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Cited by 181Epigenetics and DNA MethylationTreatment of Major DepressionStress Responses and Cortisol

Epigenetic mechanisms of major depression: Targeting neuronal plasticity

Open access
Uchida, Shusaku, Yamagata, Hirotaka, Seki, Tomoe, Watanabe, Yoshifumi·2018·Psychiatry and Clinical Neurosciences
DOI 10.1111/pcn.12621
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Abstract

Major depressive disorder is one of the most common mental illnesses as it affects more than 350 million people globally. Major depressive disorder is etiologically complex and disabling. Genetic factors play a role in the etiology of major depression. However, identical twin studies have shown high rates of discordance, indicating non‐genetic mechanisms as well. For instance, stressful life events increase the risk of depression. Environmental stressors also induce stable changes in gene expression within the brain that may lead to maladaptive neuronal plasticity in regions implicated in disease pathogenesis. Epigenetic events alter the chromatin structure and thus modulate expression of genes that play a role in neuronal plasticity, behavioral response to stress, depressive behaviors, and response to antidepressants. Here, we review new information regarding current understanding of epigenetic events that may impact depression. In particular, we discuss the roles of histone acetylation, DNA methylation, and non‐coding RNA. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that epigenetic mechanisms—histone acetylation/deacetylation, DNA methylation, and noncoding RNAs—link environmental stress to altered neuronal plasticity in major depressive disorder. It argues that targeting epigenetic regulators such as HDAC2/4/5, SIRT1, DNMTs, and miR-124 may yield novel antidepressant strategies.

Key findings

  • MDD affects more than 350 million people globally and is ranked second in disease burden; a twin-study meta-analysis estimated MDD heritability at only 37%, with 50% discordance in identical twins, compared with approximately 70–80% heritability for schizophrenia and bipolar disorder.
  • In rodent chronic stress models, enhanced HDAC2 function in the ventral striatum drove depression-like behavior; systemic SAHA during the last 5 days of 6 weeks of chronic stress produced antidepressant-like behavior, whereas imipramine and fluoxetine did not. Hippocampal HDAC4/5 inhibition and SIRT1 activation also exerted antidepressant-like effects, and SIRT1 activity decreased in the dentate gyrus after chronic stress.
  • DNA methylation findings included 363 CpG sites that differentiated MDD patients from healthy controls, increased DNMT3A mRNA in the nucleus accumbens of individuals with MDD, and sex-specific effects in mice: Dnmt3a knockout in the nucleus accumbens made females resistant to subchronic stress, while overexpression made males more susceptible.
  • Increased hippocampal miR-124 inhibited chronic stress-induced depression-like behaviors and prevented spine density reduction; reduced miR-124 enhanced susceptibility to subthreshold stress, and miR-124 targets Hdac4, Hdac5, and Gsk3b.

Methods

  • Narrative review; no primary experimental data, systematic search, or meta-analysis is described.
  • Synthesizes preclinical rodent chronic stress models and human studies, including post-mortem brain, peripheral blood, genetic association, and brain-imaging findings.
  • Main analysis is a qualitative synthesis of cited evidence on histone acetylation, DNA methylation, and noncoding RNA in depression and antidepressant action.

Limitations

  • The paper states that no causal evidence exists for synaptic spines controlling the cellular pathology of disease states and subsequent affective behaviors; sex differences in MDD etiology and pathophysiology remain largely unknown; and further detailed studies are needed for metabolism-dependent epigenetic pathways.
  • Evident from the text: as a narrative review, it does not systematically assess study quality or publication bias; many mechanistic conclusions rely on rodent models, and epigenetic drugs may have adverse effects because HDAC and DNMT are widely expressed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/pcn.12621

Cites

171 of 171 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingnone given

    In animal models of depression and stress, neuronal atrophy, changes in synaptic density, and cell loss have been reported.

    “In animal models of depression and stress, neuronal atrophy, changes in synaptic density, and cell loss have been reported.”
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  • Findingcitation

    The size of pyramidal neurons in the dorsal lateral prefrontal cortex and hippocampus is decreased in autopsy samples from patients with major depressive disorder.

    “The size of pyramidal neurons in the dorsal lateral PFC 10 and hippocampus 11 was decreased in autopsy samples from patients with MDD.”
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    Increasing evidence demonstrates altered neuronal and structural plasticity in patients with major depressive disorder.

