Glucocorticoids, cytokines and brain abnormalities in depression

May combine two claims.

Cytokines activate the HPA axis, elevating systemic glucocorticoids, and inhibit glucocorticoid receptor function at multiple levels including receptor translocation and induction of receptor isoforms with reduced ligand binding.

“Cytokines can activate the HPA axis, causing an elevation of systemic glucocorticoid levels, and at the same time, they can inhibit GR function at multiple levels, including GR translocation and induction of GR isoforms with reduced capacity to bind ligand”

• cites Pace et al., 2007 sourceNot checked yet

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May combine two claims.

Mineralocorticoid and glucocorticoid receptor actions are complementary in the stress response; the mineralocorticoid receptor normally prevents stress-induced disturbances, and the glucocorticoid receptor helps recovery if disturbances occur.

“Actions mediated by both receptors are complementary and operate in different time domains of the stress response: the MR normally prevents stress-induced disturbances, but, if such disturbances occur, the GR can operate and help in the recovery process.”

May combine two claims.

Reduced neurogenesis can theoretically contribute to cognitive symptoms of depression but is unlikely alone to produce the full mood disorder.

“A reduction in neurogenesis can theoretically contribute to the cognitive symptoms of depression, even though by itself is unlikely to produce the full mood disorder”

• cites Lucassen et al., 2010 sourceNot checked yet

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May combine two claims.

Dexamethasone increases neutrophils and decreases lymphocytes in healthy controls, but this effect is absent in non-suppressors.

“dexamethasone administration induced an increase in the number of neutrophils and a decrease in the number of lymphocytes in healthy controls, whereas this effect was not observed in non-suppressors”

May combine two claims.

Depressed patients show higher levels of pro-inflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules.

“depressed patients show higher levels of pro-inflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules”

• cites Raison et al., 2006 sourceNot checked yet

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• cites Howren et al., 2009 sourceNot checked yet

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May combine two claims.

Glucocorticoids act on glucocorticoid and mineralocorticoid receptors; the mineralocorticoid receptor binds cortisol with higher affinity and regulates normal HPA fluctuations, while the glucocorticoid receptor has lower affinity and is extensively occupied during stress.

“The MR binds cortisol with higher affinity, hence it regulates normal HPA fluctuations, being significantly bound even at the circadian trough, and fully bound at the circadian peak and during stressful episodes. The GR, of lower affinity, gets extensively occupied in times of stress.”

• cites de Kloet et al., 2005 sourceNot checked yet

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May combine two claims.

Depression is highly prevalent in infectious, autoimmune, and neurodegenerative diseases, and this comorbidity cannot be attributed only to psychological distress of the primary disease.

“Depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases, and this co-morbidity cannot be attributed only to the psychological distress of the starting disease”

• cites Pollak and Yirmiya, 2002 sourceNot checked yet

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

An imbalance between mineralocorticoid and glucocorticoid receptors could increase vulnerability to stress-related psychiatric disorders in predisposed individuals.

“Although it is possible that an imbalance between MR and GR could increase the vulnerability to stress-related psychiatric disorders in predisposed individuals”

• cites de Kloet et al., 2007 sourceNot checked yet

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May combine two claims.

Severe or chronic stress in early life or adulthood can cause neural cell death, atrophy of neuronal processes, and affect hippocampal neurogenesis and plasticity.

“severe or chronic stress exposure, both in early life as well as in adulthood, can cause neural cell death and atrophy of neuronal processes, and also affect hippocampal neurogenesis and plasticity”

• cites McEwen and Seeman, 1999 sourceNot checked yet

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• cites Sapolsky, 2000 sourceNot checked yet

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May combine two claims.

Failure in glucocorticoid receptor function in depression may result from reduced glucocorticoid binding, reduced receptor expression, enhanced inflammatory pathway activation, or lack of co-repressor activity.

“A failure in GR function, as hypothesized to take place in depression, may therefore result from reduced glucocorticoid binding to GR, reduced GR expression, enhanced activation of inflammatory pathways, or lack of co-repressor activity”

• cites De Bosscher and Haegeman, 2009 sourceNot checked yet

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May combine two claims.

Repeated uncontrollable and unpredictable stress can alter dendrite and spine morphology in specific brain regions and suppress adult neurogenesis.

