Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments

Duman, Ronald S.; Sanacora, Gerard; Krystal, John H.

doi:10.1016/j.neuron.2019.03.013

Cited by 1,026Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchStress Responses and Cortisol

Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments

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Duman, Ronald S., Sanacora, Gerard, Krystal, John H.·2019·Neuron

DOI 10.1016/j.neuron.2019.03.013PMC PMC6450409

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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.

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Repeated stress decreases BDNF expression in limbic and cortical brain regions, notably the hippocampus and PFC.
“Repeated stress decreases the expression of BDNF in limbic and cortical brain regions, notably the hippocampus and PFC 4,5,22 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [22]
The “GABA alterations in MDD and stress” section says stress reduces BDNF and reports that chronic stress lowers certain BDNF mRNA isoforms, in context of findings about the PFC. The “Stress and neurotrophic factors” section reports lower BDNF in the hippocampus and PFC of people with depression, but does not establish that repeated stress caused the hippocampal decrease. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Findings in mood disorders reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function in several brain regions implicated in depression.
“These findings reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function, and have been described in several brain regions implicated in depression 13-22 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [22]
The sections on stress and neurotrophic factors, genetics, and glutamate alterations describe changes in signaling, gene expression, BDNF, excitatory and inhibitory neurotransmission, and synapses in depression-related brain regions (pages unavailable). The copy does not establish altered neurogenesis, and its discussion of neuroinflammation is limited to a genetic association and proposed inflammatory mechanisms rather than a demonstrated alteration. (LLM, conf=0.86)
Experimental — accuracy not yet measured
A single dose of ketamine increases BDNF release and stimulates mTORC1 signaling, leading to increased levels of synaptic proteins (GluR1, PSD95, synapsin 1) and increased number and function of synapses in the PFC.
“A single dose of ketamine increases BDNF release and stimulates mTORC1 signaling, which leads to increased levels of synaptic proteins (i.e., GluR1, PSD95, and synapsin 1) and increased number and function of synapses in the PFC 4,22,35 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [22]
The “Novel antidepressants treatments that influence glutamate” section (page unavailable) says ketamine-induced synapse formation depends on BDNF release and mTORC1 signaling, and that a single dose increases synaptic protein levels and the number and function of mPFC synapses. It names GluA1, but does not name PSD95 or synapsin 1 among the proteins increased; the synapse findings described are from rodent studies. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Chronic stress disrupts key neurotransmitter systems, alters neuronal connectivity, and disturbs synaptic network activity, leading to dysregulated excitatory glutamatergic signaling, impaired dopaminergic transmission, and altered inhibitory GABAergic signaling in specific brain regions.
“Concurrently, chronic stress disrupts key neurotransmitter systems, alters neuronal connectivity, and disturbs synaptic network activity, leading to, for example, dysregulated excitatory glutamatergic signaling, impaired dopaminergic transmission, and altered inhibitory GABAergic signaling in specific brain regions [4,24,29,35,36,37].”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [37]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Dysregulation of mPFC activity, particularly within L5 projection neurons, is implicated in the pathophysiology of depression through clinical imaging and preclinical models.
“Dysregulation of mPFC activity—particularly within layer 5 (L5) projection neurons—has been implicated in the pathophysiology of depression through both clinical imaging studies and preclinical models [12–14].”
From A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors (2026) · cites this paper as [13]
The paper’s ‘Structural and functional connectivity alterations in depression’ section reports abnormal PFC connectivity in clinical imaging studies. Its ‘Glutamate alterations in MDD and stress’ section reports that chronic stress reduces dendritic branching in mPFC layer V pyramidal neurons. These passages support the broad link, but the imaging findings do not establish activity changes specifically in L5 projection neurons, and the layer V preclinical finding concerns neuronal structure rather than measured activity. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured

