The DOI matches its Crossref record; 204 of the 204 references it cites were found in a registry or an index.
An excitatory synapse hypothesis of depression
Open accessAbstract
Depression is a common cause of mortality and morbidity, but the biological bases of the deficits in emotional and cognitive processing remain incompletely understood. Current antidepressant therapies are effective in only some patients and act slowly. Here, we propose an excitatory synapse hypothesis of depression in which chronic stress and genetic susceptibility cause changes in the strength of subsets of glutamatergic synapses at multiple locations, including the prefrontal cortex (PFC), hippocampus, and nucleus accumbens (NAc), leading to a dysfunction of corticomesolimbic reward circuitry that underlies many of the symptoms of depression. This hypothesis accounts for current depression treatments and suggests an updated framework for the development of better therapeutic compounds.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It appears that increased strength of excitatory neurotransmission, in particular involving AMPARs, represents a common downstream target that is necessary for antidepressant efficacy among classical and rapid-acting antidepressants (Alt et al., 2006; Gould et al., 2019; Thompson et al., 2015).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Thompson et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Collectively, these patterns observed in human patients are consistent with the premise that neuronal and molecular plasticity deficits may feed forward to impairments in the coordinated function of prefrontal and limbic regions 66 , resulting in impaired PFC regulation and unchecked stimulus-driven responses to salient negative stimuli.”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [66]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although stress-induced structural changes in the PFC are equally important in their contribution to the pathophysiology of neuropsychiatric conditions [256–262]”
From Development of prefrontal cortex (2022) · cites this paper as [259]
Experimental — accuracy not yet measuredIn the citing paper
“Conventional antidepressant therapeutics including selective serotonin reuptake inhibitors (SSRIs) or non-typical therapeutics, including ketamine and brain stimulation, may alleviate depression symptoms by acting on excitatory brain systems (33).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [33]
In the citing paper
“Stress-induced dysfunction in forebrain excitatory transmission has led to the development of the excitatory synaptic transmission hypothesis of depression (22, 32, 33).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [33]
In the citing paper
“As glutamate clearance modulates neuronal excitability [200] and glutamatergic synapse strength contributes to depression [202], how astrocytic glutamate clearance contributes to excitatory synapse strength and subsequent depressive behavior is also worth further investigation in the reward circuit.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [202]
In the citing paper
“Indeed, a net result of all these processes is a sustained potentiation of excitatory synapses in cortico-mesolimbic brain circuits involved in the maintenance of mood and stress-reactivity 190.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [190]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.593 · Cited by 20,391
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
Deep Brain Stimulation for Treatment-Resistant Depression
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., Schwalb, J. M., & Kennedy, S. H. (2005) · Neuron · doi:10.1016/j.neuron.2005.02.014 · Cited by 4,059
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766
The Neuroendocrinology of Stress: A Never Ending Story
Lightman, S. L. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01711.x · Cited by 3,588
THE CATECHOLAMINE HYPOTHESIS OF AFFECTIVE DISORDERS: A REVIEW OF SUPPORTING EVIDENCE
Schildkraut, J. J. (1965) · American Journal of Psychiatry · doi:10.1176/ajp.122.5.509 · Cited by 3,568