    “Increasing evidence has demonstrated altered neuronal and structural plasticity in patients with MDD.”
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    Brain-imaging studies show cortical and limbic region atrophy, including decreased volumes in the prefrontal cortex and hippocampus, associated with the duration of illness and treatment.

    “Studies utilizing brain-imaging methods have shown that cortical and limbic region atrophy, including decreased volumes in the prefrontal cortex (PFC) and hippocampus, is associated with the duration of illness and treatment.”
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    Electron microscopic studies reveal reduced numbers of dendritic spines within the dorsal lateral prefrontal cortex of patients with major depressive disorder.

    “In addition, electron microscopic studies have revealed reduced numbers of dendritic spines within the dorsal lateral PFC of patients with MDD.”
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    Findingcitation

    Various types of chronic stress in rodents lead to abnormal behavior, including the inability to experience pleasure, which is one of the main symptoms of depression.

    “Various types of chronic stress (e.g., chronic unpredictable stress, repeated restraint stress, or chronic social defeat stress) in rodents lead to abnormal behavior, including the inability to experience pleasure, which is one of the main symptoms of depression.”
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    Findingcitation

    Chronic stress results in decreases in the length and branching of apical dendrites as well as in the quantity and function of synapses at spines of pyramidal neurons of the medial prefrontal cortex, the CA3 region of the hippocampus, and granule cell neurons of the dentate gyrus.

    “Chronic stress results in decreases in the length and branching of apical dendrites as well as in the quantity and function of synapses at spines of pyramidal neurons of the medial PFC, the CA3 region of the hippocampus, and granule cell neurons of the dentate gyrus.”
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    Findingcitation

    Long-term use of antidepressants can increase spine density or decrease atrophy of spines and dendrites after chronic stress.

    “Other studies have concluded that long-term use of antidepressants can increase spine density or decrease atrophy of spines and dendrites after chronic stress.”
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    Findingcitation

    Viral-mediated knockdown of Hdac2 restores synaptic plasticity deficits, enhances synapse number, and improves behavioral abnormalities in a mouse model of neurological disease.

    “Supporting this notion, viral-mediated knockdown of Hdac2 restores synaptic plasticity deficits, enhances synapse number, and improves behavioral abnormalities in a mouse model of neurological disease.”
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    Findingcitation

    Long-term treatment with typical antidepressants leads to an increase in neurotrophic factors and improves synaptic plasticity.

    “Longterm treatment with typical antidepressants leads to an increase in neurotrophic factors and improves synaptic plasticity.”
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    Findingcitation

    Selective serotonin reuptake inhibitors increased long-term potentiation and synaptic transmission.

    “For example, a previous study showed that selective serotonin reuptake inhibitors increased long-term potentiation (LTP), a type of heterosynaptic plasticity that is likely involved in learning and memory, as well as synaptic transmission.”
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    Findingcitation

    HDAC2 overexpression reduced synapse number, decreased synaptic plasticity, and impaired memory.

    “Conversely, Guan et al. 52 found that HDAC2 overexpression reduced synapse number, decreased synaptic plasticity, and impaired memory.”
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    Findingcitation

    Administration of an HDAC inhibitor increased histone acetylation, enhanced long-term potentiation, and led to greater memory performance.

    “Administration of an HDAC inhibitor increased histone acetylation, enhanced LTP, and led to greater memory performance.”
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    Findingcitation

    The detrimental effects of HDAC2 overexpression on plasticity and memory are reversed by the HDAC inhibitor suberoylanilide hydroxamic acid, whereas suberoylanilide hydroxamic acid was unable to further enhance memory in HDAC2 knockout mice.

    “Importantly, the detrimental effects of HDAC2 overexpression on plasticity and memory are reversed by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), whereas SAHA was unable to further enhance memory in HDAC2 knockout mice.”
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    Findingcitation

    Increased hippocampal HDAC4 following chronic stress exposure has been reported, whereas suppression of hippocampal HDAC4 abolished the long-lasting behavioral deficits induced by stress.

    “Another study reported increased hippocampal HDAC4 following chronic stress exposure, 84 whereas suppression of hippocampal HDAC4 abolished the long-lasting behavioral deficits induced by stress.”
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    Findingcitation

    Virus-mediated overexpression of HDAC4 in the hippocampus induced depression-like behavior but not anxiety-like behavior in adult rats.