Altered connectivity and disruptions in E/I balance contribute to the core pathophysiology of major depressive disorder.
“These findings align with previous reports indicating altered connectivity [13] and disruptions in E/I balance contribute to the core pathophysiology of major depressive disorder [28, 31, 32].”
From A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors (2026) · cites this paper as [13]
Approximately one-third of depressed patients fail to remit even after four adequate therapeutic trials.
“Approximately one-third of depressed patients fail to remit, even after four adequate therapeutic trials [3].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [3]
Multiple SNPs in BDNF-associated regions have been associated with treatment response to ketamine and SSRIs in some patient populations, and BDNF knockout mice show reduced responsiveness to such therapies.
“Moreover, multiple SNPs in BDNF-associated regions have been associated with treatment response to ketamine and selective serotonin reuptake inhibitors (SSRIs) in some patient populations. BDNF knockout mice also show reduced responsiveness to such therapies [3,49].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [3]
Alterations in BDNF activity may contribute to the acute regional volumetric decreases associated with MDD/TRD.
“It is suggested that alterations in BDNF activity may contribute to the acute regional volumetric decreases associated with MDD/TRD [3].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [3]
BDNF levels are reduced in postmortem hippocampal and PFC samples of patients with MDD.
“Brain-derived neurotrophic factor (BDNF) levels, a primary driver of neuroplasticity and glutamate modulation, are reduced in postmortem hippocampal and PFC samples of patients with MDD.”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [3]

