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Cited by 1,750Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Open access
Duman, Ronald S, Aghajanian, George K, Sanacora, Gerard, Krystal, John H·2016·Nature Medicine
DOI 10.1038/nm.4050PMC PMC5405628
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Abstract

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

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Written from the paper’s full text.

TL;DR

This review proposes that depression arises from disrupted synaptic connectivity in mood-regulating circuits, driven by stress-related endocrine, neurotrophic, gonadal, metabolic, and inflammatory factors. It highlights rapid-acting antidepressants such as ketamine and scopolamine, which quickly restore synapses through mTORC1-dependent mechanisms, unlike slower monoamine-based treatments.

Key findings

  • Depression is associated with reduced prefrontal cortex and hippocampal volume and fewer prefrontal synapses; stress and glucocorticoids cause neuronal atrophy and synapse loss in rodent models. The paper notes depression affects about 17% of the U.S. population and is roughly twice as common in women.
  • Neurotrophic support, especially BDNF, is reduced in stress and depression. The Val66Met BDNF allele, found in approximately 25% of people, impairs BDNF processing and release, is linked to neuronal atrophy, and increases depression risk after early-life stress.
  • A single subanesthetic dose of ketamine, given intravenously or intranasally, produces rapid antidepressant effects lasting several days in many treatment-resistant unipolar and bipolar patients and reduces suicidal ideation. Scopolamine also shows rapid antidepressant action. Ketamine’s dissociative effects fade within about one hour, while synaptic and behavioral changes persist for a week or more.
  • Mechanistically, ketamine and other NMDA antagonists increase glutamate/AMPA transmission, activate mTORC1, and raise synaptic protein synthesis and synapse number in the prefrontal cortex; rapamycin blocks these effects. Typical SSRIs do not increase mTORC1 signaling. Inflammatory cytokines show a similar dichotomy: low levels support plasticity, while elevated levels contribute to synapse loss; TNF-α neutralization reduced depressive symptoms in psoriasis, and infliximab helped only patients with elevated C-reactive protein.

Methods

  • Narrative review synthesizing clinical and preclinical literature on stress, depression, synaptic plasticity, and rapid-acting antidepressants; no primary data collection or systematic search strategy is described.
  • Evidence discussed includes human postmortem studies, brain imaging, clinical trials, genetic studies, and rodent chronic stress models. The main analysis is a conceptual integration of molecular and cellular pathways—HPA axis, BDNF, estrogen, metabolic factors, and immune signaling—with synaptic connectivity in depression circuits.

Limitations

  • The paper states that clinical heterogeneity, broad diagnostic criteria, and lack of reliable biomarkers complicate understanding depression pathophysiology. It also notes genetic studies are hampered by heterogeneity, low heritability, and multiple low-impact loci.
  • The paper states that links between diabetes, obesity, and depression are correlative and need direct functional evidence; ketamine and scopolamine require larger clinical trials; and negative phase II trials for some NMDA and mGlu2/3 targets raise concerns about those targets’ general efficacy.
  • Evident from the text: as a narrative review, it does not systematically assess study quality, publication bias, or effect sizes, and many mechanistic claims rely on rodent models and postmortem correlations, leaving causal direction in humans uncertain.

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Integrity signals

Registry

Crossref · 10.1038/nm.4050

Cites

198 of 198 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 95 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Current antidepressants such as serotonin reuptake inhibitors produce subtle changes that take effect in weeks or months.

    “Although current antidepressants such as serotonin reuptake inhibitors produce subtle changes that take effect in weeks or months, new agents have recently shown improvement in mood ratings within hours of dosing in patients resistant to typical antidepressants.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Studies in rodent models confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus.

    “Studies in rodent models have extended these human studies, and confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus1011,12.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Duman, R.S. & Aghajanian, G.K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012). source

      Not checked in the free run.

    • cites [11] McEwen, B.S., Eiland, L., Hunter, R.G. & Miller, M.M. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology 62, 3–12 (2012). source

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    • cites [12] Morrison, J.H. & Baxter, M.G. The aging cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012). source

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    • Rests on an assumption: Rodent models of chronic stress and depression are valid models for human depression.
  • Premisecitation

    Among the findings of altered brain structure and function in depression, the most consistent is reduced volume of the prefrontal cortex (PFC) and hippocampus.