    “Virus-mediated overexpression of HDAC4 in the hippocampus induced depressionlike behavior but not anxiety-like behavior in adult rats.”
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    Findingcitation

    Increased HDAC2 expression and reduced GDNF expression have been shown in patients with major depressive disorder.

    “Further, some reports have shown increased HDAC2 expression and reduced GDNF expression in patients with MDD”
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    Findingcitation

    A gain-of-function HDAC2 mutation leads to increased stress vulnerability, whereas downregulation of HDAC2 induces a stress-resilient phenotype.

    “Indeed, a gain-offunction HDAC2 mutation leads to increased stress vulnerability, whereas downregulation of HDAC2 induces a stress-resilient phenotype.”
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    Findingcitation

    Chronic stress decreases histone acetylation of the Gdnf promoter, whereas genetic and pharmacological inhibition of HDAC2 prevents stress-induced downregulation of histone acetylation at the Gdnf promoter.

    “Supporting this notion, chronic stress decreases histone acetylation of the Gdnf promoter, whereas genetic and pharmacological inhibition of HDAC2 prevents stress-induced downregulation of histone acetylation at the Gdnf promoter.”
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    Findingcitation

    Prodepressant effects and reduced histone H3 acetylation were observed in mice with hippocampal overexpression of HDAC5.

    “Prodepressant effects and reduced histone H3 acetylation were observed in mice with hippocampal overexpression of HDAC5.”
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    Findingcitation

    Suberoylanilide hydroxamic acid has a rapid antidepressant action and may be effective for depressive-like behaviors in mice that are resistant to conventional treatments.

    “other reports have also shown that SAHA has a rapid antidepressant action 66 and that SAHA treatment may be effective for depressive-like behaviors in mice that are resistant to conventional treatments.”
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    Findingcitation

    Chronic stress decreases Gdnf expression in the ventral striatum, whereas knockdown of HDAC2 or suberoylanilide hydroxamic acid treatment prevents the reduction in Gdnf expression induced by chronic stress.

    “Chronic stress decreases Gdnf expression in the ventral striatum, whereas knockdown of HDAC2 or SAHA treatment prevents the reduction in Gdnf expression induced by chronic stress”
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    Findingcitation

    Activation of SIRT1 in the hippocampus during chronic stress blocks depression-like behavior and abnormal dendritic structures and increases phosphorylation of extracellular signal-regulated protein kinases 1 and 2.

    “On the other hand, activation of SIRT1 in the hippocampus during chronic stress blocks depression-like behavior and abnormal dendritic structures and increases phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2).”
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    Findingcitation

    Japanese patients with major depressive disorder currently in a depressive state expressed lower levels of SIRT1 mRNA in peripheral white blood cells than healthy subjects, whereas patients in remission exhibited expression levels comparable to healthy subjects.

    “Abe et al. 99 reported that Japanese MDD patients currently in a depressive state expressed lower levels of SIRT1 mRNA in peripheral white blood cells than healthy subjects, whereas MDD patients in remission exhibited expression levels that were comparable to healthy subjects.”
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    Findingcitation

    A single-nucleotide polymorphism rs10997870 in SIRT1 is associated with a risk for panic disorders and social phobias, and a second single-nucleotide polymorphism rs12413112 in SIRT1 is associated with major depressive disorder.

    “A singlenucleotide polymorphism (SNP; rs10997870) in SIRT1 is associated with a risk for panic disorders and social phobias, and a second SNP in SIRT1 (rs12413112) is associated with MDD.”
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    Findingcitation

    A third single-nucleotide polymorphism rs10997875 in SIRT1 is associated with major depressive disorder in Japanese individuals.

    “A third SNP (rs10997875) in SIRT1 is Schroeder et al. 71 Repeated administration prevents both stressinduced reduction of histone acetylation and depression-like behaviors.”
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    Findingcitation

    Reduced SIRT1 levels in patients with major depressive disorder and an inverse correlation between SIRT1 levels and Hamilton Rating Scale for Depression scores were found.

    “In addition, Lo Iacono et al. 100 found reduced SIRT1 levels in patients with MDD and an inverse correlation between SIRT1 levels and Hamilton Rating Scale for Depression scores.”
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    Findingcitation

    Reduced SIRT1 levels in major depressive disorder were reported, in agreement with the results of Abe et al.

