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Cited by 550Stress Responses and CortisolTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology

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Belleau, Emily L., Treadway, Michael T., Pizzagalli, Diego A.·2019·Biological Psychiatry
DOI 10.1016/j.biopsych.2018.09.031PMC PMC6380948
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Abstract

Volumetric reductions in the hippocampus and medial prefrontal cortex (mPFC) are among the most well-documented neural abnormalities in major depressive disorder (MDD). Hippocampal and mPFC structural reductions have been specifically tied to MDD illness progression markers, including greater number of major depressive episodes (MDEs), longer illness duration, and nonremission/treatment resistance. Chronic stress plays a critical role in the development of hippocampal and mPFC deficits, with some studies suggesting that these deficits occur irrespective of MDE occurrence. However, preclinical and human research also points to other stress-mediated neurotoxic processes, including enhanced inflammation and neurotransmitter disturbances, which may require the presence of an MDE and contribute to further brain structural decline as the illness advances. Specifically, hypothalamic-pituitary-adrenal axis dysfunction, enhanced inflammation and oxidative stress, and neurotransmitter abnormalities (e.g., serotonin, glutamate, gamma-aminobutyric acid) likely interact to facilitate illness progression in MDD. Congruent with stress sensitization models of MDD, with each consecutive MDE it may take lower levels of stress to trigger these neurotoxic pathways, leading to more pronounced brain volumetric reductions. Given that stress and MDD have overlapping and distinct influences on neurobiological pathways implicated in hippocampal and mPFC structural decline, further work is needed to clarify which precise mechanisms ultimately contribute to MDD development and maintenance.

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Cites

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Claims the paper makes

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  • Findingown data

    The paper's own effect-size review found small to large effect sizes for medial prefrontal cortex volume reductions.

    “With respect to mPFC volume reductions, small to large effect sizes have been reported (Figure 2).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Each additional major depressive episode is associated with a 10-20% chance of failing to remit under current therapies.

    “each successive episode carries a 10–20% risk of failing to remit with current therapeutic approaches (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Monroe, 2011, Recurrence in major depression: A conceptual analysis, Psychol Rev source

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  • Premisecitation

    Major depressive disorder often follows a chronic and progressive course.

    “Major depressive disorder (MDD) is frequently a chronic, progressive illness.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Monroe, 2011, Recurrence in major depression: A conceptual analysis, Psychol Rev source

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  • Interpretationreasoning

    The estimated medial prefrontal cortex effect sizes are probably affected by antidepressant use and other psychiatric comorbidities, since most studies did not exclude these factors.

    “Additionally, these estimates are likely impacted by antidepressant use and presence of other psychiatric comorbidities, given that they were not exclusionary in most studies.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Meta-analyses report moderate effect sizes, with Cohen's d from −0.41 to −0.47, for smaller hippocampal volume in major depressive disorder.

    “These meta-analyses have reported moderate effect sizes for reduced hippocampal volume in MDD (Cohen’s d range = −0.41 to −0.47; 6,8,9).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Koolschijn, 2009, Brain volume abnormalities in major depressive disorder: A meta-analysis of magnetic resonance imaging studies, Hum Brain Mapp source

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    • cites [8] Kempton, 2011, Structural neuroimaging studies in major depressive disorder, Arch Gen Psychiatry source

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    • cites [9] Arnone, 2012, Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses, Eur Neuropsychopharmacol source

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    Premisecitation

    Hippocampal subfield analyses show smaller cornu ammonis 1-3, dentate gyrus/cornu ammonis 4, and subiculum volumes, plus anterior and posterior subdivisions, in major depressive disorder.

    “those that have parcellated the hippocampus into different subfields have found evidence for reduced cornu ammonis 1–3, dentate gyrus/cornu ammonis 4, and subiculum volumes as well as both anterior and posterior subdivisions in MDD (e.g., 15,16).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Han, 2016, Hippocampal subfield analysis in medication-naïve female patients with major depressive disorder, J Affect Disord source

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    • cites [16] Malykhin, 2010, Structural changes in the hippocampus in major depressive disorder: Contributions of disease and treatment, J Psychiatry Neurosci source

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    Premisecitation

    Roughly 60% of individuals with major depressive disorder experience recurrent episodes.

    “Approximately 60% of individuals with MDD will experience recurrent episodes”
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    • cites [1] Monroe, 2011, Recurrence in major depression: A conceptual analysis, Psychol Rev source

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    Premisecitation

    The stress autonomy model proposes that later major depressive episodes arise without dependence on stressful life events.