“if stress is repetitively experienced in an uncontrollable and unpredictable manner, it can cause alterations in dendrite and spine morphology in specific brain regions, and eventually suppress adult neurogenesis”

• cites Mirescu and Gould, 2006 sourceNot checked yet

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• cites Joels et al., 2007 sourceNot checked yet

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May combine two claims.

Prolonged peripheral immune activation during systemic infections, cancer, or autoimmune diseases could exacerbate sickness behaviour and lead to depressive symptoms in vulnerable individuals.

“If, during systemic infections, cancer or autoimmune diseases, the activation of the peripheral immune system is prolonged, the immune signalling to the brain could lead to an exacerbation of sickness behaviour and to the development of depressive symptoms in vulnerable individuals”

• cites Dantzer et al., 2008 sourceNot checked yet

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May combine two claims.

Therapeutic interferon-alpha leads to depressive symptomatology in up to 50% of patients, with biological alterations similar to major depression and treatable with antidepressants.

“therapeutic administration of the cytokine interferon-alpha (IFN-alpha) leads to a depressive symptomatology in up to 50% of patients, who show similar biological alterations as those found in MD and can be treated with antidepressant medication”

• cites Capuron and Miller, 2004 sourceNot checked yet

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• cites Raison et al., 2005 sourceNot checked yet

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• cites Maddock et al., 2005 sourceNot checked yet

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May combine two claims.

Dexamethasone suppresses mitogen-induced lymphocyte proliferation and IL-1beta production in healthy controls, while MD patients show dexamethasone non-suppression.

“While dexamethasone administration significantly suppressed the mitogen-induced lymphocyte proliferation and the interleukin-1beta (IL-1beta) production in healthy controls, MD patients exhibited dexamethasone non-suppression”

• cites Maes et al, 1991 sourceNot checked yet

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May combine two claims.

Glucocorticoids bind cytosolic glucocorticoid receptors, causing dissociation from chaperones, nuclear translocation, and either DNA binding to activate anti-inflammatory genes or protein interaction to repress NF-kappaB.

“Glucocorticoids act by binding to the cytosolic GR, which is subsequently activated and is thus able to translocate into the nucleus.”

• Also stated in: § 2.3. Molecular basis of glucocorticoid action · plain

  “Once in the nucleus, the GR either binds to DNA and switches on the expression of anti-inflammatory genes, or acts indirectly by protein–protein interaction to repress the activity of a number of distinct signalling pathways such as nuclear factor-kappaB (NF-kappaB)”

• cites Revollo and Cidlowski, 2009 sourceNot checked yet

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May combine two claims.

HPA axis hyperactivity in major depression is demonstrated by altered feedback inhibition, increased circulating cortisol, and non-suppression of cortisol after dexamethasone.

“Hyperactivity of the HPA axis in MD can be demonstrated by the altered feedback inhibition, as seen by increased circulating cortisol and non-suppression of cortisol following administration of dexamethasone”

• cites Holsboer et al., 1982 sourceNot checked yet

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• cites Holsboer-Trachsler et al., 1991 sourceNot checked yet

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May combine two claims.

Functional glucocorticoid resistance was accompanied by accumulation of glucocorticoid-insensitive cells in the spleen with impaired glucocorticoid receptor nuclear translocation and lack of glucocorticoid-induced NF-kappaB suppression.

“The development of functional glucocorticoid resistance was accompanied by the accumulation of glucocorticoid-insensitive cells in the spleen that exhibit impaired nuclear translocation of the GR and lack of glucocorticoid-induced suppression of NF-kappaB”

• cites Engler et al., 2008 sourceNot checked yet

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May combine two claims.

IL-1beta and IL-6 increase during infection and play central roles in synaptic plasticity, neurogenesis, and neuromodulation.

“IL-1beta and IL-6, both of which increase during infection, have been described as playing a central role in synaptic plasticity, neurogenesis and neuromodulation”

• cites McAfoose and Baune 2009 sourceNot checked yet

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May combine two claims.

Acute or short-term stress can enhance immune responses, while chronic or long-term stress can suppress immunity.

“Whereas an acute or short-term stressful life event can enhance immune responses, chronic or long-term stress can suppress immunity.”

May combine two claims.