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Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine
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The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex
Oh, H., Lewis, D. A., & Sibille, E. L. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.126 · Cited by 109 · see citing works
A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice
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GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine
Liu, R.-J., Duman, C., Kato, T., Hare, B., Lopresto, D., Bang, E., Burgdorf, J., Moskal, J., Taylor, J., Aghajanian, G., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.202 · Cited by 105 · see citing works
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Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression
Seney, M. L., Tripp, A. C., McCune, S., Lewis, D. A., & Sibille, E. L. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.10.005 · Cited by 95 · see citing works
BDNF Release and Signaling Are Required for the Antidepressant Actions of GLYX-13
Kato, T., Fogaça, M. V., Deyama, S., Li, X.-Y., Fukumoto, K., & Duman, R. S. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.220 · Cited by 88 · see citing works
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The Genetics of Major Depression
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Ketamine administration reduces amygdalo‐hippocampal reactivity to emotional stimulation
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Neurosteroids and GABAergic signaling in health and disease
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Activity-dependent brain-derived neurotrophic factor expression regulates cortistatin-interneurons and sleep behavior
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Decrease in somatostatin-positive cell density in the amygdala of females with major depression: Douillard-Guilloux et al.
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Neuropsychiatric Phenotypes Produced by GABA Reduction in Mouse Cortex and Hippocampus
Kolata, S., Nakao, K., Jeevakumar, V., Farmer-Alroth, E. L., Fujita, Y., Bartley, A. F., Jiang, S. Z., Rompala, G. R., Sorge, R. E., Jimenez, D. V., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.296 · Cited by 44 · see citing works
Area-specific effects of brain-derived neurotrophic factor (BDNF) genetic ablation on various neuronal subtypes of the mouse brain
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Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists
Koike, H., Iijima, M., & Chaki, S. (2011) · Neuroscience Research · doi:10.1016/j.neures.2011.07.860 · Cited by 36 · see citing works
Anxiolytic-like effects of somatostatin isoforms SST 14 and SST 28 in two animal models (Rattus norvegicus) after intra-amygdalar and intra-septal microinfusions
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Alterations in hippocampal calcium-binding neurons induced by stress models of depression: a preliminary assessment
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BDNF-Dependent Effects on Amygdala–Cortical Circuitry and Depression Risk in Children and Youth
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Different pattern of changes in calcium binding proteins immunoreactivity in the medial prefrontal cortex of rats exposed to stress models of depression
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Hormones, heart disease, and health: individualized medicine versus throwing the baby out with the bathwater
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Cortical GABA neurons and self-focus in depression: a model linking cellular, biochemical and neural network findings
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Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task
Chuang, J.-Y., Hagan, C. C., Murray, G. K., Graham, J. M., Ooi, C., Tait, R. J., Holt, R., Elliott, R., van Nieuwenhuizen, A. O., Bullmore, E. T., et al. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00119 · Cited by 24 · see citing works
The potential efficacy of GABA B antagonists in depression
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A spectroscopic approach toward depression diagnosis: local metabolism meets functional connectivity
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Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model
Price, R. B., & Duman, R. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0615-x · Cited by 721 · see citing works
Self-citation
Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories
Hassamal, S. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1130989 · Cited by 578 · see citing works
“Newer treatments are focusing on restoring the glutamate and GABAergic neurotransmission balance (151).”
Background
Molecular pathways of major depressive disorder converge on the synapse
Fries, G. R., Saldana, V. A., Finnstein, J., & Rein, T. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01806-1 · Cited by 504 · see citing works
Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions
Hare, B. D., & Duman, R. S. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0685-9 · Cited by 366 · see citing works
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GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions
Gerhard, D. M., Pothula, S., Liu, R.-J., Wu, M., Li, X.-Y., Girgenti, M. J., Taylor, S. R., Duman, C. H., Delpire, E., Picciotto, M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci130808 · Cited by 345 · see citing works
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Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction.
Karlsson Linnér, R., Mallard, T. T., Barr, P. B., Sanchez-Roige, S., Madole, J. W., Driver, M. N., Poore, H. E., de Vlaming, R., Grotzinger, A. D., Tielbeek, J. J., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00908-3 · Cited by 317 · see citing works
“…of action for alcohol and benzodiazepines, extensively studied in relation to alcohol dependence 35,36 and candidate gene for psychiatric disorders 37,38 ), neuronal growth regulator 1 ( NEGR1 ; associated with intelligence and educational attainment 39,40 ) and paired basic amino acid cleaving…”
Background
Role of BDNF in the Pathophysiology and Treatment of Depression: Activity-Dependent Effects Distinguish Rapid-Acting Antidepressants
Duman, R. S., Deyama, S., & Fogaça, M. V. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14630 · Cited by 321 · see citing works