    “the stress autonomy model posits that successive MDEs develop independently of stressful life events.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Monroe, 2005, Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective, Psychol Rev source

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    Interpretationcitation

    The study indicates that hippocampal changes arise from stress and are probably independent of whether a major depressive episode develops.

    “Instead, this study suggests that hippocampal changes result from stress and are likely independent of MDE development.”
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    • cites [46] Jayatissa, 2010, A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression, Stress source

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    • Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.

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    Interpretationcitation

    These findings conflict with both the idea that hippocampal abnormalities cause major depressive disorder and the idea that they result from it.

    “These results contradict both causal and consequence hypotheses of hippocampal abnormalities in MDD.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The stress sensitization model holds that after repeated depressive episodes, smaller stressors become capable of triggering major depressive episodes.

    “the stress sensitization model hypothesizes that with recurrent episodes of depression, more minor stressors are capable of triggering MDEs”
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    • cites [50] Monroe, 2005, Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective, Psychol Rev source

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    Premisecitation

    Both models propose that initial major depressive episodes are very likely to follow severe stress, but that this association weakens as the illness advances.

    “Both models posit that while first MDEs are highly likely to follow periods of severe stress, the strength of this relationship declines as a function of illness course.”
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    • cites [50] Monroe, 2005, Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective, Psychol Rev source

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    Interpretationreasoning

    One explanation is that chronic stress produces early hippocampal and medial prefrontal cortex abnormalities, while additional risk factors such as genetic vulnerability or an atypical physiological stress response are required for a major depressive episode to occur.

    “A possible explanation for these seemingly contradictory findings may be that chronic stress drives initial hippocampal and mPFC abnormalities, but other risk factors need to be present (e.g., genetic, abnormal physiological response to stress) for development of a MDE.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    The evidence suggests that smaller hippocampal and medial prefrontal cortex volumes may mark either a predisposition to recurrent episodes or a consequence of them.

    “These findings suggest that hippocampal and mPFC volume reductions may be a selective marker for the propensity towards and/or the consequence of episodic recurrence.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Lower cortisol output could indicate either its bioavailability or diminished responsiveness to glucocorticoids.

    “A lower cortisol output may reflect its bioavailability or it may be an indicator of reduced responsiveness to the presence of glucocorticoids (77).”
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    • cites [77] Raison, 2003, When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders, Am J Psychiatry source

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    Premisecitation

    A meta-analysis linked a history of childhood maltreatment to a higher likelihood of recurrent and persistent depression and to treatment resistance.

    “a meta-analysis found that a history of childhood maltreatment was associated with a greater probability of developing recurrent and persistent cycles of depression as well as treatment-resistance (56).”
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    • cites [56] Nanni, 2012, Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: A meta-analysis, Am J Psychiatry source

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    Premisecitation

    People with multiple prior major depressive episodes had smaller hippocampal and medial prefrontal cortex volumes yet reported lower perceived life stress than those with fewer episodes.

    “individuals with a history of multiple MDEs exhibited smaller hippocampal and mPFC volumes, yet reported less perceived life stress, compared to those with fewer episodes (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Treadway, 2015, Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression, Biol Psychiatry source

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    Interpretationreasoning

    This suggests that high stress may play a role in starting hippocampal vulnerability in first episodes, but that link may be weaker in recurrent episodes.

    “This suggests that while high levels of stress may have an important role in initiating hippocampal vulnerabilities amongst individuals with a first MDE, this relationship may be weaker amongst those with recurrent MDEs.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Animal models show that prolonged stress can produce HPA axis hyperreactivity, depressive behaviors, and hippocampal and medial prefrontal cortex abnormalities.

    “Animal models have established that prolonged stress can lead to HPA axis hyperreactivity and depressive behaviors along with hippocampal and mPFC abnormalities (68,69).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Moylan, 2013, The neuroprogressive nature of major depressive disorder: Pathways to disease evolution and resistance, and therapeutic implications, Mol Psychiatry source

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    • cites [69] Saaltink, 2014, Stress, glucocorticoid receptors, and adult neurogenesis: A balance between excitation and inhibition?, Cell Mol Life Sci source

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    • Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.

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    Premisecitation

    In major depressive disorder, higher oxidative stress, lower antioxidants, and oxidant-antioxidant imbalance are well documented in the hippocampus and medial prefrontal cortex, along with markers of DNA/RNA damage.