    “Moreover, Luo and Zhang 101 reported reduced SIRT1 levels in MDD, in agreement with the results of Abe et al.”
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    Findingcitation

    Increasing ERK2 activity in the hippocampus using a virus-mediated approach has antidepressant-like effects, and inhibiting ERK2 promotes depression.

    “Increasing ERK2 activity in the hippocampus using a virus-mediated approach has antidepressant-like effects, and inhibiting ERK2 promotes depression.”
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    Findingcitation

    SIRT1 knockout mice showed decreased dendritic branching, branch length, and complexity of dendritic arbors.

    “Also, SIRT1 knockout mice showed decreased dendritic branching, branch length, and complexity of dendritic arbors.”
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    Findingcitation

    Dnmt1 and Dnmt3a were expressed at higher levels in the nucleus accumbens in mice exposed to chronic stress with severe depression-like behaviors, and DNMT inhibitors reversed such behaviors.

    “Dnmt1 and Dnmt3a were expressed at higher levels in the nucleus accumbens in mice exposed to chronic stress with severe depression-like behaviors; and DNMT inhibitors reversed such behaviors.”
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    Findingcitation

    DNMT1 and DNMT3B expression was decreased in the amygdala of those who committed suicide, whereas DNMT3B expression was increased in the paraventricular nucleus of such individuals.

    “DNMT1 and DNMT3B expression was decreased in the amygdala of those who committed suicide, whereas DNMT3B expression was increased in the paraventricular nucleus of such individuals.”
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    Findingcitation

    Dnmt3a knockout specifically in the nucleus accumbens causes female mice to become more resistant to subchronic stress, whereas overexpression renders male mice more susceptible.

    “Dnmt3a knockout specifically in the nucleus accumbens causes female mice to become more resistant to subchronic stress, whereas overexpression renders male mice more susceptible, directly implicating this gene in stress resistance.”
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    Findingcitation

    Rat pups reared by females that exhibited high levels of nurturing behavior had less anxiety, a reduced stress response, and higher expression of mRNA for the glucocorticoid receptor gene Nr3c1 in the hippocampus than offspring reared by females with low levels of nurturing behavior.

    “Weaver et al. 70 and Meaney et al. 118 showed that rat pups reared by females that exhibited high levels of nurturing behavior, such as licking, grooming, and arched-back nursing (high-LG-ABN), had less anxiety, a reduced stress response (activation of the hypothalamic-pituitary-adrenal [HPA] axis), and higher expression of mRNA for the glucocorticoid receptor gene Nr3c1 (specifically the altern”
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    Findingcitation

    Female mice exposed to subchronic stress showed depression-like behavior, whereas male mice did not develop abnormal behavior in response to the same stress episode.

    “Hodes et al. 121 reported that female mice exposed to subchronic stress showed depression-like behavior, whereas male mice did not develop abnormal behavior in response to the same stress episode.”
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    Findingcitation

    Lower levels of both glucocorticoid receptor mRNA and GR1 F splice variant mRNA but higher cytosine methylation of the GR1 F promoter were found in the group with abuse.

    “The authors reported lower levels of both glucocorticoid receptor mRNA and GR1 F splice variant mRNA but higher cytosine methylation of the GR1 F promoter in the group with abuse.”
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    Findingcitation

    Multiplex DNA methylation markers (363 CpG sites) can be used to accurately differentiate major depressive disorder patients and healthy controls, a result that was replicated in a separate group of specimens.

    “Multiplex DNA methylation markers (363 CpG sites) can be used to accurately differentiate MDD patients and healthy controls, a result that was replicated in a separate group of specimens.”
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    Findingnone given

    Chronic stress increases CRF expression in susceptible mice along with lower levels of DNA methylation at the Crf promoter.

    “In contrast to Bdnf, chronic stress increases CRF expression in susceptible mice along with lower levels of DNA methylation at the Crf promoter.”
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    Findingcitation

    Increased SLC6A4 promoter methylation is significantly associated with childhood trauma, a family history of depression, and more extensive psychopathological problems.

    “Increased SLC6A4 promoter methylation is significantly associated with childhood trauma, a family history of depression, and more extensive psychopathological problems.”
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    Findingcitation

    Adult rats exposed to mistreatment at an early age exhibited higher levels of DNA methylation at CpG sites within the Bdnf promoter as well as decreased levels of Bdnf mRNA.