    “among the findings of altered brain structure and function in depression, the most consistent is reduced volume of the Prefrontal cortext (PFC) and hippocampus7,8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] MacQueen, G.M., Yucel, K., Taylor, V.H., Macdonald, K. & Joffe, R. Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder. Biol. Psychiatry 64, 880–883 (2008). source

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  • Premisecitation

    Some factors increase resilience and boost the ability to avoid the damaging effects of traumatic or chronic stress.

    “Conversely, some factors increase resilience and boost the ability to avoid the damaging effects of traumatic or chronic stress6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Russo, S.J., Murrough, J.W., Han, M.H., Charney, D.S. & Nestler, E.J. Neurobiology of resilience. Nat. Neurosci. 15, 1475–1484 (2012). source

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  • Premisecitation

    Recent postmortem studies demonstrate reduced synapse number in PFC of depressed subjects.

    “Recent postmortem studies also demonstrate reduced synapse number in PFC of depressed subjects9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Kang, H.J. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat. Med. 18, 1413–1417 (2012). source

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    • Rests on an assumption: Synaptic deficits observed in postmortem PFC of depressed subjects are causally related to depressive symptoms.
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 5

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    Premisecitation

    Currently available antidepressant medications, alone and in combination, are associated with high rates of partial- or non-response, delayed response onset of weeks to months, and limited duration of efficacy.

    “Currently available antidepressant medications, alone and in combination, are associated with high rates of partial- or non-response, delayed response onset of weeks to months, and limited duration of efficacy5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Gaynes, B.N. et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr. Serv. 60, 1439–1445 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The extent of volume reduction is correlated with length of illness and time of treatment, and with the severity of depression.

    “The extent of volume reduction is correlated with length of illness and time of treatment, and with the severity of depression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Abnormal abundance or function of the hypothalamic-pituitary-adrenal (HPA) axis, neurotrophic factors, sex steroids, metabolic and/or inflammatory cytokines can lead to alterations in neurotransmitters, intracellular signaling, gene transcription, translation, and epigenetic changes that can contribute to short-term and long-lasting imbalances of neuronal function and behavior.

    “Abnormal abundance or function of the hypothalamic-pituitary-adrenal (HPA) axis, neurotrophic factors, sex steroids, metabolic and/or inflammatory cytokines can lead to alterations in neurotransmitters, intracellular signaling, gene transcription, translation, and epigenetic changes that can contribute to short-term and long-lasting imbalances of neuronal function and behavior.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    Susceptibility to depression, as well as other psychiatric illnesses, is influenced by a variety of genetic, epigenetic, endocrine, and environmental risk factors.

    “Susceptibility to depression, as well as other psychiatric illnesses is influenced by a variety of genetic, epigenetic, endocrine, and environmental risk factors (Fig. 1; Box 1,2).”
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    • cites Fig. 1; Box 1,2

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    Premisenone given

    Susceptible individuals exposed to traumatic or stressful life events may develop depression; whether they develop disease may be influenced by differences in genetic make-up, prior stressful experiences, and other physiological parameters.

    “For example, susceptible individuals exposed to traumatic or stressful life events may develop depression; whether they develop disease may be influenced by differences in genetic make-up, prior stressful experiences, and other physiological parameters (e.g., gonadal hormone levels, metabolic imbalances).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The expression and function of mTORC1 signaling proteins is reduced in postmortem PFC of depressed subjects, which could contribute to decreased synthesis of synaptic proteins in PFC of depressed subjects.

    “It is interesting to note that the expression and function of mTORC1 signaling proteins is reduced in postmortem PFC of depressed subjects, which could contribute to decreased synthesis of synaptic proteins in PFC of depressed subjects50,51.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Feyissa, A.M., Chandran, A., Stockmeier, C.A. & Karolewicz, B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 70–75 (2009). source

      Not checked in the free run.

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    Premisecitation

    Depression is often associated with elevated HPA axis activity and increased levels of glucocorticoids, as well as disruption of negative feedback mechanisms.

    “Depression is often associated with elevated HPA axis activity and increased levels of glucocorticoids, as well as disruption of negative feedback mechanisms21–23.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Krishnan, V. & Nestler, E.J. The molecular neurobiology of depression. Nature 455, 894–902 (2008). source

      Not checked in the free run.

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    Premisecitation

    Estrogen administration has antidepressant actions in rodent behavioral models, and there has been clinical evidence of estrogen's antidepressant effects in humans, although there have also been negative reports.