Stockmeier et al. found increased packing density of glia, pyramidal neurons, and granule cell neurons in hippocampal subfields and the dentate gyrus, decreased pyramidal neuron soma size, suggesting that reduced neuropil may account for decreased hippocampal volume.

“Stockmeier et al. (2004) observed that the packing density of glia, pyramidal neurons and granule cell neurons is significantly increased in all hippocampal subfields and the dentate gyrus, and pyramidal neuron soma size is significantly decreased, suggesting that a significant reduction in neuropil in MD may account for the decreased hippocampal volume detected by neuroimaging.”

• cites Stockmeier et al. (2004) sourceNot checked yet

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May combine two claims.

Chronic corticosterone produced depressive symptoms in wild type and knockout mice, and the effects of chronic mild stress on behavioural depression could be mimicked by exogenous IL-1beta.

“chronic administration of corticosterone produced depressive symptoms both in wild type and knockout mice, and the effects of CMS on behavioural depression could be mimicked by exogenous administration of IL-1beta”

• cites Goshen et al., 2008 sourceNot checked yet

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May combine two claims.

Splenocytes from mice stimulated with lipopolysaccharide and repeatedly subjected to social disruption were less sensitive to the anti-inflammatory actions of glucocorticoids, with increased pro-inflammatory cytokines.

“splenocytes of mice stimulated with the bacterial cell wall component lipopolysaccharide (LPS) and also repeatedly subjected to social disruption were less sensitive to the anti-inflammatory actions of glucocorticoids, showing increased levels of pro-inflammatory cytokines”

• cites Engler et al., 2008 sourceNot checked yet

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May combine two claims.

Inhibiting the IL-1 receptor and using IL-1 receptor null mice prevented anhedonic behaviour caused by chronic stress.

“both inhibiting the IL-1 receptor and using IL-1 receptor null mice prevented the anhedonic behaviour caused by chronic stress exposure”

• cites Koo and Duman, 2008 sourceNot checked yet

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May combine two claims.

HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA hyperactivity is a marker of glucocorticoid resistance leading to immune activation, and inflammation could stimulate HPA axis activity via cytokines and by inducing glucocorticoid resistance.

“HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing gluc”

• AssumptionRests on an assumption: Communication occurs between the endocrine, immune, and central nervous systems, so activation of inflammatory responses can affect neuroendocrine processes and vice versa.

May combine two claims.

In caregivers of patients with malignant brain cancer, cortisol secretion patterns were similar to controls, but monocytes showed diminished glucocorticoid-response transcripts and heightened NF-kappaB-response transcripts.

“The caregivers’ patterns of cortisol secretion were similar to those of matched control. However, their monocytes showed diminished expression of transcripts bearing response elements for glucocorticoids, and heightened expression of transcripts with response elements for the key pro-inflammatory transcription factor NF-kappaB”

• cites Miller et al., 2008 sourceNot checked yet

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• cites Hayden et al., 2006 sourceNot checked yet

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May combine two claims.

In a spared nerve injury model, chronic restraint stress before injury exacerbated depressive-like behaviour and increased IL-1beta gene expression; a corticosteroid synthesis inhibitor before stress eliminated the damaging effects; an IL-1 receptor antagonist ameliorated the effects of injury on depressive-like behaviour.

“exposure to chronic restraint stress prior to the injury exacerbated a depressive-like behaviour causing also an increase in IL-1beta gene expression, whereas a pre-treatment with a corticosteroid synthesis inhibitor before stress was able to eliminate the damaging effects of chronic stress. In addition, interference with IL-1beta signalling, through administration of an IL-1 receptor antagonist,”

• cites Norman et al., 2010 sourceNot checked yet

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May combine two claims.

Immunoenhancement occurs when acute stress is experienced at early stages of immune activation, while immunosuppression may occur at late stages of the immune response.

“Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response”

• cites Dhabhar, 2009 sourceNot checked yet

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May combine two claims.

Mice lacking the IL-1 receptor exhibited adrenal hypertrophy and elevated serum corticosterone in response to stressors and failed to develop glucocorticoid resistance.

“mice lacking IL-1 receptor exhibited adrenal hypertrophy and elevated serum corticosterone levels in response to stressors and failed to develop glucocorticoid resistance”

May combine two claims.

Increased pro-inflammatory cytokines, especially IL-1 and IL-6, may contribute to depression pathophysiology by inducing glucocorticoid resistance, neurodegeneration, or unknown mechanisms.

