The DOI matches its Crossref record; 148 of the 151 references it cites were found in a registry or an index; none of the 199 sources its claims cite is checked for support yet.
The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology
Open accessAbstract
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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“With respect to mPFC volume reductions, small to large effect sizes have been reported (Figure 2).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
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“each successive episode carries a 10–20% risk of failing to remit with current therapeutic approaches (1).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Abstract
What the sources say
- Not checked yetcites [1] Monroe, 2011, Recurrence in major depression: A conceptual analysis, Psychol Rev source
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In the paper
“Major depressive disorder (MDD) is frequently a chronic, progressive illness.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Abstract
What the sources say
- Not checked yetcites [1] Monroe, 2011, Recurrence in major depression: A conceptual analysis, Psychol Rev source
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“Additionally, these estimates are likely impacted by antidepressant use and presence of other psychiatric comorbidities, given that they were not exclusionary in most studies.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
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In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [6] Koolschijn, 2009, Brain volume abnormalities in major depressive disorder: A meta-analysis of magnetic resonance imaging studies, Hum Brain Mapp source
- Not checked yetcites [8] Kempton, 2011, Structural neuroimaging studies in major depressive disorder, Arch Gen Psychiatry source
- Not checked yetcites [9] Arnone, 2012, Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses, Eur Neuropsychopharmacol source
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“several meta-analyses have demonstrated that, relative to healthy controls (HCs), individuals with MDD show reduced hippocampus and mPFC volumes, including dorsal and ventral mPFC portions (dmPFC/vmPFC) extending into the medial orbital frontal cortex (mOFC) as well as dorsal and rostral portions of the anterior cingulate cortex (rACC/dACC) (2,4–14).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [2] McKinnon, 2009, A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder, J Psychiatry Neurosci source
- Not checked yetcites [4] Videbech, 2004, Hippocampal volume and depression: A meta-analysis of MRI studies, Am J Psychiatry source
- Not checked yetcites [5] Campbell, 2004, Lower hippocampal volume in patients suffering from depression: A meta-analysis, Am J Psychiatry source
- Not checked yetcites [6] Koolschijn, 2009, Brain volume abnormalities in major depressive disorder: A meta-analysis of magnetic resonance imaging studies, Hum Brain Mapp source
- Not checked yetcites [7] Cole, 2011, Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies, J Affect Disord source
- Not checked yetcites [8] Kempton, 2011, Structural neuroimaging studies in major depressive disorder, Arch Gen Psychiatry source
- Not checked yetcites [9] Arnone, 2012, Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses, Eur Neuropsychopharmacol source
- Not checked yetcites [10] Bora, 2012, Gray matter abnormalities in major depressive disorder: A meta-analysis of voxel based morphometry studies, J Affect Disord source
- Not checked yetcites [11] Du, 2012, Voxelwise meta-analysis of gray matter reduction in major depressive disorder, Prog Neuropsychopharmacol Biol Psychiatry source
- Not checked yetcites [12] Lai, 2013, Gray matter volume in major depressive disorder: A meta-analysis of voxel-based morphometry studies, Psychiatry Res Neuroimaging source
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In the paper
“the hippocampus and medial prefrontal cortex (mPFC) have been repeatedly implicated in the pathophysiology and progression of this illness (2,3).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Abstract
What the sources say
- Not checked yetcites [2] McKinnon, 2009, A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder, J Psychiatry Neurosci source
- Not checked yetcites [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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In the paper
“Notably, longitudinal studies have shown that common antidepressants lead to increases in hippocampus and mPFC volumes (17).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [17] Frodl, 2008, Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: A 3-year prospective magnetic resonance imaging study, J Psychiatry Neurosci source
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In the paper
“greater baseline life stress was associated with the development of smaller hippocampal volumes three months later in a sample of HCs (48).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [48] Papagni, 2011, Effects of stressful life events on human brain structure: A longitudinal voxel-based morphometry study, Stress source
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In the paper
“and non-remission/treatment resistance (28,31–38).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [28] Sheline, 2003, Untreated depression and hippocampal volume loss, Am J Psychiatry source
- Not checked yetcites [31] Hsieh, 2002, Hippocampal volume and antidepressant response in geriatric depression, Int J Geriatr Psychiatry source
- Not checked yetcites [32] Frodl, 2004, Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up, J Clin Psychiatry source
- Not checked yetcites [33] MacQueen, 2008, Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder, Biol Psychiatry source
- Not checked yetcites [34] Hoogenboom, 2012, Feasibility of studying brain morphology in major depressive disorder with structural magnetic resonance imaging and clinical data from the electronic medical record, Psychiatry Res source
- Not checked yetcites [35] Taylor, 2014, Hippocampus atrophy and the longitudinal course of late-life depression, Am J Geriatr Psychiatry source
- Not checked yetcites [36] Phillips, 2015, A prospective, longitudinal study of the effect of remission on cortical thickness and hippocampal volume in patients with treatment-resistant depression, Int J Neuropsychopharmacol source
- Not checked yetcites [37] Serra-Blasco, 2016, Naturalistic course of major depressive disorder predicted by clinical and structural neuroimaging data: A 5-year follow-up, Depress Anxiety source
- Not checked yetcites [38] Frodl, 2008, Depression-related variation in brain morphology over 3 years, Arch Gen Psychiatry source