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Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond
Zorumski, C. F., Paul, S. M., Covey, D. F., & Mennerick, S. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100196 · Cited by 305 · see citing works
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor
Wei, Y., Chang, L., & Hashimoto, K. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01121-1 · Cited by 248 · see citing works
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders
Sanacora, G., Yan, Z., & Popoli, M. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00540-x · Cited by 197 · see citing works
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BDNF signaling during the lifetime of dendritic spines
Zagrebelsky, M., Tacke, C., & Korte, M. (2020) · Cell and Tissue Research · doi:10.1007/s00441-020-03226-5 · Cited by 147 · see citing works
Antidepressant actions of ketamine engage cell-specific translation via eIF4E
Aguilar-Valles, A., De Gregorio, D., Matta-Camacho, E., Eslamizade, M. J., Khlaifia, A., Skaleka, A., Lopez-Canul, M., Torres-Berrio, A., Bermudez, S., Rurak, G. M., et al. (2021) · Nature · doi:10.1038/s41586-020-03047-0 · Cited by 144 · see citing works
Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression
Ling, S., Ceban, F., Lui, L. M. W., Lee, Y., Teopiz, K. M., Rodrigues, N. B., Lipsitz, O., Gill, H., Subramaniapillai, M., Mansur, R. B., et al. (2022) · CNS Drugs · doi:10.1007/s40263-021-00877-y · Cited by 127 · see citing works
Brain-wide changes in excitation-inhibition balance of major depressive disorder: a systematic review of topographic patterns of GABA- and glutamatergic alterations
Hu, Y.-T., Tan, Z.-L., Hirjak, D., & Northoff, G. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02193-x · Cited by 127 · see citing works
The molecular pathophysiology of depression and the new therapeutics
Tian, H., Hu, Z., Xu, J., & Wang, C. (2022) · MedComm · doi:10.1002/mco2.156 · Cited by 122 · see citing works
Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals
Mkrtchian, A., Evans, J. W., Kraus, C., Yuan, P., Kadriu, B., Nugent, A. C., Roiser, J. P., & Zarate, C. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00878-1 · Cited by 110 · see citing works
Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder
Kantrowitz, J. T., Dong, Z., Milak, M. S., Rashid, R., Kegeles, L. S., Javitt, D. C., Lieberman, J. A., & John Mann, J. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01541-1 · Cited by 100 · see citing works
Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants
Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaa087 · Cited by 99 · see citing works
Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents
Ghosal, S., Duman, C. H., Liu, R.-J., Wu, M., Terwilliger, R., Girgenti, M. J., Wohleb, E., Fogaca, M. V., Teichman, E. M., Hare, B., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104669 · Cited by 89 · see citing works
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A developmental reduction of the excitation:inhibition ratio in association cortex during adolescence
Larsen, B., Cui, Z., Adebimpe, A., Pines, A., Alexander-Bloch, A., Bertolero, M., Calkins, M. E., Gur, R. E., Gur, R. C., Mahadevan, A. S., et al. (2022) · Science Advances · doi:10.1126/sciadv.abj8750 · Cited by 80 · see citing works
A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression
Tiger, M., Veldman, E. R., Ekman, C.-J., Halldin, C., Svenningsson, P., & Lundberg, J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0844-4 · Cited by 81 · see citing works
Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony
Chang, C.-W., Evans, M. D., Yu, X., Yu, G.-Q., & Mucke, L. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109855 · Cited by 81 · see citing works
How does the tea L-theanine buffer stress and anxiety
Wang, L., Brennan, M., Li, S., Zhao, H., Lange, K. W., & Brennan, C. (2022) · Food Science and Human Wellness · doi:10.1016/j.fshw.2021.12.004 · Cited by 80 · see citing works
Glutamatergic Modulators for Major Depression from Theory to Clinical Use
McIntyre, R. S., & Jain, R. (2024) · CNS Drugs · doi:10.1007/s40263-024-01114-y · Cited by 69 · see citing works
Rapid Neuroplasticity Changes and Response to Intravenous Ketamine: A Randomized Controlled Trial in Treatment-Resistant Depression
Kopelman, J., Keller, T. A., Panny, B., Griffo, A., Degutis, M., Spotts, C., Cruz, N., Bell, E., Do-Nguyen, K., Wallace, M. L., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02451-0 · Cited by 60 · see citing works
A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity “Shati/Nat8l-BDNF System” in the Dorsal Striatum
Miyanishi, H., & Nitta, A. (2021) · Pharmaceuticals · doi:10.3390/ph14090889 · Cited by 57 · see citing works
Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits
Yao, H. K., Guet-McCreight, A., Mazza, F., Moradi Chameh, H., Prevot, T. D., Griffiths, J. D., Tripathy, S. J., Valiante, T. A., Sibille, E., & Hay, E. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110232 · Cited by 55 · see citing works
Neurobiology of the rapid-acting antidepressant effects of ketamine: impact and opportunities
Shinohara, R., Aghajanian, G. K., & Abdallah, C. G. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.006 · Cited by 54 · see citing works
The role of eEF2 kinase in the rapid antidepressant actions of ketamine
(2020) · Advances in Pharmacology · doi:10.1016/bs.apha.2020.04.005 · Cited by 52 · see citing works
Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology
Lim, B., Sproule, B. A., Zahra, Z., Sunderji, N., Kennedy, S. H., & Rizvi, S. J. (2020) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000316 · Cited by 50 · see citing works
Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression
Vecera, C. M., C. Courtes, A., Jones, G., Soares, J. C., & Machado-Vieira, R. (2023) · Pharmaceuticals · doi:10.3390/ph16111572 · Cited by 48 · see citing works
“BDNF knockout mice also show reduced responsiveness to such therapies [3,49].”
BackgroundInfluential
Sensory stimulation via the visual, auditory, olfactory and gustatory systems can modulate mood and depression
Canbeyli, R. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15507 · Cited by 48 · see citing works
Chemokine profile in women with moderate to severe anxiety and depression during pregnancy