    “increased oxidative stress, lower antioxidant levels, and imbalanced oxidant:antioxidant levels have been well documented within the hippocampus (103,104) and mPFC (104–106), resulting in associated markers of DNA/RNA damage in these regions.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Che, 2010, Oxidative damage to RNA but not DNA in the hippocampus of patients with major mental illness, J Psychiatry Neurosci source

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    • cites [104] Meyer, 2009, Brain monoamine oxidase A binding in major depressive disorder, Arch Gen Psychiatry source

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    • cites [105] Michel, 2007, Evidence for oxidative stress in the frontal cortex in patients with recurrent depressive disorder—A postmortem study, Psychiatry Res source

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    • cites [106] Gawryluk, 2011, Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders, Int J Neuropsychopharmacol source

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    Premisecitation

    Preclinical studies show that chronic stress increases oxidative stress and impairs antioxidant defenses in the hippocampus and medial prefrontal cortex.

    “preclinical studies have also demonstrated that chronic stress initiates production of oxidative stress and impairment of antioxidant defense mechanisms in the hippocampus and mPFC (102).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Filipović, 2017, Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms, Brain Struct Funct source

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    • Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.

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    Interpretationcitation

    This may cause cellular damage in the hippocampus and medial prefrontal cortex and lower hippocampal neurogenesis, probably contributing to atrophy.

    “This can result in hippocampal and mPFC cellular damage and reduced hippocampal neurogenesis (102), likely contributing to hippocampal and mPFC atrophy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Filipović, 2017, Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms, Brain Struct Funct source

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    Interpretationcitation

    This suggests that certain stress-related serotonergic changes occur independently of depressive behavior, whereas others are specific to the emergence of anhedonia.

    “This suggests that some stress-related serotonergic abnormalities are independent of the development of depressive behavior, whereas others were specific to anhedonia development.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In a comparison of stress-resilient and anhedonic mice, stress-elevated 5HT2A receptor expression in the medial prefrontal cortex appeared in both groups, but extra 5-HT transporter elevations appeared only in depression-susceptible mice.

    “a study comparing stress-resilient mice versus those exhibiting anhedonic behavior noted that stress-elevated expression of 5HT2A receptors within the mPFC occurred in both groups of mice, whereas additional 5-HT transporter elevations occurred exclusively in the depression-susceptible mice (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Couch, 2013, Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia, Brain Behav Immun source

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    • Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.

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    Interpretationcitation

    These discrepancies may reflect clinical heterogeneity such as illness stage, because greater serotonin dysfunction has been reported in people with more prior major depressive episodes.

    “Discrepancies may be due to clinical heterogeneity, including illness stage, particularly since greater serotonin dysfunction has been described amongst individuals with MDD who have experienced a greater number of past MDEs (120).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Maes, 2012, Increased autoimmune activity against 5-HT: A key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression, J Affect Disord source

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    Premisecitation

    In major depressive disorder, higher peripheral pro-inflammatory cytokines, more inflammation-related gene expression, and less neuroprotective gene expression are associated with greater hippocampal volume loss and medial prefrontal cortex thinning.

    “higher levels of peripheral pro-inflammatory cytokines, greater expression of inflammation-related genes, and reduced expression of neuroprotective genes, have all been associated with greater hippocampal volume decline and mPFC thinning in MDD (95–97).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [95] Frodl, 2012, Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: High IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder, Transl Psychiatry source

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    • cites [96] van Velzen, 2017, Immunometabolic dysregulation is associated with reduced cortical thickness of the anterior cingulate cortex, Brain Behav Immun source

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    • cites [97] Savitz, 2013, Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities, Brain Behav Immun source

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    Premisecitation

    Higher oxidative stress, lower antioxidants, and more oxidative stress-related DNA/RNA damage are linked to clinical markers of major depressive disorder progression such as greater chronicity, more episodes, and treatment resistance.

    “greater oxidative stress, lower antioxidant, and greater oxidative stress-related DNA/RNA damage have been linked to clinical markers of MDD illness progression, including greater chronicity, more MDEs, and treatment resistance (98,108–113).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [98] Sowa-Kućma, 2018, Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts, Prog Neuropsychopharmacol Biol Psychiatry source

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    • cites [108] Baek, 2016, Decreased total antioxidant activity in major depressive disorder patients non-responsive to antidepressant treatment, Psychiatry Investig source

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    • cites [109] Śliwiński, 2015, Elevated level of DNA damage and impaired repair of oxidative DNA damage in patients with recurrent depressive disorder, Med Sci Monit source

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    • cites [110] Czarny, 2017, Impact of single nucleotide polymorphisms of base excision repair genes on DNA damage and efficiency of DNA repair in recurrent depression disorder, Mol Neurobiol source

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    • cites [111] Jorgensen, 2013, Systemic oxidatively generated DNA/RNA damage in clinical depression: Associations to symptom severity and response to electroconvulsive therapy, J Affect Disord source

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    • cites [112] Stefanescu, 2012, The relevance of oxidative stress status in first episode and recurrent depression, J Affect Disord source

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    • cites [113] Talarowska, 2014, Manganese superoxide dismutase gene expression and cognitive functions in recurrent depressive disorder, Neuropsychobiology source

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    Premisecitation

    Peripheral pro-inflammatory cytokines can activate brain microglia and lead to lower hippocampal neurogenesis.