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“amongst the susceptible rats, the development of depressive behaviors occurred prior to reductions in hippocampal cell proliferation (46).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [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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In the paper
“Moreover, possibly via the upregulation of stress-induced neurotoxic processes (e.g., inflammation, oxidative stress), further hippocampal decline occurs among individuals who develop chronic MDD.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
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“This study found that both resilient rats and susceptible rats exhibiting a depressive phenotype were characterized by reduced hippocampal cell proliferation.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [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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In the paper
“other preclinical work has demonstrated similar stress-related microstructural changes in the hippocampus in both resilient mice and mice exhibiting depressive behavior (47).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [47] Delgado y Palacios, 2011, Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model, Biol Psychiatry source
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In the paper
“individuals with MDD and an anxiety disorder were found to have more pronounced mPFC reductions than those with just one disorder (18).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [18] van Tol, 2010, Regional brain volume in depression and anxiety disorders, Arch Gen Psychiatry source
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In the paper
“longitudinal work has shown that hippocampal and mPFC volume reductions become more pronounced when depressive symptoms do not remit (35,38).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
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“recent work has shown that the induction of long-term potentiation within the hippocampus is sufficient to generate antidepressant effects (49).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [49] Kanzari, 2018, Inducing a long-term potentiation in the dentate gyrus is sufficient to produce rapid antidepressant effects, Mol Psychiatry source
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In the paper
“a meta-analysis found that hippocampus volume reduction was only found in patients who had been depressed for at least two years and had more than one episode (2).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [2] McKinnon, 2009, A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder, J Psychiatry Neurosci source
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In the paper
“they have been consistently associated with markers of a progressive course of MDD characterized by more recurrent episodes/relapses (3,19–25)”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [3] Treadway, 2015, Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression, Biol Psychiatry source
- Not checked yetcites [19] MacQueen, 2003, Course of illness, hippocampal function, and hippocampal volume in major depression, Proc Natl Acad Sci U S A source
- Not checked yetcites [20] Kronmüller, 2008, Hippocampal volume and 2-year outcome in depression, Br J Psychiatry source
- Not checked yetcites [21] Yucel, 2008, Anterior cingulate volumes in never-treated patients with major depressive disorder, Neuropsychopharmacology source
- Not checked yetcites [22] Stratmann, 2014, Insular and hippocampal gray matter volume reductions in patients with major depressive disorder, PLoS One source
- Not checked yetcites [23] Wisse, 2015, Major depressive episodes over the course of 7 years and hippocampal subfield volumes at 7 Tesla MRI: The PREDICT-MR study, J Affect Disord source
- Not checked yetcites [24] Bludau, 2016, Medial prefrontal aberrations in major depressive disorder revealed by cytoarchitectonically informed voxel-based morphometry, Am J Psychiatry source
- Not checked yetcites [25] Mathias, 2016, Recurrent major depression and right hippocampal volume: A bivariate linkage and association study, Hum Brain Mapp source
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In the paper
“Thus, abnormalities within these structures may nevertheless contribute to the maintenance or exacerbation of depressive symptoms”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
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In the paper
“longer illness duration (24,26–30)”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [24] Bludau, 2016, Medial prefrontal aberrations in major depressive disorder revealed by cytoarchitectonically informed voxel-based morphometry, Am J Psychiatry source
- Not checked yetcites [26] Sheline, 1996, Hippocampal atrophy in recurrent major depression, Proc Natl Acad Sci U S A source
- Not checked yetcites [27] Sheline, 1999, Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression, J Neurosci source
- Not checked yetcites [28] Sheline, 2003, Untreated depression and hippocampal volume loss, Am J Psychiatry source
- Not checked yetcites [29] Serra-Blasco, 2013, Effects of illness duration and treatment resistance on grey matter abnormalities in major depression, Br J Psychiatry source
- Not checked yetcites [30] Travis, 2015, Dentate gyrus volume and memory performance in major depressive disorder, J Affect Disord source
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In the paper
“Despite these effects, the volume reduction findings remain significant even when accounting for antidepressant use and common psychiatric comorbidities (5,7,8).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [5] Campbell, 2004, Lower hippocampal volume in patients suffering from depression: A meta-analysis, Am J Psychiatry source
- Not checked yetcites [7] Cole, 2011, Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies, J Affect Disord source
- Not checked yetcites [8] Kempton, 2011, Structural neuroimaging studies in major depressive disorder, Arch Gen Psychiatry source
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In the paper
“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 Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [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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In the paper
“several other studies have found that these structural changes may reflect a pre-existing vulnerability to a MDE, particularly for individuals with certain genetic profiles and/or early life stress (ELS) histories (39–45).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [39] Chen, 2010, Decreased hippocampal volume in healthy girls at risk of depression, Arch Gen Psychiatry source
- Not checked yetcites [40] Rao, 2011, Hippocampal changes associated with early-life adversity and vulnerability to depression, Biol Psychiatry source