    “In a related study, adult rats exposed to mistreatment at an early age exhibited higher levels of DNA methylation at CpG sites within the Bdnf promoter as well as decreased levels of Bdnf mRNA.”
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    Findingown data

    Chronic-stress-induced reduction of spine density is prevented by miR-124 overexpression, and blockade of miR-124 reduces spine density under mild stress.

    “Chronic-stress-induced reduction of spine density is prevented by miR-124 overexpression, and blockade of miR-124 reduces spine density under mild stress.”
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    Findingown data

    Increased levels of miR-124 in the hippocampus inhibit depression-like behaviors induced by chronic stress and result in stress resilience.

    “Increased levels of miR-124 in the hippocampus inhibit depression-like behaviors induced by chronic stress and result in stress resilience.”
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    Findingcitation

    Fluoxetine downregulated miR-16 expression in the locus coeruleus, and blocking miR-16 in this region inhibited depression-like behavior due to chronic stress by altering serotonin transporter expression.

    “Fluoxetine downregulated miR-16 expression in the locus coeruleus, and blocking miR-16 in this region inhibited depression-like behavior due to chronic stress by altering serotonin transporter expression.”
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    Findingcitation

    Hypermethylation at the CpG island shore of SLC6A4 was observed in a twin with bipolar.

    “Hypermethylation at the CpG island shore of SLC6A4 was observed in a twin with bipolar.”
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    Findingcitation

    Depressed individuals and suicide victims showed reduced miR-135a levels in their blood and post-mortem dorsal raphe nucleus, respectively, and blood miR-135a levels in depressed patients increased after antidepressant treatment.

    “Importantly, depressed individuals and suicide victims showed reduced miR-135a levels in their blood and post-mortem dorsal raphe nucleus, respectively, and blood miR-135a levels in depressed patients increased after antidepressant treatment.”
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    Findingown data

    Chronic stress and clinical antidepressants alter miRNA expression.

    “Our studies and the results of others provide strong evidence for a role for miRNA in depression and show that chronic stress and clinical antidepressants alter miRNA expression.”
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    Findingnone given

    No causal evidence exists for synaptic spines controlling the cellular pathology of disease states and subsequent affective behaviors.

    “However, no causal evidence exists for synaptic spines controlling the cellular pathology of disease states and subsequent affective behaviors.”
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    Findingcitation

    MicroRNA-124 is abundantly expressed in neurons, where it regulates adult neurogenesis and promotes dendritic maturation.

    “MicroRNA-124 is abundantly expressed in neurons, where it regulates adult neurogenesis and promotes dendritic maturation.”
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    Premisecitation

    The heritability of schizophrenia and bipolar disorder is approximately 70-80%.

    “In contrast, the heritability of other psychiatric diseases, including schizophrenia and bipolar disorder, is approximately 70-80%.”
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    Premisecitation

    Identical twin studies show a high discordance rate for major depressive disorder of 50%, indicating the importance of non-genetic factors.

    “Identical twin studies have shown a high discordance rate for MDD of 50%, indicating the importance of non-genetic factors.”
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    Premisecitation

    Experience-dependent neuronal plasticity allows organisms to adapt and respond to changes in the environment.

    “Experience-dependent neuronal plasticity allows organisms to adapt and respond to changes in the environment.”
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    Premisecitation

    Neuronal plasticity includes sustained modifications in synaptic structure and function that require de novo gene expression.

    “Neuronal plasticity includes sustained modifications in synaptic structure and function that require de novo gene expression.”
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    Interpretationcitation

    The pathophysiology of major depressive disorder and the response to antidepressants are suggested to be controlled by epigenetic modulation of transcription.

    “The pathophysiology of MDD and response to antidepressants are suggested to be controlled by epigenetic modulation of transcription.”
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    Premisecitation

    Histone deacetylases increase ionic interactions between histones and DNA, resulting in more tightly packed DNA, more highly condensed chromatin, reduced access of transcription factors to promoters, and reduced transcription.

    “HDAC increase ionic interactions between histones and DNA, resulting in more tightly packed DNA, more highly condensed chromatin, reduced access of transcription factors to promoters, and finally, reduced transcription”
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    Interpretationcitation

    Severe or chronic stressors are detrimental and can disrupt the ability of the brain to respond to stress normally, eventually leading to depression.