    “Estrogen administration also has antidepressant actions in rodent behavioral models, and there has been clinical evidence of estrogen’s antidepressant effects in humans, although there have also been negative reports57,59.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Rubinow, D.R. & Girdler, S.S. Hormones, heart disease and health: individualized medicine versus throwing the baby out with the bathwater. Depress. Anxiety 28, E1–E15 (2011). source

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    Premisecitation

    The Val66Met allele, found in approximately 25 percent of the population, blocks the processing and release of mature BDNF and is sufficient to cause atrophy of neurons in the hippocampal and mPFC of mice with this allele.

    “Studies of a human BDNF polymorphism, Val66Met found in approximately 25 percent of the population have been insightful. The Val66Met allele, which blocks the processing and release of mature BDNF, is sufficient to cause atrophy of neurons in the hippocampal37 and mPFC of mice with this allele38.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Chen, H., Pandey, G.N. & Dwivedi, Y. Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport 17, 863–867 (2006). source

      Not checked in the free run.

    • cites [38] Liu, R. et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry 71, 996–1005 (2012). source

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    • Rests on an assumption: The Val66Met allele in mice models the human BDNF polymorphism sufficiently to infer human risk.

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    Premisecitation

    Serum levels of the pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) are increased in depressed patients, and levels are normalized by antidepressant treatment.

    “Serum levels of the pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) are increased in depressed patients, and levels are normalized by antidepressant treatment118,119.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010). source

      Not checked in the free run.

    • cites [119] Howren, M.B., Lamkin, D.M. & Suls, J. Associations of depression with C-reactive protein, IL-1 and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depression is approximately twice as common in women compared to men.

    “Depression is approximately twice as common in women compared to men2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Kessler, R.C. et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). J. Am. Med. Assoc. 289, 3095–3105 (2003). source

      Not checked in the free run.

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    Premisecitation

    BDNF is required for the behavioral actions of antidepressants, and deletion increases vulnerability to depression.

    “Mutant mouse studies also demonstrate that BDNF is required for the behavioral actions of antidepressants, and that deletion increases vulnerability to depression41,42.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Autry, A.E., Adachi, M., Cheng, P. & Monteggia, L.M. Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior. Biol. Psychiatry 66, 84–90 (2009). source

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    • cites [42] Duman, C.H., Schlesinger, L., Kodama, M., Russell, D.S. & Duman, R.S. A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol. Psychiatry 61, 661–670 (2007b). source

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    Premisecitation

    Stress and depression decrease the expression and function of BDNF in prefrontal cortex and hippocampus, as well as decrease the levels in the blood of depressed patients.

    “Stress and depression decrease the expression and function of BDNF (Figure 2) in prefrontal cortex and hippocampus, structures implicated in depression, as well as decrease the levels in the blood of depressed patients21,32–35.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [21] Krishnan, V. & Nestler, E.J. The molecular neurobiology of depression. Nature 455, 894–902 (2008). source

      Not checked in the free run.

    • cites [32] Bocchio-Chiavetto, L. et al. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J. Biol. Psychiatry 11, 763–773 (2010). source

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    • cites [33] Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006). source

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    • cites [34] Dwivedi, Y. Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr. Dis. Treat. 5, 433–449 (2009). source

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      Not checked in the free run.

    • Rests on an assumption: Changes in BDNF levels in blood reflect brain BDNF function relevant to depression.

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    Premisenone given

    In humans, individuals with the Val66Met allele have reduced episodic memory and executive function, and reduced hippocampal volume.

    “In humans, individuals with the Val66Met allele have reduced episodic memory and executive function, and reduced hippocampal volume.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Chronic exposure of rodents to adrenal-glucocorticoids decreases synaptic number and function and causes atrophy of neurons in the prefrontal cortex and hippocampus, regions undergoing atrophy and disruption of connectivity in depressed subjects.

    “Notably, chronic exposure of rodents to adrenal-glucocorticoids decreases synaptic number and function and causes atrophy of neurons in the prefrontal cortex and hippocampus, regions undergoing atrophy and disruption of connectivity in depressed subjects24,25.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Liu, R.J. & Aghajanian, G.K. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc. Natl. Acad. Sci. USA 105, 359–364 (2008). source

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      Not checked in the free run.

    • Rests on an assumption: Rodent models of chronic stress and depression are valid models for human depression.

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    Premisenone given

    Typical antidepressant treatments (e.g., SSRIs) increase BDNF expression and block the deficits in growth factor expression caused by stress and depression.