- Not checked yetcites [41] Amico, 2011, Structural MRI correlates for vulnerability and resilience to major depressive disorder, J Psychiatry Neurosci source
- Not checked yetcites [42] Carballedo, 2012, Early life adversity is associated with brain changes in subjects at family risk for depression, World J Biol Psychiatry source
- Not checked yetcites [43] Holmes, 2012, Individual differences in amygdala-medial prefrontal anatomy link negative affect, impaired social functioning, and polygenic depression risk, J Neurosci source
- Not checked yetcites [44] Little, 2014, Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: A longitudinal prospective study, Transl Psychiatry source
- Not checked yetcites [45] Little, 2015, Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: A prospective imaging gene × environment analysis, J Abnorm Psychol source
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In the paper
“Higher circulating levels of glucocorticoids have also been shown to cause neuronal atrophy and dendritic retraction within the mPFC (70).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [70] Willner, 2013, The neurobiology of depression and antidepressant action, Neurosci Biobehav Rev source
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In the paper
“several imaging studies in MDD have failed to find associations between cortisol and structural abnormalities (82–87).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [82] Kaymak, 2010, Hippocampus, glucocorticoids and neurocognitive functions in patients with first-episode major depressive disorders, Eur Arch Psychiatry Clin Neurosci source
- Not checked yetcites [83] O’Brien, 2004, A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects, Am J Psychiatry source
- Not checked yetcites [84] Vythilingam, 2004, Hippocampal volume, memory, and cortisol status in major depressive disorder: Effects of treatment, Biol Psychiatry source
- Not checked yetcites [85] Colla, 2007, Hippocampal volume reduction and HPA-system activity in major depression, J Psychiatr Res source
- Not checked yetcites [86] Gerritsen, 2011, Depression, hypothalamic pituitary adrenal axis, and hippocampal and entorhinal cortex volumes—the SMART Medea study, Biol Psychiatry source
- Not checked yetcites [87] Schuhmacher, 2012, Association of amygdala volumes with cortisol secretion in unipolar depressed patients, Psychiatry Res source
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In the paper
“excessively high as well as blunted glucocorticoid receptor expression has been linked to reduced neurogenesis within the dentate gyrus (69).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [69] Saaltink, 2014, Stress, glucocorticoid receptors, and adult neurogenesis: A balance between excitation and inhibition?, Cell Mol Life Sci source
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In the paper
“Imaging studies have also demonstrated that an ELS history was associated with hippocampal and mPFC volumetric decline (57–65).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [57] Vythilingham, 2002, Childhood trauma associated with smaller hippocampal volume in women with major depression, Am J Psychiatry source
- Not checked yetcites [58] Treadway, 2009, Early adverse events, HPA activity and rostral anterior cingulate volume in MDD, PLoS One source
- Not checked yetcites [59] Frodl, 2010, Childhood stress, serotonin transporter gene and brain structures in major depression, Neuropsychopharmacology source
- Not checked yetcites [60] Frodl, 2010, Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression, J Psychiatr Res source
- Not checked yetcites [61] Opel, 2014, Hippocampal atrophy in major depression: A function of childhood maltreatment rather than diagnosis, Neuropsychopharmacology source
- Not checked yetcites [62] Gerritsen, 2015, Childhood maltreatment modifies the relationship of depression with hippocampal volume, Psychol Med source
- Not checked yetcites [63] Colle, 2017, Early life adversity is associated with a smaller hippocampus in male but not female depressed in-patients: A case-control study, BMC Psychiatry source
- Not checked yetcites [64] Chaney, 2014, Effect of childhood maltreatment on brain structure in adult patients with major depressive disorder and healthy participants, J Psychiatry Neurosci source
- Not checked yetcites [65] Teicher, 2012, Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum, Proc Natl Acad Sci U S A source
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In the paper
“prospective studies have found that the likelihood of a severe stressful life event occurring in the three months prior to an MDE onset was reduced amongst those with a prior history of depression compared to those experiencing their first MDE (51,52).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [51] Ormel, 2001, The interplay of neuroticism, difficulties, and life events in the etiology of major and subsyndromal, first and recurrent depressive episodes in later life, Am J Psychiatry source
- Not checked yetcites [52] Stroud, 2011, Severe and nonsevere events in first onsets versus recurrences of depression: Evidence for stress sensitization, J Abnorm Psychol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“individuals with an ELS history are more prone to developing an MDE under less amounts of recent life stress than those without an ELS history (54,55).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [54] Hammen, 2000, Depression and sensitization to stressors among young women as a function of childhood adversity, J Consult Clin Psychol source
- Not checked yetcites [55] Oldehinkel, 2014, Childhood adversities and adolescent depression: A matter of both risk and resilience, Dev Psychopathol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“even in the presence of cortisol hypersecretion, elevated cortisol may represent an attempt to counteract inflammatory responses in the presence of high glucocorticoid levels (77).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Individuals with both an MDD diagnosis and an ELS history showed the highest stress-related ACTH response (66).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [66] Heim, 2000, Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood, JAMA source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the link between ELS and the development of chronic courses of depression marked by greater hippocampal and mPFC damage may be mediated by the persistent manifestation of neurotoxic processes that are triggered by even minor stressors.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Some of these studies have noted that the relationship may be independent of the presence of MDD (61,64,65).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [61] Opel, 2014, Hippocampal atrophy in major depression: A function of childhood maltreatment rather than diagnosis, Neuropsychopharmacology source