“it is possible that increased levels of pro-inflammatory cytokines, especially IL-1 and IL-6, may contribute to the pathophysiology of depression inducing, as we will discuss below, glucocorticoid resistance, neurodegeneration, or indeed other yet unknown mechanism”

May combine two claims.

Glucocorticoids administered before a peripheral immune challenge potentiate peripheral and central pro-inflammatory responses, whereas administered after the challenge they suppress IL-1beta and IL-6.

“glucocorticoids potentiate both the peripheral and central pro-inflammatory response to a peripheral immune challenge if they are administered prior to the challenge. Contrarily, when glucocorticoids are administered after the peripheral immune challenge, they suppress the pro-inflammatory response measured as IL-1beta and IL-6.”

• cites Frank et al. (2010) sourceNot checked yet

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May combine two claims.

Chronic stress is accompanied by glucocorticoid resistance and activation of pro-inflammatory pathways.

“An interesting recent study supports the idea that chronic stress is accompanied by GR resistance and activation of pro-inflammatory pathways”

• cites Miller et al., 2008 sourceNot checked yet

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May combine two claims.

Multiple inflammatory cytokines, oxygen radical damage, tryptophan catabolites, and neurodegenerative biomarkers have been established in major depression patients and corroborated by animal models.

“Multiple inflammatory cytokines, oxygen radical damage, tryptophan catabolites (see below) and neurodegenerative biomarkers have all been established in patients with MD and corroborated by animal models of depression”

• cites Maes et al., 2009 sourceNot checked yet

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May combine two claims.

Glucocorticoid resistance can underlie HPA axis disturbances and might be caused by cytokines.

“Glucocorticoid resistance can underlie the HPA axis disturbances and this might be caused by cytokines.”

• AssumptionRests on an assumption: Communication occurs between the endocrine, immune, and central nervous systems, so activation of inflammatory responses can affect neuroendocrine processes and vice versa.

May combine two claims.

Mice subjected to chronic mild stress showed increased hippocampal IL-1beta and depressive-like behaviours, while IL-1 receptor deletion prevented these behavioural changes.

“mice subjected to chronic mild stress (CMS) showed increased IL-1beta levels in the hippocampus and in parallel a development of changes in behaviour resembling depressive symptoms, such as decreased sucrose preference and reduced social exploration. In contrast, mice with deletion of the IL-1 receptor did not display such behavioural changes”

• cites Goshen et al., 2008 sourceNot checked yet

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May combine two claims.

Selective and persistent loss of hippocampal volume could be induced by neurodegeneration and decreased neurogenesis.

“The selective and persistent loss of hippocampal volume could be induced by neurodegeneration, leading to hippocampal neuronal death, and also by decreased neurogenesis”

• cites Sapolsky, 2004 sourceNot checked yet

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May combine two claims.

Acute IL-1beta injection increases sickness and plasma corticosterone, and these effects are attenuated after subchronic treatment.

“an acute injection of IL-1beta increases sickness and levels of plasma corticosterone, while these effects are attenuated after subchronic treatment”

• cites Anisman et al., 2008aNot checked yet

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May combine two claims.

Müller et al. found no evidence of reactive astrogliosis, synaptic density changes, or synaptic reorganization in major depression patients.

“the study of MD patients done by Müller et al. (2001) did not found any proof of patterns of reactive astrogliosis, synaptic density or synaptic reorganization”

• cites Müller et al. (2001) sourceNot checked yet

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May combine two claims.

Neuroimaging meta-analyses consistently show reduced hippocampal volume in major depression, especially in recurrent depression and with longer illness duration.

“neuroimaging studies have consistently shown reduced size of hippocampal volume in MD as reported by meta-analysis studies of patients with recurrent depression”

• Also stated in: § 5. Neurodegeneration · plain

  “and with longer duration of illness”

• cites Videbech and Ravnkilde, 2004 sourceNot checked yet

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• cites Campbell et al., 2004 sourceNot checked yet

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• cites McKinnon et al., 2009Not checked yet

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May combine two claims.

Depressed patients with increased inflammatory biomarkers are more likely resistant to antidepressant therapy, and treatment response is associated with decreased inflammatory responses.