A Neurotrophic Model for Stress-Related Mood Disorders
Duman, R. S., & Monteggia, L. M. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.02.013 · Cited by 3,375
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)00653-0 · Cited by 3,217
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–267 of 267
Deng, Y., Liang, X., Li, Y., Jiang, L. H., Wang, J., Tang, J., Li, J., Xie, Y., Xiao, K., Zhu, P., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109908 · Cited by 6
Cell-Based Systems of Depression: An Overview
Jantas, D. (2016) · Springer eBooks · doi:10.1007/978-3-319-14021-6_3 · Cited by 6
Robert, A., Combalbert, N., Pennequin, V., Deperrois, R., & Ouhmad, N. (2021) · Psychologie Française · doi:10.1016/j.psfr.2021.04.003 · Cited by 6
Barrutieta-Arberas, I., Ortuzar, N., Vaquero-Rodríguez, A., Picó-Gallardo, M., Bengoetxea, H., Guevara, M., Gargiulo, P. A., & Lafuente, J. V. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702231170007 · Cited by 6
Gilbert, K. F., Amontree, M., Deasy, S., Ma, J., & Conant, K. E. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16570 · Cited by 5
Wróbel, J., Iwaniak, P., Dobrowolski, P., Chwil, M., Sadok, I., Kluz, T., Wdowiak, A., Bojar, I., Poleszak, E., Misiek, M., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312630 · Cited by 5
Aberrant anterior cingulate processing of anticipated threat as a mechanism for psychosis
Kvarta, M. D., Chiappelli, J., West, J., Goldwaser, E. L., Bruce, H. A., Ma, Y., Kochunov, P., Hatch, K. S., Gao, S., Jones, A., et al. (2021) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2021.111300 · Cited by 5
Self-citationLiu, Y., Chen, C., Zhao, Y., Li, M., Gao, Y., Yan, B., Jing, Y., Zhang, B., & Li, J. (2025) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2025.107472 · Cited by 4
Furuta, R., & Miyake, A. (2025) · Differentiation · doi:10.1016/j.diff.2025.100860 · Cited by 4
Liang, H., Zhao, Z.-B., Liu, Z., Samsom, J., Chen, K., Chen, Y., Chen, L., Cai, C.-Y., & Liu, F. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02163-7 · Cited by 4
Gardner, W., Fuchs, F., Durieux, L., Bourgin, P., Coenen, V. A., Döbrössy, M. D., & Lecourtier, L. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.06.023 · Cited by 4
Bhatti, D. L., Jin, J., Cheng, J., McCabe, K. A., Lee, K.-W., Berdasco, C., Jeong, Y. Y., Sinha, S. C., & Kim, Y. D. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1350716 · Cited by 4
A serial mediation model of physical exercise and loneliness: the role of frailty and depression
Gu, S., & Liu, S. (2025) · BMC Geriatrics · doi:10.1186/s12877-025-05988-5 · Cited by 4
Depression: Evolutionary New Neural Circuitries Are Still Adjusting for Cognition
Graczynska, A., & Stefano, G. B. (2015) · Medical science monitor basic research/Medical science monitor. Basic research · doi:10.12659/msmbr.895991 · Cited by 4
Knott, M. V., Ngwenya, L. B., Correll, E. A., Bohnert, J., Ziemba, N. J., Allgire, E., Hopkins, T., & McGuire, J. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158086 · Cited by 4
Yi, Y., Li, J., & Chen, W. (2021) · Tropical Journal of Pharmaceutical Research · doi:10.4314/tjpr.v18i3.23 · Cited by 4
Riggs, L. M., Aronson, S., Mou, T.-C. M., Pereira, E. F. R., Thompson, S. M., & Gould, T. D. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115743 · Cited by 4
Self-citationRominto, A. M., Montarolo, F., Berrino, L., Loddo, M., Bertolotto, A., Tempia, F., & Hoxha, E. (2025) · Scientific Reports · doi:10.1038/s41598-025-22321-7 · Cited by 4
de Schultz, T. F., Braun, K. A., & Bock, J. (2023) · Developmental Neuroscience · doi:10.1159/000530050 · Cited by 3
Bailey, A. M., Barrett, A., Havens, L., Leyder, E. C., Merchant, T., Starnes, H. M., & Thompson, S. M. (2023) · Behavioural Brain Research · doi:10.1016/j.bbr.2023.114554 · Cited by 3
Self-citationRapid Anti-Depressant Relief by Ketamine: Exploring A Complex Mechanism of Action
Blum, K., Pappas, T. C., Clifton, B., Baron, D. A., Madigan, M. A., Lott, L., Moran, M., Clifton, C., Worrich, S., Clarke, E., et al. (2019) · Current Psychopharmacologye · doi:10.2174/2211556008666190827150018 · Cited by 3