- Not checked yetcites [64] Chaney, 2014, Effect of childhood maltreatment on brain structure in adult patients with major depressive disorder and healthy participants, J Psychiatry Neurosci source
- Not checked yetcites [65] Teicher, 2012, Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum, Proc Natl Acad Sci U S A source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“One of the factors complicating the interpretation of abnormal cortisol levels in MDD is the potential presence of glucocorticoid resistance (77).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“this meta-analysis highlighted substantial variability in HPA axis functioning in MDD (71).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [71] Stetler, 2011, Depression and hypothalamic-pituitary-adrenal activation: A quantitative summary of four decades of research, Psychosom Med source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A human study found that a greater number of stressful life events in the three-months prior to an initial MDE was linked to increased hippocampal volume reductions in males with a first MDE (53).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [53] Kronmüller, 2008, Life events and hippocampal volume in first-episode major depression, J Affect Disord source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“animal models have shown that DHEA reduces the adverse effects of cortisol on the central nervous system (81)”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [81] Maninger, 2009, Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), Front Neuroendocrinol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“there is also evidence that ELS enhances inflammatory responses to minor daily life stressors in adulthood (67).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [67] Gouin, 2012, Childhood abuse and inflammatory responses to daily stressors, Ann Behav Med source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“further highlighting the importance of stress (rather than the presence of MDD per se) in facilitating initial structural damage.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“cortisol responses to a laboratory psychosocial stressor in MDD are mixed, with some showing cortisol hyperreactivity, while others hyporeactivity (75,76).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [75] Zorn, 2017, Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis, Psychoneuroendocrinology source
- Not checked yetcites [76] Morris, 2014, Cortisol response to psychosocial stress during a depressive episode and remission, Stress source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“these longitudinal studies also found that the likelihood of a MDE onset increased when nonsevere life stressors were present in the three months prior to the episode amongst those with a prior history of depression (51,52).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [51] Ormel, 2001, The interplay of neuroticism, difficulties, and life events in the etiology of major and subsyndromal, first and recurrent depressive episodes in later life, Am J Psychiatry source
- Not checked yetcites [52] Stroud, 2011, Severe and nonsevere events in first onsets versus recurrences of depression: Evidence for stress sensitization, J Abnorm Psychol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Longitudinal studies have found that both enhanced and blunted cortisol levels predicted MDE recurrence amongst those with a prior history of MDD (72–74).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [72] Bockting, 2012, Lower cortisol levels predict recurrence in remitted patients with recurrent depression: A 5.5 year prospective study, Psychiatry Res source
- Not checked yetcites [73] Lok, 2012, Longitudinal hypothalamic-pituitary-adrenal axis trait and state effects in recurrent depression, Psychoneuroendocrinology source
- Not checked yetcites [74] Vreeburg, 2013, Salivary cortisol levels and the 2-year course of depressive and anxiety disorders, Psychoneuroendocrinology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“antidepressant use, which has been found to reduce HPA axis activity (78).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [78] McKay, 2010, The impact of treatment on HPA axis activity in unipolar major depression, J Psychiatr Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“higher baseline cortisol levels as well as higher cortisol/dehydroepiandrosterone (DHEA) ratios have been linked to smaller hippocampal and mPFC volumes amongst HC and MDD samples (79,80)”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [79] Travis, 2016, Effects of cortisol on hippocampal subfields volumes and memory performance in healthy control subjects and patients with major depressive disorder, J Affect Disord source
- Not checked yetcites [80] Jin, 2016, Cortisol/DHEA ratio and hippocampal volume: A pilot study in major depression and healthy controls, Psychoneuroendocrinology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“a meta-analysis of clinical studies noted that individuals with MDD showed higher basal cortisol levels, particularly in the afternoon when cortisol levels should be dropping (71).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [71] Stetler, 2011, Depression and hypothalamic-pituitary-adrenal activation: A quantitative summary of four decades of research, Psychosom Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“recent imaging studies in depressed individuals have reported enhanced neuroinflammation in the hippocampus and mPFC compared to HCs (93,94).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [93] Setiawan, 2015, Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes, JAMA Psychiatry source
- Not checked yetcites [94] Holmes, 2018, Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: A positron emission tomography study, Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“two recent meta-analyses failed to find significant alterations in serotonin transporter binding/availability in the hippocampus and mPFC in MDD (118,119).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [118] Gryglewski, 2014, Meta-analysis of molecular imaging of serotonin transporters in major depression, J Cereb Blood Flow Metab source
- Not checked yetcites [119] Kambeitz, 2015, The serotonin transporter in depression: Meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression, J Affect Disord source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“One of these studies noted that greater parental display of positive behaviors was protective against hippocampal volume reductions amongst those carrying the s allele.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [44] Little, 2014, Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: A longitudinal prospective study, Transl Psychiatry source