    “However, severe or chronic stressors are detrimental and can disrupt the ability of the brain to respond to stress normally, eventually leading to depression.”
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    Premisecitation

    Acetylation and deacetylation affect chromatin structure and modulate gene expression.

    “Acetylation and deacetylation, which are covalent histone modifications, affect chromatin structure and hence modulate gene expression.”
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    Interpretationnone given

    Aberrant neuronal plasticity caused by epigenetic dysregulation of gene expression is pivotal for depression and antidepressant actions.

    “Then, we discuss recent studies that have shown that the aberrant neuronal plasticity caused by epigenetic dysregulation of gene expression is pivotal for depression and antidepressant actions.”
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    Premisecitation

    Mammalian sirtuins SIRT1-7 modulate various cellular processes, including gene silencing, cell cycle, apoptosis, metabolism, energy homeostasis, and age-related processes.

    “Mammalian sirtuins SIRT1-7 modulate various cellular processes, including gene silencing, cell cycle, apoptosis, metabolism, energy homeostasis, and age-related processes.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The SIR2 family of histone deacetylases deacetylates both histones and nonhistone proteins and thus modulates multiple cellular functions and affects gene expression.

    “The SIR2 family of HDAC, also known as class III HDAC or SIRT, deacetylates both histones and nonhistone proteins and thus modulates multiple cellular functions 40,41 and affects gene expression.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] source

      Not checked in the free run.

    • cites [41] source

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    • cites [42] source

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  • May combine two claims.

    Interpretationreasoning

    Epigenetic regulation of gene transcription is influenced by chronic stress episodes, suggesting that environmental factors may affect neuronal plasticity via epigenetic regulation within the brain, which in turn leads to depression.

    “It should be noted that epigenetic regulation of gene transcription is influenced by chronic stress episodes, suggesting that environmental factors may affect neuronal plasticity via epigenetic regulation within the brain, which in turn leads to depression.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Chromatin remodeling plays a role in multiple physiological and pathological processes in the brain, including circadian rhythms, learning and memory, drug addiction, and depression.

    “Chromatin remodeling plays a role in multiple physiological and pathological processes in the brain, including circadian rhythms, 32 learning and memory, 33 drug addiction, 34 and depression.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32]

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    • cites [33] source

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    • cites [34] source

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  • May combine two claims.

    Premisecitation

    Phosphorylation of HDAC4 by Ca2+/calmodulin-dependent protein kinases maintains cytoplasmic localization of HDAC4, leads to its nuclear export, and suppresses the transcription factor MEF2.

    “Phosphorylation of HDAC4 by Ca 2+ /calmodulin-dependent protein kinases (CAMK) maintains cytoplasmic localization of HDAC4, leads to its nuclear export, 55,56 and suppresses the transcription factor MEF2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] source

      Not checked in the free run.

    • cites [56]

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  • May combine two claims.

    Premisecitation

    HDAC4 binds to chromatin, MEF2A, and CREB, followed by histone deacetylation and suppression of gene expression in neurons.

    “HDAC4 binds to chromatin, MEF2A, and CREB, followed by histone deacetylation and suppression of gene expression in neurons.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58]

      Not checked in the free run.

    • cites [59]

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  • May combine two claims.

    Interpretationreasoning

    HDAC2 inhibition may enhance synapse number and memory.

    “Thus, these finding suggest that HDAC2 inhibition may enhance synapse number and memory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    HDAC play important roles in the response to stress, depression-related behavior, and antidepressant action.

    “HDAC play important roles in the response to stress, depression-related behavior, and antidepressant action.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    Genome-wide changes in chromatin structure may indicate a general trend toward more permissive or restrictive genomic activity.

    “Genome-wide changes may indicate a general trend toward more permissive or restrictive genomic activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chronic stress enhances HDAC2 function and this can suppress Gdnf transcription, thereby inducing depression-like behaviors.

    “These findings suggest that chronic stress enhances HDAC2 function and that this can suppress Gdnf transcription, thereby inducing depression-like behaviors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Gdnf is a primary target of HDAC2 and is related to depression.

    “suggesting that Gdnf is a primary target of HDAC2 and is related to depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Histone modifications and the status of DNA methylation are closely linked.

