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Cited by 362Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

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Duman, Ronald S., Li, Nanxin·2012·Philosophical Transactions of the Royal Society B: Biological Sciences
DOI 10.1098/rstb.2011.0357PMC PMC3405673
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Abstract

Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N -methyl- d -aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.

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  • These results lend substantial support to the neuroplasticity hypothesis of depression.

    “These results lend substantial support to the neuroplasticity hypothesis of depression (sometimes referred to as the neurotrophin hypothesis) (11, 23–36).”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [30]

  • Diverse NMDA receptor antagonism has demonstrated rapid antidepressant efficacy in preclinical depression paradigms and in some clinical trials.

    “Diverse NMDA receptor antagonism has demonstrated rapid antidepressant efficacy in preclinical depression paradigms [24,29,70,71] and in some clinical trials [72,73].”

    From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [70]

  • The neurotrophic hypothesis proposes that reduced neurotrophic factor signaling underlies dentate granule cell dysgenesis and dendritic and synaptic atrophy in depressed brain.

    “A neurotrophic hypothesis of depression has been proposed, which posits that a decrease in neurotrophic factor signaling as the root of dysgenesis of dentate granule cells and atrophy of dendrites and synapses in depressed brain [87,97,98].”

    From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [97]

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Cited by

Sorted by citations

Authors
Duman, R. S., & Li, N.
Affiliations
Yale University (US)
ORCID
Venue
Philosophical Transactions of the Royal Society B: Biological Sciences
Publisher
The Royal Society
Published
2012-09-05
Volume
367
Issue
1601
Pages
2475-2484
ISSN
  • 0962-8436 (ISSN-L)
  • 1471-2970
DOI
10.1098/rstb.2011.0357
PMC
PMC3405673
OpenAlex
W2117124193
Cited by
362
References
12
Citations by year
2026: 15 · 2025: 32 · 2024: 21 · 2023: 25 · 2022: 31 · 2021: 34 · 2020: 29 · 2019: 39 · 2018: 30 · 2017: 17 · 2016: 24 · 2015: 28 · 2014: 18 · 2013: 14 · 2012: 4
FWCI
2.35
Type
journal article
Language
en
Open access
Licence
royalsociety.org/journals/ethics-policies/data-sharing-mining/ (tdm)
Locations
  • Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (MH-45481, R01MH093897, MH93897, R37MH045481, R01MH045481)
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, neurotrophic hypothesis, synaptogenesis, NMDA receptor antagonists, ketamine, brain-derived neurotrophic factor, chronic stress, prefrontal cortex, hippocampus, synaptic plasticity, mTOR signaling, synaptic proteins, rapid-acting antidepressants, treatment-resistant depression, dendritic spine formation, neurogenesis
MeSH terms
Animals, Antidepressive Agents, Dendrites, Depression, Humans, Ketamine, Stress, Psychological, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Brain-Derived Neurotrophic Factor, Sirolimus, Neurogenesis, TOR Serine-Threonine Kinases, Gene-Environment Interaction

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