- Not checked yetcites [45] Little, 2015, Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: A prospective imaging gene × environment analysis, J Abnorm Psychol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This may partly reflect evidence supporting the impact of chronic stress and persistent types of MDD on mPFC and hippocampal morphology.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“response to antidepressant treatment has been shown to normalize the oxidant: antioxidant imbalance seen in MDD (108).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
What the sources say
- Not checked yetcites [108] Baek, 2016, Decreased total antioxidant activity in major depressive disorder patients non-responsive to antidepressant treatment, Psychiatry Investig source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“human imaging findings in MDD have been more mixed (117–119).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [117] López-Figueroa, 2004, Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia, Biol Psychiatry source
- Not checked yetcites [118] Gryglewski, 2014, Meta-analysis of molecular imaging of serotonin transporters in major depression, J Cereb Blood Flow Metab source
- Not checked yetcites [119] Kambeitz, 2015, The serotonin transporter in depression: Meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression, J Affect Disord source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Findings to date suggest a psychosocial stress-induced oxidative stress pathway that contributes to hippocampus and mPFC structural deficits in MDD.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Enhanced peripheral inflammation has also been related to MDD recurrence/relapse, number of episodes, illness duration, and treatment non-response (98–100).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [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
- Not checked yetcites [99] Dunjic-Kostic, 2013, Melancholic and atypical major depression—Connection between cytokines, psychopathology and treatment, Prog Neuropsychopharmacol Biol Psychiatry source
- Not checked yetcites [100] Eller, 2008, Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder, Prog Neuropsychopharmacol Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neurotransmitter disturbances, such as serotonin dysfunction, are likely prominent pathways to illness progression in MDD.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“animal models have demonstrated that chronic unpredictable stress promotes the production of pro-inflammatory cytokines in the hippocampus (89) and mPFC (90,91).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [89] Iwata, 2016, Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor, Biol Psychiatry source
- Not checked yetcites [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
- Not checked yetcites [91] Pan, 2014, Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats, Brain Behav Immun source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, stress-mediated enhancement of central and peripheral pro-inflammatory cytokines may contribute to subsequent structural alterations.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“a preclinical chronic stress study demonstrated that mice exhibiting anhedonic behavior (but not stress-resilient mice) showed enhanced inflammation in the mPFC (90).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
None of the sources cited for this claim have been checked yet.
In the paper
“Preclinical chronic mild stress models of depression show reduced serotonin concentration, expression, release, and neurotransmission in both the hippocampus and mPFC (114–116).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [114] Bekris, 2005, Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains, Behav Brain Res source
- Not checked yetcites [115] Luo, 2008, Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress, Brain Res Bull source
- Not checked yetcites [116] Harro, 2001, Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat: Effects on behavior and monoamine neurochemistry, Brain Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“responders to antidepressant treatment showed reduced peripheral inflammation over the course of treatment compared to nonresponders (101).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [101] Lindqvist, 2017, Oxidative stress, inflammation and treatment response in major depression, Psychoneuroendocrinology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“one found that lower antioxidant levels were associated with more pronounced hippocampal volume reductions in MDD (107).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
What the sources say
- Not checked yetcites [107] Lindqvist, 2014, Peripheral antioxidant markers are associated with total hippocampal and CA3/dentate gyrus volume in MDD and healthy controls—Preliminary findings, Psychiatry Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“There has been evidence of decreased 5HT1A mRNA levels within the hippocampus of individuals with MDD compared to HCs (117).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [117] López-Figueroa, 2004, Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia, Biol Psychiatry source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent longitudinal studies have linked smaller hippocampal volumes to MDD onset among individuals with ELS and carrying the s allele of the serotonin transporter gene, which is associated with reduced serotonin uptake (44,45).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [44] Little, 2014, Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: A longitudinal prospective study, Transl Psychiatry source
- Not checked yetcites [45] Little, 2015, Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: A prospective imaging gene × environment analysis, J Abnorm Psychol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that some stress-related mPFC and hippocampal inflammatory processes may require the presence of depressive symptomology in addition to stress.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Several human MRS studies have reported lower mPFC GABA levels in MDD (139–141).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [139] Abdallah, 2015, Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder, Eur Neuropsychopharmacol source
- Not checked yetcites [140] Gabbay, 2012, Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: Relationship to anhedonia, Arch Gen Psychiatry source
