA neurotransmitter function.

Chronic stress and depression are associated with reductions of both glutamate and GABA function, including atrophy of pyramidal neurons and reductions of glutamate and GABA neuronal markers in the medial PFC and hippocampus. Rapid acting antidepressants, notably ketamine and esketamine that produce rapid antidepressant actions in depressed patients, rapidly up-regulate glutamate synapse density, synaptic protein levels (i.e., PSD95, GluA1, VGLUTs), and function, and also increase GABA function, including increased VGAT, GAD, and gephyrin. Ketamine causes a transient burst of glutamate, resulting from blockade of NMDA receptors on tonic firing GABA interneurons. This glutamate burst causes synaptic remodeling and resetting of glutamate and GABA systems. Other rapid acting antidepressants, including the muscarinic receptor antagonist scopolamine and mGluR2/3 antagonists also produce rapid antidepressant actions via transient stimulation of glutamate. The glutamate burst stimulates BDNF release, which activates downstream signaling, including the Akt-mTORC1 pathway that increases synaptic proteins synthesis. Blockade of this pathway with the selective mTORC1 inhibitor rapamycin blocks the synaptic and antidepressant behavioral actions of ketamine. Deficits of GABA, combined with evidence that fluctuations of neuroactive steroids contribute to depression in women have led to development of GABAergic agents, including formulations of alloprenanolone (brexanolone and SAGE-217), which act as positive allosteric modulators of the GABAAR complex.