Magbri, A. (2021) · Archives in Neurology & Neuroscience · doi:10.33552/ann.2021.10.000739 · Cited by 2
LeGates, T. A. (2020) · Science · doi:10.1126/science.abe1481 · Cited by 3
Self-citationPark, H.-Y., Ryu, H., Zhang, S., Kim, S. M., & Chung, C. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-02025-8 · Cited by 2
Troppoli, T. A., & Thompson, S. M. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.10.036 · Cited by 3
Self-citationThe Impacts of Associative Memory Cells on Pathology
Wang, J. (2019) · Springer eBooks · doi:10.1007/978-981-13-9501-7_9 · Cited by 2
Optimizing psychedelic compounds for neuropsychiatric therapy
Thompson, S. M. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01004-7 · Cited by 2
Self-citationZhuang, Y., Song, W., Kuang, S., Li, W., Pan, S., Wang, Z., Qu, W., Chen, J., Tan, Y., Wang, C., et al. (2025) · Depression and Anxiety · doi:10.1155/da/7376934 · Cited by 1
Abu-Moch, M., Azab, A. N., Yousef, M., & Agam, G. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119356 · Cited by 1
Jehli, E., Denier, N., Federspiel, A., Dierks, T., Strik, W. K., Soravia, L. M., & Grieder, M. (2024) · Brain Connectivity · doi:10.1089/brain.2024.0031 · Cited by 1
Gutiérrez-Vega, I., Schneider, I., Cáceres, C., Herrera‐Marschitz, M., Romanelli, M. N., Morales, P., Quintanilla, M. E., Vásquez, D., & Rivera‐Meza, M. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.124043 · Cited by 1
Synaptic Modulation in the Effect of Ketamine
Okada, D. (2020) · Springer eBooks · doi:10.1007/978-981-15-2902-3_5 · Cited by 1
Diniz, D. M., Bosch, K., Calabrese, F., Brivio, P., Riva, M. A., Grandjean, J., & Homberg, J. R. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.01.180604 · Cited by 1
The molecular fingerprint of stress resiliencePreprint
Włodarczyk, J., Bączyńska, E., Zaręba-Kozioł, M., Ruszczycki, B., Krzystyniak, A., Wójtowicz, T., Bijata, K., Pochwat, B., Magnowska, M., Roszkowska, M., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1780322/v1 · Cited by 1
Resting and Functional Magnetic Resonance Spectroscopy of Glutamate in Schizophrenia at 7 Tesla
Taylor, R. (2015) · Scholarship@Western (Western University)
Understanding Mood Disorders Using Electrophysiology and Circuit Breaking
Liu, H., & Chaudhury, D. (2017) · Springer eBooks · doi:10.1007/978-3-319-57363-2_14
Bravo‐Hernández, M., Shigyo, M., Granados‐Soto, V., & Maršala, M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.97282-9
Efeitos comportamentais e neuroplásticos da combinação de escitalopram e canabinóides
Scarante, F. F. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.17.2018.tde-25072018-103829
Developing Therapeutic Alternatives for Treatment-resistant Bipolar Depression: The Role of Riluzole
Çöpür, S., & Çöpür, M. (2020) · Çocuk ve Gençlik Ruh Sağlığı Dergisi / Turkish Journal of Child and Adolescent Mental Health · doi:10.4274/tjcamh.galenos.2020.92485
Bicaudal-C protein, a potential antidepressant target
Han, Q., Jiang, J., Yuan, Y., Tang, B., & Zhang, J. (2021) · Neuroreport · doi:10.1097/wnr.0000000000001729
Wu, Z., Huang, X., Cai, M., Huang, P., & Guan, Z. (2021) · Research Square · doi:10.21203/rs.3.rs-958945/v1
Basic Hypothesis and Therapeutics Targets of Depression: A Review
Kumar, A. (2021) · Archives in Neurology & Neuroscience · doi:10.33552/ann.2021.10.000738
Coutens, B., Bouisset, G., Verret, L., Rampon, C., & Guiard, B. P. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.10.657
The Effect of Natural Therapies in Combination with Usual Care for Depression: A Narrative Review
Chohan, P., & Gratton, A. (2022) · Undergraduate Research in Natural and Clinical Science and Technology (URNCST) Journal · doi:10.26685/urncst.321
Möhler, H. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.726820572.793560273
Möhler, H. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727390292.793560280
Effect of Somatostatin-Expressing Interneuron Deficits in Depression
郭, 沉. (2019) · Advances in Psychology · doi:10.12677/ap.2019.910214
Carreno, F. R. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.05.018