- Not checked yetcites [141] Hasler, 2007, Reduced prefrontal glutamate/glutamine and γ-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy, Arch Gen Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A preclinical study showed that inhibiting glutamine synthase and glutamine transport in the mPFC led to the development of depressive behavior (131).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [131] Lee, 2013, Glutamate deficiency in the prefrontal cortex increases depressive-like behaviors in male mice, J Psychiatry Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“another preclinical study showed that enhanced stimulation of glutamate cycling in the mPFC via three different classes of antidepressants was associated with the onset of rapid antidepressant action (132).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [132] Chowdry, 2017, Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant effects, Mol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“The glutamate system is also highly impacted by stress.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [121] Grimm, 2012, Region-specific glutamate changes in patients with unipolar depression, J Psychiatr Res source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Several human postmortem studies have also shown reductions in the expression of several components critical to astrocyte function, largely in the mPFC, but also some evidence in the hippocampus, suggesting impaired glutamate-glutamine cycling (133).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [133] Sancora, 2013, From pathophysiology to novel antidepressant drugs: Glial contributions to the pathology and treatment of mood disorders, Biol Psychiatry source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“GABA is also likely centrally involved in hippocampal and mPFC abnormalities in MDD (134).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [134] Luscher, 2011, The GABAergic deficit hypothesis of major depressive disorder, Mol Psychiatry source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“antidepressants known to target the monoaminergic system have also shown to counteract GABAergic abnormalities (134).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [134] Luscher, 2011, The GABAergic deficit hypothesis of major depressive disorder, Mol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Serotonin is known to regulate the GABAergic system (137).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [137] Feng, 2001, Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons, J Neurosci source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Early life stress and genetic risk profiles may program this vulnerability early on by enhancing psychological and biological reactivity to minor stressful life events (Figure 3).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“reduced glutamate clearance (and thus enhanced accumulation of glutamate in the mPFC) has been shown to produce anhedonic behaviors (126).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [126] John, 2012, Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia, Neuropsychopharmacology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“There is also emerging evidence of impaired glutamate-glutamine cycling in the mPFC and hippocampus amongst those with MDD.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [133] Sancora, 2013, From pathophysiology to novel antidepressant drugs: Glial contributions to the pathology and treatment of mood disorders, Biol Psychiatry source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on the above evidence, it is likely that these neurotoxic processes interact to form multiple pathways leading to hippocampal and mPFC volume decline and MDD illness progression.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Together, this pathway may trigger hippocampal and mPFC cellular damage and volume reductions (138,144,145).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
What the sources say
- Not checked yetcites [138] Rubio-Casillas, 2016, The dose makes the poison: From glutamate-mediated neurogenesis to neuronal atrophy and depression, Rev Neurosci source
- Not checked yetcites [144] Capuron, 2011, Immune system to brain signaling: Neuropsychopharmacological implications, Pharmacol Ther source
- Not checked yetcites [145] Lugo-Huitron, 2013, Quinolinic acid: An endogenous neurotoxin with multiple targets, Oxid Med Cell Longev source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“reduced glutamate levels may reflect cellular abnormalities associated with decreased glutamate availability resulting from hyperactive glutamate neurotransmission (129).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [129] Croarkin, 2013, Evidence for increased glutamatergic cortical facilitation in children and adolescents with major depressive disorder, JAMA Psychiatry source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“magnetic resonance spectroscopy (MRS) studies have provided evidence of glutamate dysfunction in MDD (e.g., 127,128).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“chronic stress has been shown to decrease GABA expression in the hippocampus and mPFC (135,136).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [135] Hemanth Kumar, 2012, Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7T, Behav Brain Res source
- Not checked yetcites [136] Ma, 2016, Impaired GABA synthesis, uptake and release are associated with depression-like behaviors induced by chronic mild stress, Transl Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“Kynurenine is then converted to neuroprotective metabolites (kynurenic acid (KynA)) or neurotoxic metabolites (3-hydroxykynurenine (3HK), and quinolinic acid (QA)) (68).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
What the sources say
- Not checked yetcites [68] Moylan, 2013, The neuroprogressive nature of major depressive disorder: Pathways to disease evolution and resistance, and therapeutic implications, Mol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these findings indicate that glutamate dysregulation likely has a strong role in neural and clinical markers of MDD illness progression MDD.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that GABA may have a key role in multiple pathways leading to hippocampal and mPFC structural deficits in MDD and treatment resistance.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the connection between serotonin and GABA, reduced serotonin also contributes to decreased GABA expression.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In line with stress sensitization models, with each successive MDE, it may take smaller amounts of stress to trigger these pathways and produce further brain structural decline.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A study that directly compared stress-resilient to stress-susceptible mice displaying depressive behaviors indicated that enhanced hippocampal glutamate expression was unique to depression-susceptible mice (122).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [122] Sun, 2017, Hippocampal GR- and CB1-mediated mGluR5 differentially produces susceptibility and resilience to acute and chronic mild stress in rats, Neuroscience source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Accordingly, increased chronic-stress related glutamate expression in the hippocampus and mPFC may be unique to those who develop the depressive phenotype.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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 Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
