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Cited by 249Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections

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Duman, Ronald S.·2014·Dialogues in Clinical Neuroscience
DOI 10.31887/dcns.2014.16.1/rdumanPMC PMC3984887
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Abstract

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.

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  • Evidence for ECM/PNN pathology in psychiatric disorders supports the hypothesis that ECM/PNN abnormalities may contribute to a critical pathological component shared by psychiatric disorders, i.e., disruption of synaptic functions.

    “Evolving in parallel with our understanding of these functions, evidence for ECM/PNN pathology in psychiatric disorders supports the intriguing hypothesis that ECM/PNN abnormalities may contribute to a critical pathological component shared by psychiatric disorders, i.e., disruption of synaptic functions (e.g.Penzes et al., 2013;Duman, 2014;Xu et al., 2014).”

    From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Duman, 2014

    The Introduction links altered synaptogenesis and neural plasticity to functional disconnection in depression. The paper does not link that disruption to ECM or perineuronal-net abnormalities, or establish it as a component shared across psychiatric disorders; searches for those terms returned no such passage. Page numbers were not available in our copy. (LLM, conf=0.86)

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  • Initial studies suggested that ketamine activates mTOR through disinhibition of glutamate transmission, resulting in a rapid burst of glutamate that triggers BDNF release to increase synapse formation.

    “Initial studies had suggested that ketamine activates mTOR through disinhibition of glutamate transmission, resulting in a rapid burst of glutamate that triggers BDNF release to increase synapse formation (see Duman, 2014).”

    From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Duman, 2014

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Authors
Duman, R. S.
Affiliations
Yale University (US)
Corresponding author
Duman, Ronald S.
ORCID
Duman, Ronald S.
Venue
Dialogues in Clinical Neuroscience
Publisher
Informa UK Limited
Published
2014-03-31
Volume
16
Issue
1
Pages
11-27
ISSN
  • 1294-8322 (ISSN-L)
  • 1958-5969
DOI
10.31887/dcns.2014.16.1/rduman
PMC
PMC3984887
OpenAlex
W184284683
Cited by
249
References
20
Citations by year
2026: 9 · 2025: 14 · 2024: 12 · 2023: 24 · 2022: 12 · 2021: 23 · 2020: 23 · 2019: 18 · 2018: 22 · 2017: 22 · 2016: 37 · 2015: 28 · 2014: 5
FWCI
22.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Dialogues in Clinical Neuroscience (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (RC2MH089983, P50MH096891, MH089983, MH96891, R01MH093897, R01MH105910)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
depression pathophysiology, rapid-acting antidepressants, ketamine, NMDA receptor antagonism, scopolamine, muscarinic receptor antagonism, brain-derived neurotrophic factor, glutamatergic neurotransmission, synaptic plasticity, synaptogenesis, chronic stress, neuronal atrophy, prefrontal cortex, hippocampus, treatment-resistant depression
MeSH terms
Animals, Brain, Depression, Glutamine, Humans, Synaptic Transmission, Receptors, N-Methyl-D-Aspartate, Brain-Derived Neurotrophic Factor

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