    “Conversely, typical antidepressant treatments (e.g., SSRIs) increase BDNF expression and block the deficits in growth factor expression caused by stress and depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    A hallmark feature of the stress response is activation of the HPA axis and increased circulating levels of glucocorticoids, designed to provide acute phase maximum physiological support for the fight or flight response.

    “A hallmark feature of the stress response is activation of the HPA axis and increased circulating levels of glucocorticoids, designed to provide acute phase maximum physiological support for the fight or flight response.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Synaptogenesis is regulated by a complex interaction of signaling pathways, and disruption of many key pathways has been implicated in susceptibility to depression, including loss of neurotrophic factor support, disruption of estradiol cycling, and elevation of inflammatory cytokines.

    “Synaptogenesis is regulated by a complex interaction of signaling pathways, and disruption of many of the key pathways have been implicated in the susceptibility to depression, including loss of neurotrophic factor support, disruption of estradiol cycling, and elevation of inflammatory cytokines10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Duman, R.S. & Aghajanian, G.K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012). source

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    Premisecitation

    Metabolic disorders such as obesity and diabetes are associated with elevated rates of depression and share risk factors such as social and traumatic stress.

    “Metabolic disorders such as obesity and diabetes are associated with elevated rates of depression and share risk factors such as social and traumatic stress78–82,83(Figure 4).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
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    Premisecitation

    Heterozygous deletion of BDNF decreases spine density and dendrite length of hippocampal and PFC neurons, decreases hippocampal volume, and occludes the effects of chronic stress.

    “Heterozygous deletion of BDNF also decreases spine density and dendrite length of hippocampal and PFC neurons, decreases hippocampal volume, and occludes the effects of chronic stress39,40.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Acute stress increases levels of extracellular glutamate in rodents, suggesting that excitotoxicity could contribute to neuronal atrophy.

    “Acute stress also increases levels of extracellular glutamate in rodents, suggesting that excitotoxicity could contribute to neuronal atrophy26,27.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Chronic stress decreases mTORC1 signaling proteins; overexpression of REDD1 causes loss of synapses in the PFC; REDD1 deletion mutant mice are resilient to the synaptic and behavioral deficits caused by chronic stress.

    “Rodent studies also demonstrated that chronic stress decreases mTORC1 signaling proteins30,54,55, that over expression of REDD1 causes loss of synapses in the PFC, and that REDD1 deletion mutant mice are resilient to the synaptic and behavioral deficits caused by chronic stress30”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    • cites [54] Chandran, A. et al. Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog. Neuropsychopharmacol. Biol. Psychiatry 40, 240–245 (2013). source

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  • May combine two claims.

    Interpretationreasoning

    In preclinical models, new rapid-acting antidepressant agents rapidly increase synaptic connections and reverse the loss of synapses caused by stress, thereby directly targeting the pathophysiology underlying depression.

    “Importantly, in preclinical models these new agents rapidly increase synaptic connections and reverse the loss of synapses caused by stress, thereby directly targeting the pathophysiology underlying depression (Figure 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rodent models of chronic stress and depression are valid models for human depression.

  • May combine two claims.

    Premisecitation

    Different classes of antidepressants, including SSRIs, dual and triple reuptake inhibitors, dopaminergic agents, tricyclics, and ECT increase BDNF expression and the behavioral actions of these agents are blocked in BDNF deletion mutant mice.

    “Different classes of antidepressants, including SSRIs, dual and triple reuptake inhibitors, dopaminergic agents, tricyclics, and ECT increase BDNF expression and the behavioral actions of these agents are blocked in BDNF deletion mutant mice135–137, 138.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [135] Chen, Z.-Y. Genetic variant BDNFVal66Met polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006b). source

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    • cites [136] Duman, R.S. & Voleti, B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 35, 47–56 (2012). source

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    • cites [137] Yu, H. et al. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J. Neurosci. 32, 4092–4101 (2012). source

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    • cites [138] Jiang, B. et al. SKF83959 produces antidepressant effects in a chronic social-defeat stress model of depression through the BDNF-TrkB pathway. Int. J. Neuropsychopharmacol. 18, pyu096 (2015).

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    Premisecitation

    Ketamine and other NMDA receptor antagonists increase mTORC1 signaling via activation of Akt and ERK and increase synaptic number and function in the PFC.