    “Histone modifications and the status of DNA methylation are closely linked”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    SIRT1 plays a critical role in regulating depression-like behaviors, and pharmacological activation of SIRT1 is another possible novel strategy for treating major depressive disorder.

    “Thus, SIRT1 appears to play a critical role in regulating depression-like behaviors, and pharmacological activation of SIRT1 is another possible novel strategy for treating MDD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antidepressant-like effects of HDAC inhibitors, SIRT1 activators, and other epigenetic drugs in rodents predict therapeutic efficacy in human major depressive disorder.

  • May combine two claims.

    Premisecitation

    SIRT1 plays an important role in normal brain function and depression.

    “SIRT1 plays an important role in normal brain function and depression.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    DNA methylation generally reduces gene expression and involves covalent addition of a methyl group to cytosine residues of CpG dinucleotides.

    “DNA methylation, which generally reduces gene expression, is the second major epigenetic mechanism and involves covalent addition of a methyl group to cytosine residues of CpG dinucleotides.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The effectiveness of antidepressants may vary over time in the same patient because of the tendency of DNA methylation to change.

    “The effectiveness of antidepressants may vary over time in the same patient because of the tendency of DNA methylation to change.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Analysis of DNA methylation status may allow treating physicians to predict clinical outcomes in treatment-resistant patients.

    “Analysis of the DNA methylation status may allow treating physicians to predict clinical outcomes in treatment-resistant patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: DNA methylation changes measured in peripheral blood or post-mortem brain reflect epigenetic regulation relevant to major depressive disorder pathophysiology.

  • May combine two claims.

    Interpretationcitation

    DNA methylation likely modulates synaptic and structural plasticity and memory formation, and may be involved in vulnerability to stress and depression.

    “DNA methylation likely modulates synaptic and structural plasticity and memory formation, 112 and may be involved in vulnerability to stress and depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112]

      Not checked in the free run.

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

    Premisecitation

    Women are twice as likely to experience depression as men.

    “Women are twice as likely to experience depression as men.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Environmental factors produce changes in DNA methylation levels at specific promoters, and medications may exert their effect by altering these epigenetic marks.

    “Environmental factors produce changes in DNA methylation levels at specific promoters, and medications may exert their effect by altering these epigenetic marks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Epigenetic modifications that occur early in life may last for a lifetime and increase vulnerability to stress.

    “Epigenetic modifications that occur early in life may last for a lifetime and increase vulnerability to stress.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Men and women show different symptoms of depression and methods of coping.

    “Men and women show different symptoms of depression and methods of coping.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DNA methylation-mediated induction and repression of Gdnf modulate stress resistance and susceptibility, respectively.

    “Taken together, these observations indicate that DNA methylation-mediated induction and repression of Gdnf modulate stress resistance and susceptibility, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    MicroRNA may impact both the pathophysiology of depression and the response to antidepressant drugs, as shown in both animal and human studies.

    “miRNA may impact both the pathophysiology of depression and the response to antidepressant drugs, as shown in both animal and human studies.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [138]

      Not checked in the free run.

    • cites [139]

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    • cites [140]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DNA methylation appears to be an important epigenetic and biological marker that may be useful for both diagnosis and prediction of the response to antidepressants.

    “DNA methylation appears to be an important epigenetic and biological marker that may be useful for both diagnosis and prediction of the response to antidepressants.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: DNA methylation changes measured in peripheral blood or post-mortem brain reflect epigenetic regulation relevant to major depressive disorder pathophysiology.

  • May combine two claims.

    Interpretationreasoning

    The results described in this review support the hypothesis that environmental stressors act through epigenetic mechanisms, including histone acetylation/deacetylation and CpG methylation/demethylation, and interact with an individual's genetic make-up to determine the risk for depression throughout life.

    “In fact, the results described in this review support the hypothesis that environmental stressors act through epigenetic mechanisms, including histone acetylation/deacetylation and CpG methylation/demethylation, and interact with an individual's genetic make-up to determine the risk for depression throughout life.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Another novel therapeutic strategy for depression may involve direct manipulation of miRNA pathways.

    “Thus, another novel therapeutic strategy for depression may involve direct manipulation of miRNA pathways.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antidepressant-like effects of HDAC inhibitors, SIRT1 activators, and other epigenetic drugs in rodents predict therapeutic efficacy in human major depressive disorder.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Epigenetic regulation of gene transcription is important for dendritic development and spine formation.