Basha, E., Faheem, H., Ibrahim, H. A., Ismail, R., Seleem, M., Elkordy, A. M., & Khattab, H. A. (2023) · Bulletin of Egyptian Society for Physiological Sciences · doi:10.21608/besps.2022.171592.1131
Dissociable neurofunctional and molecular characterizations of reward and punishment sensitivityPreprint
Xu, T., Zhu, C., Zhou, X., Chen, Z., Gan, X., Cui, X., Zhou, F., Zhang, R., Zhao, W., Zhang, X., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.30.630747
Hummel, K., Stefansson, L., Gilbert, K. F., Amontree, M., Ma, J., Pak, D. T. S., & Conant, K. E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.12.675856
Meng, P., Zhang, X., Liu, T.-T., Liu, J., Luo, Y., Xie, M., Yang, H., Fang, R., Guo, D.-W., Zhong, Z.-Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26597522
Yin, M.-Y., Guo, L., Zhao, L.-J., Zhang, C., Liu, W.-P., Zhang, C., Huo, J.-H., Wang, L., Li, S., Zheng, C.-B., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23689506
Yin, M.-Y., Guo, L., Zhao, L.-J., Zhang, C., Liu, W.-P., Zhang, C.-Y., Huo, J.-H., Wang, L., Li, S., Zheng, C.-B., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23689509
Zeng, T., Li, J., Xie, L., Dong, Z., Chen, Q., Huang, S., Xie, S., Lai, Y., Li, J., Yan, W., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24180905
Wang, M., Qi, X., Yang, X., Fan, H., Dou, Y., Guo, W., Wang, Q., Chen, E., Li, T., & Ma, X. (2022) · Figshare · doi:10.6084/m9.figshare.20423771
Kim, H. R., Lee, Y.-J., Kim, T.-W., Lim, R.-N., Hwang, D. Y., Moffat, J. J., Kim, S., Seo, J.-W., & Ka, M. (2020) · Figshare · doi:10.6084/m9.figshare.13152013
Meng, P., Zhang, X., Liu, T.-T., Liu, J., Luo, Y., Xie, M., Yang, H., Fang, R., Guo, D.-W., Zhong, Z.-Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26597525
Hummel, K., Shautidze, G., Thorland, E., Amontree, M., Wonnenberg, P. M., Blanco, I., & Conant, K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.12.693967
Sc-RNA seq Reveals the Protective Effects of Baoyuan Jieyu Formula on Spaceflight Depression Rats
Yin, Y., Wu, X., Liu, J., Xu, C. B., Zhu, Y., Zeng, D., Ju, T., Duan, F., Li, Y., & Lu, W. (2026) · Space Science & Technology · doi:10.34133/space.0321
Lewandrowski, K. U., Blum, K., Schmidt, S., Fiorelli, R. K. A., Gold, M. S., Mohankumar, K., Sharafshah, A., Bagchi, D., Pinhasov, A., Lorio, M. P., et al. (2026) · Substance Use & Misuse · doi:10.1080/10826084.2025.2612330
LaChapelle-Sproat, M. V., Anderson, N. S., & LeGates, T. A. (2026) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2026.100757 · Cited by 1
Self-citationDrug Repurposing Patent Applications October–December 2025
Mucke, H. A. (2026) · Drug repurposing · doi:10.58647/drugrepo.26.1.0002
BindingDB Entry 50011888: Repurposing of Drugs-The Ketamine Story.
BindingDB (2022) · UC San Diego · doi:10.7270/q2t15797
BindingDB (2021) · UC San Diego · doi:10.7270/q2ks6w2r
Metadata
- Authors
- Thompson, S. M., Kallarackal, A. J., Kvarta, M. D., Van Dyke, A. M., LeGates, T. A., & Cai, X.
- Affiliations
- University of Maryland, Baltimore (US)
- Southern Illinois University Carbondale (US)
- Corresponding author
- Thompson, Scott M.
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 38
- Issue
- 5
- Pages
- 279-294
- ISSN
- 0166-2236 (ISSN-L)
- PMC
- PMC4417609
- OpenAlex
- W2088861514
- Cited by
- 265
- References
- 203
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 23 · 2023: 34 · 2022: 23 · 2021: 33 · 2020: 29 · 2019: 28 · 2018: 20 · 2017: 22 · 2016: 17 · 2015: 14
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Neurosciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2t32ns063391-21)
- National Institute of Mental Health (R01MH086828)
- National Institute of General Medical Sciences (T32GM008181, T32GM092237)
- National Institute of Neurological Disorders and Stroke (T32NS007375, T32-NS063391)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- depression, glutamatergic synapses, chronic stress, genetic susceptibility, prefrontal cortex, hippocampus, nucleus accumbens, antidepressant treatment, synaptic plasticity
- MeSH terms
- Animals, Antidepressive Agents, Brain, Depression, Humans, Synapses, Excitatory Postsynaptic Potentials
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