“depressed patients with increased inflammatory biomarkers are more likely to be resistant to antidepressant therapy, a response to treatment has been associated with decreased inflammatory responses”

• cites Raison et al., 2006 sourceNot checked yet

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• cites Miller et al., 2009 sourceNot checked yet

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May combine two claims.

Removal of endogenous glucocorticoids abolished the depressive-like effects of chronic mild stress, indicating that blunting adrenocortical activation may play a role in resistance to depression.

“the removal of endogenous glucocorticoids abolished the depressive-like effects of CMS, indicating that the blunting of the adrenocortical activation may play a role in their resistance to develop depression”

• cites Goshen et al., 2008 sourceNot checked yet

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

Many structural changes and volume reductions appear to be reversible.

“many of the structural changes and the volume reduction appear to be reversible”

May combine two claims.

Dexamethasone is used in premature infants to prevent or treat bronchopulmonary dysplasia, which can adversely affect early neurodevelopment and probably cause loss of cerebral volume.

“Dexamethasone is used in premature infants to prevent and/or treat bronchopulmonary dysplasia that can adversely affect early neurodevelopment and can probably cause a loss of cerebral volume (Grier and Halliday, 2003).”

• cites Grier and Halliday, 2003 sourceNot checked yet

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May combine two claims.

In mice, peripheral administration of LPS activates IDO, inducing a depressive-like behavioral syndrome and increasing brain serotonin turnover.

“They showed that peripheral administration of LPS in mice activates IDO to induce a depressive-like behavioural syndrome and to increase the brain serotonin turnover.”

• cites O’Connor et al., 2009Not checked yet

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May combine two claims.

In diabetic mice, blockade of the glucocorticoid receptor attenuated hippocampal abnormalities and rescued the animals from cognitive deficits.

“Interestingly, this GR blockade attenuated the hippocampal abnormalities and rescued the diabetic mice from the cognitive deficits (Revsin et al., 2009).”

• cites Revsin et al., 2009 sourceNot checked yet

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May combine two claims.

Thus, dexamethasone can have neurodegenerative effects in the developing brain while also increasing VEGF levels, which may be neuroprotective.

“Therefore, while dexamethasone can exert neurodegenerative effects in the developing brain, it can also increase VEGF levels, which, in contrast, may play a neuroprotective role (Feng et al., 2009).”

• cites Feng et al., 2009 sourceNot checked yet

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Classified as probably not a substantial claim.

The glucocorticoid cascade hypothesis of stress and hippocampal damage has been proposed to contribute to age-related accumulation of hippocampal damage in disorders such as Alzheimer's disease and depression.

“This ‘glucocorticoid cascade hypothesis’ of stress and hippocampal damage was proposed to be involved in age-related accumulation of hippocampal damage in disorders like Alzheimer’s disease and depression (Sapolsky et al., 1986).”

• cites Sapolsky et al., 1986 sourceNot checked yet

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May combine two claims.

The simple model that glucocorticoids cause neurodegeneration cannot be unequivocally accepted; instead, elevated cytokines in the context of glucocorticoid resistance are probably the offenders.

“Therefore, we cannot unequivocally accept the simple model that glucocorticoids cause neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders.”

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

Chronic inflammation is currently considered to play a central role in the pathogenesis of cardiovascular disease, multiple sclerosis, diabetes, cancer, and major depression.

“Chronic inflammation is now considered to play a central role in the pathogenesis of cardiovascular disease, multiple sclerosis, diabetes, cancer and MD.”

May combine two claims.

Cells produce several cytokines in response to LPS, and glucocorticoids regulate their expression; without this negative feedback, certain cytokines, especially TNF-alpha, become highly toxic and cause nonselective cell death.

“In response to LPS, cells produce several cytokines, and glucocorticoids control their expression. In the absence of this negative feedback, some cytokines, in particular tumor necrosis factor alpha (TNF-alpha), become highly toxic and cause a nonselective cell death.”

May combine two claims.

Dexamethasone increases mRNA and protein levels of vascular endothelial growth factor A (VEGF), which has neurotrophic and neurogenesis-enhancing effects.

“At the same time, dexamethasone causes an increase in mRNA and protein levels of vascular endothelial growth factor A (VEGF), which has neurotrophic and neurogenesis enhancing effects.”