Camacho-Arroyo, I., Flores-Ramos, M., Mancilla-Herrera, I., Cruz, F. M. C., Hernández-Ruiz, J., Diaz, G. P., Labonne, B. F., del Pilar Meza-Rodríguez, M., & Gelman, P. L. (2021) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-021-04225-2 · Cited by 41 · see citing works
Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis
Conley, A. A., Norwood, A. E. Q., Hatvany, T. C., Griffith, J. D., & Barber, K. E. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05825-8 · Cited by 39 · see citing works
Plasticity of synapses and reward circuit function in the genesis and treatment of depression
Thompson, S. M. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01422-1 · Cited by 40 · see citing works
miR-9-5p is involved in the rescue of stress-dependent dendritic shortening of hippocampal pyramidal neurons induced by acute antidepressant treatment with ketamine
Mingardi, J., La Via, L., Tornese, P., Carini, G., Trontti, K., Seguini, M., Tardito, D., Bono, F., Fiorentini, C., Elia, L., et al. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100381 · Cited by 36 · see citing works
Stress, resilience, and emotional well-being in children and adolescents with specific learning disabilities
Stein, B., Hoeft, F., & Richter, C. G. (2024) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2024.101410 · Cited by 38 · see citing works
Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials
Akbar, D., Rhee, T. G., Ceban, F., Ho, R., Teopiz, K. M., Cao, B., Subramaniapillai, M., Kwan, A. T. H., Rosenblat, J. D., & McIntyre, R. S. (2023) · CNS Drugs · doi:10.1007/s40263-023-01032-5 · Cited by 38 · see citing works
ACh signaling modulates activity of the GABAergic signaling network in the basolateral amygdala and behavior in stress-relevant paradigms
Mineur, Y. S., Mose, T. N., Maibom, K. L., Pittenger, S. T., Soares, A. R., Wu, H., Taylor, S. R., Huang, Y., & Picciotto, M. R. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01749-7 · Cited by 36 · see citing works
Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review
Demchenko, I., Tassone, V. K., Kennedy, S. H., Dunlop, K., & Bhat, V. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.864902 · Cited by 29 · see citing works
“According to this theory, altered levels of synaptic and extrasynaptic glutamate transmission would result in impaired synaptic connectivity in these regions, manifested by decreased synaptogenesis, excitation-inhibition imbalance, neuronal loss and atrophy, and deficits in the inhibitory fine-tuning (18).”
Background
Differences in Quantification of the Metabotropic Glutamate Receptor 5 Across Bipolar Disorder and Major Depressive Disorder
Holmes, S. E., Asch, R. H., Davis, M. T., DellaGioia, N., Pashankar, N., Gallezot, J.-D., Nabulsi, N., Matuskey, D., Sanacora, G., Carson, R. E., et al. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.10.018 · Cited by 27 · see citing works
Self-citation
The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways
Ren, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110910 · Cited by 23 · see citing works
All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants
Freudenberg, F., Reif-Leonhard, C., Dawson, G. R., McKernan, R. M., & Reif, A. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107918 · Cited by 23 · see citing works
Effects of chronic exposure to haloperidol, olanzapine or lithium on SV2A and NLGN synaptic puncta in the rat frontal cortex
Halff, E. F., Cotel, M.-C., Natesan, S., McQuade, R., Ottley, C. J., Srivastava, D. P., Howes, O. D., & Vernon, A. C. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113203 · Cited by 18 · see citing works
Chronic Stress Induces Coordinated Cortical Microcircuit Cell–Type Transcriptomic Changes Consistent With Altered Information Processing
Newton, D. F., Oh, H., Shukla, R., Misquitta, K., Fee, C., Banasr, M., & Sibille, E. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.10.015 · Cited by 19 · see citing works
Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression
Gilbert, J. R., Gerner, J. L., Burton, C. R., Nugent, A. C., Zarate, C. A., & Ballard, E. D. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.06.025 · Cited by 18 · see citing works
Selective ablation of type 3 adenylyl cyclase in somatostatin-positive interneurons produces anxiety- and depression-like behaviors in mice
Yang, X.-Y., Ma, Z.-L., Storm, D. R., Cao, H., & Zhang, Y.-Q. (2021) · World Journal of Psychiatry · doi:10.5498/wjp.v11.i2.35 · Cited by 12 · see citing works
Advances in neurotransmitter-mediated prefrontal circuitry in depression
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Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress
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The Relationship between Personality Advantage and Happiness among College Students: The Moderating Effect of Stressful Life Events
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Authors: Duman, R. S., Sanacora, G., & Krystal, J. H.
Affiliations: Yale University (US)
Corresponding author: Duman, Ronald S.
ORCID: Duman, Ronald S.
Sanacora, Gerard
Krystal, John H.
Venue: Neuron
Publisher: Elsevier BV
Published: 2019-04
Volume: 102
Issue: 1
Pages: 75-90
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2019.03.013
PMC: PMC6450409
OpenAlex: W2933289315
Cited by: 1,026
References: 175
Citations by year: 2026: 137 · 2025: 173 · 2024: 175 · 2023: 146 · 2022: 153 · 2021: 130 · 2020: 93 · 2019: 19
FWCI: 12.72
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 368 d)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIMH (MH045481, MH093897)
NIAAA Center for the Translational Neuroscience of Alcohol (P50AA12870)
CT Department of Mental Health and Addiction Services
Yale-New Haven Health
Yale Center for Clinical Investigation (UL1 RR024139)
U.S. Department of Veterans Affairs
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: depression, chronic stress, GABAergic interneurons, glutamatergic neurons, neural network connectivity, excitotoxicity, glucocorticoids, inflammatory cytokines, sex differences, rapid-acting antidepressants, hippocampus, cortical atrophy, schizophrenia, bipolar disorder, immune mechanisms
MeSH terms: Animals, Antidepressive Agents, Brain, Cerebral Cortex, Depressive Disorder, gamma-Aminobutyric Acid, Hippocampus, Humans, Interneurons, Ketamine, Synaptic Transmission, Neurons, Sex Factors, Glutamic Acid

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