    “In contrast to the effects of stress, ketamine and other NMDA receptor antagonists increase mTORC1 signaling via activation of Akt and ERK and increase synaptic number and function in the PFC52,156–158(Figure 4).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [52] Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010). source

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    • cites [156] Miller, O.H. et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. eLife 3, e03581 (2014). source

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    • cites [158] Zhou, W. et al. Ketamine-induced antidepressant effects are associated with AMPA receptor–mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur. Psychiatry 29, 419–423 (2014). source

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    Premisecitation

    Chronic administration of typical antidepressants that block the reuptake and breakdown of monoamines increase synaptic plasticity at several levels including increased birth of new neurons in the adult hippocampus, increased neurotrophic factor expression, and regulation of synapse formation.

    “Chronic administration of typical antidepressants that block the reuptake and breakdown of monoamines increase synaptic plasticity at several levels including increased birth of new neurons in the adult hippocampus, increased neurotrophic factor expression, and regulation of synapse formation10,132,133.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Duman, R.S. & Aghajanian, G.K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012). source

      Not checked in the free run.

    • cites [132] Castrén, E. & Hen, R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 36, 259–267 (2013). source

      Not checked in the free run.

    • cites [133] Krishnan, V. & Nestler, E.J. Linking molecules to mood: new insight into the biology of depression. Am. J. Psychiatry 167, 1305–1320 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse chronic stress model of depression, exposure to stress for several weeks causes atrophy of PFC neurons and anhedonia, and these morphological and behavioral deficits are rapidly reversed by a single dose of ketamine.

    “This possibility is supported by studies in a mouse chronic stress model of depression, in which exposure to stress for several weeks causes atrophy of PFC neurons and anhedonia, a hallmark feature of depression55. These morphological and behavioral deficits are rapidly reversed by a single dose of ketamine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Li, N. et al. Glutamate N-methyl-d-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry 69, 754–761 (2011). source

      Not checked in the free run.

    • Rests on an assumption: Rodent models of chronic stress and depression are valid models for human depression.
27 of 27

  • The paper relies on this without support.

    Rodent models of chronic stress and depression are valid models for human depression.

    “Studies in rodent models have extended these human studies, and confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus1011,12.”
    “This possibility is supported by studies in a mouse chronic stress model of depression, in which exposure to stress for several weeks causes atrophy of PFC neurons and anhedonia, a hallmark feature of depression55.”

  • The paper relies on this without support.

    Synaptic deficits observed in postmortem PFC of depressed subjects are causally related to depressive symptoms.

    “Recent postmortem studies also demonstrate reduced synapse number in PFC of depressed subjects9.”
    “The atrophy of neurons and loss of glutamatergic synaptic connections caused by stress are key contributors to the symptoms of depression.”

  • The paper relies on this without support.

    Changes in BDNF levels in blood reflect brain BDNF function relevant to depression.

    “Stress and depression decrease the expression and function of BDNF (Figure 2) in prefrontal cortex and hippocampus, structures implicated in depression, as well as decrease the levels in the blood of depressed patients21,32–35.”

  • The paper relies on this without support.

    The Val66Met allele in mice models the human BDNF polymorphism sufficiently to infer human risk.

    “The Val66Met allele, which blocks the processing and release of mature BDNF, is sufficient to cause atrophy of neurons in the hippocampal37 and mPFC of mice with this allele38.”
    “In addition, carriers of the Val66Met allele are at increased risk for depression when exposed to early life stress or trauma43–45.”

  • The paper relies on this without support.

    The mTORC1 signaling changes observed in rodents and postmortem tissue are causally involved in human depression and antidepressant response.

    “Together, these studies provide additional supporting evidence that the mTORC1 dendritic translational cascade and synapse formation may represent a common final pathway for a wide range of rapid acting, efficacious antidepressants.”
5 of 5

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?

  • BDNF is a peptide of 118 highly conserved amino acids among vertebrates that regulates neuronal survival and synaptic plasticity in the adult brain and has been implicated in several neuropsychiatric disorders.