What the sources say
- Not checked yetcites [68] Moylan, 2013, The neuroprogressive nature of major depressive disorder: Pathways to disease evolution and resistance, and therapeutic implications, Mol Psychiatry source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“preclinical evidence suggests that neurotoxic dorsal hippocampal kynurenine metabolism may drive depressive behavior when inflammation is enhanced (148).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
What the sources say
- Not checked yetcites [148] Parrott, 2016, Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation, Transl Psychiatry source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
- It may state two separate claims as one. 30
- Probably not a substantial claim. 4
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [15] Han, 2016, Hippocampal subfield analysis in medication-naïve female patients with major depressive disorder, J Affect Disord source
- Not checked yetcites [16] Malykhin, 2010, Structural changes in the hippocampus in major depressive disorder: Contributions of disease and treatment, J Psychiatry Neurosci source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Approximately 60% of individuals with MDD will experience recurrent episodes”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Abstract
What the sources say
- Not checked yetcites [1] Monroe, 2011, Recurrence in major depression: A conceptual analysis, Psychol Rev source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the stress autonomy model posits that successive MDEs develop independently of stressful life events.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [50] Monroe, 2005, Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective, Psychol Rev source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Instead, this study suggests that hippocampal changes result from stress and are likely independent of MDE development.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results contradict both causal and consequence hypotheses of hippocampal abnormalities in MDD.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“the stress sensitization model hypothesizes that with recurrent episodes of depression, more minor stressors are capable of triggering MDEs”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [50] Monroe, 2005, Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective, Psychol Rev source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [50] Monroe, 2005, Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective, Psychol Rev source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Hippocampus and mPFC volume reductions: Cause versus consequence of MDD?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A lower cortisol output may reflect its bioavailability or it may be an indicator of reduced responsiveness to the presence of glucocorticoids (77).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [56] Nanni, 2012, Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: A meta-analysis, Am J Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
What the sources say
- Not checked yetcites [3] Treadway, 2015, Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression, Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress and hippocampal/mPFC volume reduction in MDD
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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 Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
What the sources say
- Not checked yetcites [68] Moylan, 2013, The neuroprogressive nature of major depressive disorder: Pathways to disease evolution and resistance, and therapeutic implications, Mol Psychiatry source
- Not checked yetcites [69] Saaltink, 2014, Stress, glucocorticoid receptors, and adult neurogenesis: A balance between excitation and inhibition?, Cell Mol Life Sci source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
What the sources say
- Not checked yetcites [103] Che, 2010, Oxidative damage to RNA but not DNA in the hippocampus of patients with major mental illness, J Psychiatry Neurosci source
- Not checked yetcites [104] Meyer, 2009, Brain monoamine oxidase A binding in major depressive disorder, Arch Gen Psychiatry source
- Not checked yetcites [105] Michel, 2007, Evidence for oxidative stress in the frontal cortex in patients with recurrent depressive disorder—A postmortem study, Psychiatry Res source
- Not checked yetcites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“This can result in hippocampal and mPFC cellular damage and reduced hippocampal neurogenesis (102), likely contributing to hippocampal and mPFC atrophy.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that some stress-related serotonergic abnormalities are independent of the development of depressive behavior, whereas others were specific to anhedonia development.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models of stress and depression can be generalized to human major depressive disorder neurobiology.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Serotonin dysfunction contribute to brain structural decline and MDD illness progression
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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 Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [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
- Not checked yetcites [96] van Velzen, 2017, Immunometabolic dysregulation is associated with reduced cortical thickness of the anterior cingulate cortex, Brain Behav Immun source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Oxidative stress as a mechanism contributing to MDD-related brain structural deficits
What the sources say
- Not checked yetcites [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
- Not checked yetcites [108] Baek, 2016, Decreased total antioxidant activity in major depressive disorder patients non-responsive to antidepressant treatment, Psychiatry Investig source
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [112] Stefanescu, 2012, The relevance of oxidative stress status in first episode and recurrent depression, J Affect Disord source
- Not checked yetcites [113] Talarowska, 2014, Manganese superoxide dismutase gene expression and cognitive functions in recurrent depressive disorder, Neuropsychobiology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“the stimulating effects of peripheral pro-inflammatory cytokines on brain microglia can result in reduced hippocampal neurogenesis (92).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Stress-mediated inflammatory pathways to hippocampal and mPFC deficits in MDD
What the sources say