• cites Feng et al., 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

It has been hypothesized that depression is not a true neurodegenerative disorder, or at least does not involve only a deficit in neurogenesis.

“it has been hypothesized that depression is not a true neurodegenerative disorder (Thompson et al., 2008) or at least it does not involve only a deficit in neurogenesis”

• cites Thompson et al., 2008 sourceNot checked yet

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May combine two claims.

Chronic stressors cause sustained increases in cortisol, which over time lead immune cells to downregulate glucocorticoid receptor activity as a compensatory response.

“Chronic stressors induce sustained elevations in cortisol, which, over time, cause immune cells to undergo a compensatory downregulation of GR activity.”

May combine two claims.

Clinical evidence indicates that depression is a common antecedent of Alzheimer's disease and may be an early manifestation of dementia before cognitive decline becomes apparent.

“Indeed there is clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia before the cognitive declines become apparent.”

May combine two claims.

Both the anti-inflammatory drug and the IDO antagonist normalize the kynurenine/tryptophan ratio.

“Interestingly, both the anti-inflammatory drug and the IDO antagonist are able to normalize the kynurenine/tryptophan ratio.”

• cites O’Connor et al., 2009Not checked yet

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May combine two claims.

In contrast to findings that glucocorticoids have neurodegenerative effects in the developing brain, some studies indicate that dexamethasone may also have neurotrophic and neuroprotective effects.

“Contrary to the studies shown above where glucocorticoids exert neurodegenerative effects in the developing brain, a few studies have shown that dexamethasone may also play a neurotrophic and neuroprotective role.”

May combine two claims.

Kynurenic acid acts as an NMDA receptor antagonist and is generally regarded as neuroprotective.

“kynurenic acid is an N-methyl d-aspartate (NMDA) receptor antagonist, and is generally considered neuroprotective”

• cites Wichers and Maes 2004Not checked yet

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• cites Wichers et al., 2005 sourceNot checked yet

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• cites Müller and Schwarz, 2007 sourceNot checked yet

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May combine two claims.

This limits cortisol's ability to further reduce immune responses despite high circulating glucocorticoid levels, resulting in low-grade inflammation that is hypothesized to contribute to infectious, autoimmune, and cardiac diseases linked to stress.

“This limits the ability of cortisol to further reduce immune responses, even in the presence of high circulating glucocorticoid levels, and as a result there is low-grade inflammation, which is hypothesized to contribute to the infectious, autoimmune, and cardiac diseases, whose risk is linked to stress.”

May combine two claims.

Type 1 diabetes is a common metabolic disorder characterized by increased glucocorticoid secretion and cognitive deficits.

“An additional useful model to assess the effect of glucocorticoids on neurodegeneration is Type 1 diabetes, a common metabolic disorder characterized by an increased secretion of glucocorticoids and cognitive deficits.”

May combine two claims.

3-hydroxykynurenine and quinolinic acid are NMDA receptor agonists that are potentially neurotoxic and may contribute to depression.

“3-hydroxykynurenine and quinolinic acid are NMDA receptor agonists, potentially neurotoxic and thus potentially contributing to depression”

• cites Wichers and Maes 2004Not checked yet

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• cites Wichers et al., 2005 sourceNot checked yet

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• cites Hashimoto, 2009 sourceNot checked yet

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May combine two claims.

Depressive symptoms are a frequent side effect of glucocorticoid treatment and occur in Cushing's syndrome.

“The development of depressive symptomatology is a frequent side effect of glucocorticoid treatment and one of the symptoms of Cushing’s syndrome.”

May combine two claims.

Boldrini et al. showed increased progenitor cells in major depression patients treated with antidepressants; treated patients had more dividing cells in the hippocampus than untreated patients and controls.

“Boldrini et al. (2009) showed increased progenitor cells in MD patients treated with antidepressants. More specifically, patients receiving these drugs had more dividing cells in the hippocampus than untreated patients and controls.”

• cites Boldrini et al. (2009) sourceNot checked yet

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May combine two claims.

Because the hippocampus inhibits the HPA axis, damage to the hippocampus is expected to disinhibit the HPA axis, leading to increased glucocorticoid levels over time.

“Due to an inhibitory control of the hippocampus on the HPA axis, damage to this structure is expected to disinhibit the HPA axis, causing increased glucocorticoid levels over time.”