    “Brain derived neurotrophic factor (BDNF) is a peptide consisting of 118 highly conserved amino acids among vertebrate species that regulates cellular and molecular mechanisms of neuronal survival and synaptic plasticity in the adult brain and has therefore been implicated in several neuropsychiatric disorders (Autry & Monteggia, 2012; Duman et al., 2016; Götz et al., 1992; Radziejewski et al., 199”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Duman et al., 2016

    The “Reduced neurotrophic factor expression in stress and depression” section (page not provided) links BDNF to synaptic connections, neuronal survival pathways, and depression; “Antidepressants and synaptic plasticity” (page not provided) describes BDNF-dependent plasticity in adult animals. Our copy does not state that BDNF has 118 amino acids conserved among vertebrates or implicate it in several neuropsychiatric disorders beyond depression. (LLM, conf=0.88)

    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 [4]

    The “Rapid acting antidepressants: mechanism of action” section reports that ketamine increases mTORC1 signaling, synaptic-protein synthesis, and synapse number and function in the PFC; it also describes reversal of stress-related deficits after a single dose. It links BDNF release to AMPA-driven mTORC1 signaling in cultured neurons, but does not directly state that a single dose of ketamine increases BDNF release or identify GluR1, PSD95, and synapsin 1 as the proteins increased. Page numbers were not provided in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Microglial activation through the ERK pathway facilitates BDNF production and modulates inflammatory cytokines and neuroimmune signaling, which are often dysregulated in depression.

    “microglial activation through the ERK pathway not only facilitates BDNF production but also modulates inflammatory cytokines and neuroimmune signaling, processes that are often dysregulated in depression [65,81].”

    From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [65]

    The section “Innate immune system, the inflammasome, and inflammatory cytokines” links microglia-derived cytokines and abnormal cytokine elevations to stress and depression. “Reduced neurotrophic factor expression in stress and depression” discusses BDNF and Raf–MEK–ERK signaling, but does not say that ERK activates microglia to produce BDNF or modulate cytokines and neuroimmune signaling. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Postmortem PFC of human subjects with Major Depressive Disorder has reduced levels of BDNF, elevated levels of REDD1, and decreased levels of mTOR.

    “postmortem PFC of human subjects with Major Depressive Disorder (MDD), similar to stressed rodents, have reduced levels of BDNF,168–173 elevated levels of REDD1,92 and decreased levels of mTOR.92,169”

    From Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes. (2021) · cites this paper as [170]

    The “Reduced neurotrophic factor expression in stress and depression” section reports increased REDD1 and reduced expression and function of mTORC1 signaling proteins in postmortem PFC of depressed subjects. It also says BDNF expression decreases in the PFC with stress and depression, but does not explicitly identify that finding as a measurement in human postmortem PFC. The source describes mTORC1 signaling proteins, rather than specifically a decreased level of mTOR itself. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Increased synaptic plasticity is a key contributor to ketamine's antidepressant effects.

    “Enhancement in synaptic plasticity is one of the key phenomena that contributes to the antidepressant effects of ketamine (Duman et al., 2016; Riggs & Gould, 2021).”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Duman et al., 2016

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Liu, R.J. et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry 71, 996–1005 (2012). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H.
Affiliations
Yale University (US)
Corresponding author
Duman, Ronald S
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-03
Volume
22
Issue
3
Pages
238-249
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.4050
PMC
PMC5405628
OpenAlex
W2291443053
Semantic Scholar
cb1fcffcccbd09f3e331fe7d8e63de0c3285a0c1
Cited by
1,750
References
198
Citations by year
2026: 211 · 2025: 233 · 2024: 209 · 2023: 168 · 2022: 190 · 2021: 192 · 2020: 151 · 2019: 147 · 2018: 125 · 2017: 93 · 2016: 27 · 2015: 1
FWCI
105.76
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UH2TR000960)
  • National Institute on Alcohol Abuse and Alcoholism (P50 AA12870, P50AA012870)
  • National Institute of Mental Health (MH045481, MH093897, R01MH093897, R01MH105910)
  • National Center for Research Resources (M01RR000125, M01 RR-00125, UL1RR024139)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Pharmacology › 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, synaptic plasticity, stress, rapid-acting antidepressants, antidepressant resistance, serotonin reuptake inhibitors, mood regulation, neuronal dysfunction, neurobiology of stress
MeSH terms
Antidepressive Agents, Depressive Disorder, Diabetes Mellitus, Female, Glucocorticoids, Humans, Hypothalamo-Hypophyseal System, Inflammation, Ketamine, Male, Neuronal Plasticity, Pituitary-Adrenal System, Sex Factors, Stress, Psychological, Time Factors, Signal Transduction, Cytokines, Selective Serotonin Reuptake Inhibitors, Excitatory Amino Acid Antagonists, Brain-Derived Neurotrophic Factor

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Statistics and arithmetic are recomputed, not judged.

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