    “the stimulating effects of peripheral pro-inflammatory cytokines on brain microglia can result in reduced hippocampal neurogenesis (92).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Chesnokova, 2016, Chronic peripheral inflammation, hippocampal neurogenesis, and behavior, Brain Behav Immun source

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    Premisecitation

    IDO is an enzyme that breaks down tryptophan, causing serotonin depletion and kynurenine production.

    “IDO is an enzyme that catabolizes tryptophan leading to serotonin depletion and production of kynurenine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Moylan, 2013, The neuroprogressive nature of major depressive disorder: Pathways to disease evolution and resistance, and therapeutic implications, Mol Psychiatry source

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    Premisecitation

    Some studies report increased chronic stress-related glutamate release and receptor expression alongside reduced glutamate clearance or metabolism in the hippocampus.

    “Some studies have reported enhanced chronic stress-related glutamate release and glutamate receptor expression, but reduced glutamate clearance/metabolism in the hippocampus (122,123).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [122] Sun, 2017, Hippocampal GR- and CB1-mediated mGluR5 differentially produces susceptibility and resilience to acute and chronic mild stress in rats, Neuroscience source

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    • cites [123] De Vasconcellos-Bittencourt, 2011, Chronic stress and lithium treatments alter hippocampal glutamate uptake and release in the rat and potentiate necrotic cellular death after oxygen and glucose deprivation, Neurochem Res source

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    Premisecitation

    Chronic stress disrupts glutamate release, synaptic clearance, and transmitter expression, but the direction of these effects varies by brain region.

    “Chronic stress disrupts glutamate release, glutamate clearance from the synapse, and glutamate transmitter expression, but the direction of the effects is region-specific (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Grimm, 2012, Region-specific glutamate changes in patients with unipolar depression, J Psychiatr Res source

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    Premisecitation

    Lower medial prefrontal cortex GABA levels in major depressive disorder have been linked to smaller hippocampal volumes and to treatment resistance.

    “Reduced mPFC GABA levels in MDD have been associated with smaller hippocampal volumes (139) and treatment resistance (142,143).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [139] Abdallah, 2015, Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder, Eur Neuropsychopharmacol source

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    • cites [142] Levinson, 2010, Evidence of cortical inhibitory deficits in major depressive disorder, Biol Psychiatry source

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    • cites [143] Price, 2009, Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: Relationship to treatment resistance in major depressive disorder, Biol Psychiatry source

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

    Premisecitation

    In the medial prefrontal cortex, some studies report lower chronic stress-related glutamate receptor expression, which has been speculated to protect against excessive glutamate signaling and excitotoxicity.

    “A different pattern has been described in the mPFC, with some reporting reduced chronic stress-related glutamate receptor expression, which has been speculated as a potential protective mechanism against excessive glutamate signaling and excitoxicity (e.g., 124–125).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [124] Jett, 2017, Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex, Neuroscience source

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    • cites [125] Yuen, 2012, Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex, Neuron source

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  • May combine two claims.

    Interpretationreasoning

    The production of neurotoxic 3-hydroxykynurenine and quinolinic acid increases glutamate and oxidative stress and reduces GABAergic inhibitory control.

    “The production of neurotoxic 3HK and QA leads to increased glutamate and oxidative stress as well as reduced GABAergic inhibitory control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A study found that a lower kynurenic acid to 3-hydroxykynurenine ratio correlated with smaller hippocampal volumes in major depressive disorder and partly mediated the link between major depressive disorder and medial prefrontal cortex cortical thinning.

    “a study found that a lower KynA/3HK ratio correlated with reduced hippocampal volumes in MDD and partially mediated the relationship between MDD and mPFC cortical thinning (146,147).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [146] Savitz, 2015, Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder, Neuropsychopharmacology source

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    • cites [147] Meier, 2016, Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder, Brain Behav Immun source

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    Premisecitation

    A human imaging study found that higher extracellular glutamate levels were associated with smaller hippocampal volumes, although this has not yet been studied in major depressive disorder samples.

    “a human imaging study noted associations between increased extracellular glutamate levels and hippocampal volume reductions (130).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Cavus, 2008, Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients, Epilepsia source

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  • May combine two claims.

