NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS: Review: Remodeling Synaptic Connections
Open accessAbstract
Stress and depression are associated with atrophy and loss of neurons in limbic and cortical brain regions that could contribute to the symptoms of depression. Typical monoamine reuptake inhibitor antidepressants have only modest efficacy and require long-term treatment, and are only weakly effective in blocking or reversing these structural changes caused by stress. Recent findings demonstrate that ketamine, an NMDA receptor antagonist, produces rapid antidepressant actions in difficult to treat depressed patients. In addition, preclinical studies demonstrate that ketamine rapidly increases synaptic connections in the prefrontal cortex by increasing glutamate signaling and activation of pathways that control the synthesis of synaptic proteins. Moreover, ketamine rapidly reverses the synaptic deficits caused by exposure to chronic stress in rodent models. Studies of the signaling mechanisms underlying the actions of ketamine have provided novel approaches and targets for new rapid acting antidepressants with decreased side effects, as well as a better understanding of the neurobiology of stress, depression, and treatment response.
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Loss of synaptic connections in mood-related circuitry is a central pathophysiological process underlying depression and other stress-related disorders, such as PTSD.
“This discovery fits with convergent evidence implicating a loss of synaptic connections in mood-related circuitry as a central pathophysiological process underlying depression and other stress-related disorders, such as PTSD 15,16 .”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [15]
The section “Stress and Depression Cause Loss of Synaptic Connections” (page unavailable) reports fewer synapses in depressed subjects and says synaptic loss could disrupt mood regulation. It also links PTSD to reduced volume in relevant brain regions, but does not establish synaptic loss as a central underlying process in PTSD; its proposed role in depression is qualified as a possibility. (LLM, conf=0.85)
Experimental — accuracy not yet measuredKetamine administration reverses synaptic loss and depressive-like behavior induced by chronic stress in preclinical models.
“Pioneering preclinical work carried out by Duman et al. indicates that administration of ketamine reverses the synaptic loss and depressive-like behavior induced by chronic stress 15,29,30 .”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [15]
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“indicates that administration of ketamine reverses the synaptic loss and depressive-like behavior induced by chronic stress [15, 29, 30].”
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- Authors
- Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- ORCID
- Duman, Ronald S.
- Venue
- Depression and Anxiety
- Publisher
- Hindawi Limited
- Published
- 2014-03-10
- Volume
- 31
- Issue
- 4
- Pages
- 291-296
- ISSN
- 1091-4269 (ISSN-L)
- PMC
- PMC4432471
- OpenAlex
- W1814685953
- Cited by
- 213
- References
- 36
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 14 · 2023: 16 · 2022: 14 · 2021: 21 · 2020: 21 · 2019: 25 · 2018: 15 · 2017: 19 · 2016: 25 · 2015: 14 · 2014: 9
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Depression and Anxiety (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (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, stress, ketamine, rapid-acting antidepressants, synaptic plasticity, NMDA receptor antagonism, chronic stress, prefrontal cortex, glutamate signaling, synaptic proteins, monoamine reuptake inhibitors, neuroplasticity, treatment response
- MeSH terms
- Antidepressive Agents, Brain, Depressive Disorder, Humans, Synaptic Transmission, Neurobiology, Stress, Psychological
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