    “Epigenetic regulation of gene transcription is important for dendritic development and spine formation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This is the first evidence for metabolic signaling to chromatin in the brain and indicates a critical role for this type of signaling in cognitive function.

    “This is the first evidence for metabolic signaling to chromatin in the brain and indicates a critical role for this type of signaling in cognitive function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Medications targeting epigenetic modifications (e.g., HDAC and DNMT inhibitors) are already in use and are proving effective for cancers and neurodegenerative disorders.

    “Medications targeting epigenetic modifications (e.g., HDAC and DNMT inhibitors) are already in use and are proving effective for cancers and neurodegenerative disorders.[165][166][167]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [165]

      Not checked in the free run.

    • cites [166]

      Not checked in the free run.

    • cites [167]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Epigenetic drugs are effective, and they have received a great deal of attention for the possible treatment of multiple diseases.

    “Nonetheless, epigenetic drugs are effective, and they have received a great deal of attention for the possible treatment of multiple diseases.[168][169][170]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [168]

      Not checked in the free run.

    • cites [169]

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    • cites [170]

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  • May combine two claims.

    Interpretationreasoning

    Drugs that specifically target epigenetic modulators that are enriched in the brain may affect HDAC or DNMT and may be useful new therapies for depression.

    “Drugs that specifically target epigenetic modulators that are enriched in the brain may affect HDAC or DNMT and may be useful new therapies for depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Men and women with MDD differ in serotonin synthesis and the density of serotonin 5HT1A autoreceptors.

    “as well as differences in serotonin synthesis and the density of serotonin 5HT1A autoreceptors.161,162”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [161]

      Not checked in the free run.

    • cites [162] source

      Not checked in the free run.

85 of 85

  • The paper relies on this without support.

    Findings from rodent models of chronic stress and depression-like behavior are relevant to human major depressive disorder.

    “Various types of chronic stress (e.g., chronic unpredictable stress, repeated restraint stress, or chronic social defeat stress) in rodents lead to abnormal behavior, including the inability to experience pleasure, which is one of the main symptoms of depression.”

  • The paper relies on this without support.

    Antidepressant-like effects of HDAC inhibitors, SIRT1 activators, and other epigenetic drugs in rodents predict therapeutic efficacy in human major depressive disorder.

    “Systemic administration of SAHA, which inhibits HDAC, during the last 5 days of 6 weeks of chronic stress produced antidepressant-like behavior.”

  • The paper relies on this without support.

    DNA methylation changes measured in peripheral blood or post-mortem brain reflect epigenetic regulation relevant to major depressive disorder pathophysiology.

    “Analysis of the DNA methylation status may allow treating physicians to predict clinical outcomes in treatment-resistant patients.”

  • The paper relies on this without support.

    HDAC and DNMT are widely expressed.

    “because HDAC and DNMT are widely expressed”
4 of 4

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Authors
Uchida, S., Yamagata, H., Seki, T., & Watanabe, Y.
Affiliations
Yamaguchi University (JP)
Corresponding author
Uchida, Shusaku
ORCID
Venue
Psychiatry and Clinical Neurosciences
Publisher
Wiley
Published
2017-12-26
Volume
72
Issue
4
Pages
212-227
ISSN
  • 1323-1316 (ISSN-L)
  • 1440-1819
DOI
10.1111/pcn.12621
OpenAlex
W2770347656
Semantic Scholar
f980a71f6daf62c3999c57d64cabda402ce39a17
Cited by
181
References
171
Citations by year
2026: 11 · 2025: 32 · 2024: 29 · 2023: 26 · 2022: 24 · 2021: 25 · 2020: 14 · 2019: 15 · 2018: 5
FWCI
0.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Psychiatry and Clinical Neurosciences (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Japan Society for the Promotion of Science (15K09807, 15H04895)
  • Japan Science and Technology Agency
  • Naito Foundation
  • Kanae Foundation for the Promotion of Medical Science
  • Takeda Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
major depressive disorder, epigenetics, neuroplasticity, histone acetylation, DNA methylation, non-coding RNA, chromatin structure, environmental stress, antidepressant response, depression treatment
MeSH terms
Major Depressive Disorder, Depressive Disorder, Major, Humans, Neuronal Plasticity, Epigenesis, Genetic

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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