- Not checked yetcites [92] Chesnokova, 2016, Chronic peripheral inflammation, hippocampal neurogenesis, and behavior, Brain Behav Immun source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“IDO is an enzyme that catabolizes tryptophan leading to serotonin depletion and production of kynurenine.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
What the sources say
- Not checked yetcites [68] Moylan, 2013, The neuroprogressive nature of major depressive disorder: Pathways to disease evolution and resistance, and therapeutic implications, Mol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Some studies have reported enhanced chronic stress-related glutamate release and glutamate receptor expression, but reduced glutamate clearance/metabolism in the hippocampus (122,123).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [122] Sun, 2017, Hippocampal GR- and CB1-mediated mGluR5 differentially produces susceptibility and resilience to acute and chronic mild stress in rats, Neuroscience source
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Chronic stress disrupts glutamate release, glutamate clearance from the synapse, and glutamate transmitter expression, but the direction of the effects is region-specific (121).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [121] Grimm, 2012, Region-specific glutamate changes in patients with unipolar depression, J Psychiatr Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Reduced mPFC GABA levels in MDD have been associated with smaller hippocampal volumes (139) and treatment resistance (142,143).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [139] Abdallah, 2015, Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder, Eur Neuropsychopharmacol source
- Not checked yetcites [142] Levinson, 2010, Evidence of cortical inhibitory deficits in major depressive disorder, Biol Psychiatry source
- Not checked yetcites [143] Price, 2009, Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: Relationship to treatment resistance in major depressive disorder, Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [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
- Not checked yetcites [125] Yuen, 2012, Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex, Neuron source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The production of neurotoxic 3HK and QA leads to increased glutamate and oxidative stress as well as reduced GABAergic inhibitory control.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > A common pathway leading to MDD illness progression-related hippocampal and mPFC volume reductions
What the sources say
- Not checked yetcites [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
- Not checked yetcites [147] Meier, 2016, Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder, Brain Behav Immun source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“a human imaging study noted associations between increased extracellular glutamate levels and hippocampal volume reductions (130).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [130] Cavus, 2008, Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients, Epilepsia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > GABAergic disturbances associated with brain structural decline and chronic MDD
What the sources say
- Not checked yetcites [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
- Not checked yetcites [138] Rubio-Casillas, 2016, The dose makes the poison: From glutamate-mediated neurogenesis to neuronal atrophy and depression, Rev Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > Glutamatergic contributions to MDD-related brain structural decline
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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).”
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?
In the citing paper
“and the significantly reduced mPFC volume spanning across dorsomedial PFC, ventromedial (VM) PFC and ACC 205.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [205]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > The role of HPA axis dysregulation in stress-mediated hippocampal and mPFC deficits
“Additionally, given that these studies are cross-sectional, and brain structural changes may occur long after stress exposure, prospective studies are needed to link distinct cortisol trajectories with different life stress profiles, structural deficits, and illness course.”
§ The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology > References
“83. O’Brien JT, Lloyd A, McKeith I, Gholkar A, Ferrier N (2004): A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects.”
Citations
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Hippocampal atrophy in recurrent major depression
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Hippocampal volume and depression: a meta-analysis of MRI studies
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Untreated Depression and Hippocampal Volume Loss
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Lower Hippocampal Volume in Patients Suffering From Depression: A Meta-Analysis
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Cited by
Sorted by citations
Role of oxidative stress in depression
Bhatt, S., Nagappa, A. N., & Patil, C. R. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.05.001 · Cited by 854
Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway
Dang, R., Wang, M., Li, X., Wang, H., Liu, L., Wu, Q., Zhao, J., Ji, P., Zhong, L., Licinio, J., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02400-6 · Cited by 547
Correia, A. S., Cardoso, A., & Vale, N. (2023) · Antioxidants · doi:10.3390/antiox12020470 · Cited by 383
Paying attention to attention in depression
Keller, A. S., Leikauf, J. E., Holt-Gosselin, B., Staveland, B. R., & Williams, L. M. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0616-1 · Cited by 329
Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome
Cruz-Pereira, J. S., Rea, K., Nolan, Y. M., O'Leary, O. F., Dinan, T. G., & Cryan, J. F. (2020) · Annual Review of Psychology · doi:10.1146/annurev-psych-122216-011613 · Cited by 320
“In this model, intestinal T cells migrate to the meninges after a stroke, which is reversed by the depletion of particular groups of gut bacteria (Benakis et al. 2016).”
Background
Metadata
- Authors
- Belleau, E. L., Treadway, M. T., & Pizzagalli, D. A.
- Affiliations
- Harvard University (US)
- Emory University (US)
- Corresponding author
- Pizzagalli, Diego A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 85
- Issue
- 6
- Pages
- 443-453
- ISSN
- 0006-3223 (ISSN-L)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › 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.
A language model drew the claims from the paper on 2026-10-04, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-04 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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