    Interpretationreasoning

    Dysregulated serotonin can lower GABAergic inhibitory control, which increases glutamate and HPA axis reactivity and ultimately reduces hippocampal neurogenesis.

    “when the serotonin system is dysregulated, this can contribute to reduced GABAergic inhibitory control, resulting in enhanced glutamate and HPA axis reactivity, and ultimately reduced hippocampal neurogenesis (124,138).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [124] Jett, 2017, Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex, Neuroscience source

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    • cites [138] Rubio-Casillas, 2016, The dose makes the poison: From glutamate-mediated neurogenesis to neuronal atrophy and depression, Rev Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Generally, studies find lower Glx or glutamate levels in the medial prefrontal cortex and hippocampus in major depressive disorder, with greater reductions in more chronic cases than in first-episode cases.

    “Generally, studies have found reduced Glx/glutamate levels in the mPFC and hippocampus in MDD, with those having a more chronic course showing greater declines compared to individuals experiencing a first episode (127,128).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] de Diego-Adeliño, 2013, Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden, J Psychiatry Neurosci source

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    • cites [128] Portella, 2011, Ventromedial prefrontal spectroscopic abnormalities over the course of depression: A comparison among first episode, remitted recurrent and chronic patients, J Psychiatr Res source

      Not checked in the free run.

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  • The paper relies on this without support.

    Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.

    “Animal models have established that prolonged stress can lead to HPA axis hyperreactivity and depressive behaviors along with hippocampal and mPFC abnormalities (68,69).”

  • The paper relies on this without support.

    Hippocampal and medial prefrontal cortex volume reductions measured by MRI reflect cellular damage or atrophy relevant to major depressive disorder.

    “Volumetric reductions in the hippocampus and medial prefrontal cortex (mPFC) are among the most well documented neural abnormalities in major depressive disorder (MDD).”

  • The paper relies on this without support.

    Peripheral and central measures of inflammation, oxidative stress, cortisol, and neurotransmitters index the same brain processes relevant to hippocampal and medial prefrontal cortex structure.

    “higher levels of peripheral pro-inflammatory cytokines, greater expression of inflammation-related genes, and reduced expression of neuroprotective genes, have all been associated with greater hippocampal volume decline and mPFC thinning in MDD (95–97).”

  • The paper relies on this without support.

    The stress sensitization and stress autonomy models apply to structural brain changes, not only to the onset of major depressive episodes.

    “Two classes of stress-related models, the stress sensitization and stress autonomy models, have been proposed to explain how relationships between stress and depression change as a function of illness course (50).”

  • The paper relies on this without support.

    The proposed indoleamine 2,3-dioxygenase-kynurenine pathway operates in humans with major depressive disorder as described.

    “One possible common pathway involves chronic stress triggering HPA axis dysfunction and enhanced production of cell-mediated immune cytokines, which activate indoleamine 2,3-dioxygenase (IDO;68).”

  • The paper relies on this without support.

    Major depressive disorder illness progression markers such as episode count, illness duration, and treatment resistance reflect a common progressive disease process.

    “they have been consistently associated with markers of a progressive course of MDD characterized by more recurrent episodes/relapses (3,19–25), longer illness duration (24,26–30), and non-remission/treatment resistance (28,31–38).”
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    The statement characterizes the cited cortisol and imaging studies as cross-sectional, but reference 83 explicitly identifies itself as a longitudinal study.

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Authors
Belleau, E. L., Treadway, M. T., & Pizzagalli, D. A.
Affiliations
  • Harvard University (US)
  • Emory University (US)
Corresponding author
Pizzagalli, Diego A.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2019-03
Volume
85
Issue
6
Pages
443-453
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2018.09.031
PMC
PMC6380948
OpenAlex
W2895959992
Cited by
550
References
151
Citations by year
2026: 67 · 2025: 94 · 2024: 83 · 2023: 85 · 2022: 89 · 2021: 70 · 2020: 41 · 2019: 20
FWCI
3.68
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Harvard Medical School
  • McLean Hospital
  • Klingenstein Third Generation Foundation
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
major depressive disorder, chronic stress, hippocampal volume, medial prefrontal cortex, brain structure, hippocampal atrophy, disease progression, major depressive episode, treatment resistance, hypothalamic-pituitary-adrenal axis, neuroinflammation, oxidative stress, neurotransmitter abnormalities, stress sensitization, structural neuroplasticity
MeSH terms
Animals, Depressive Disorder, Major, Major Depressive Disorder, Hippocampus, Humans, Stress, Psychological, Prefrontal Cortex

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 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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