Control of Redox Homeostasis by Short-Chain Fatty Acids: Implications for the Prevention and Treatment of Breast Cancer.

Breast cancer is the leading cause of death among women worldwide, and certain subtypes are highly aggressive and drug resistant. As oxidative stress is linked to the onset and progression of cancer, new alternative therapies, based on plant-derived compounds that activate signaling pathways involved in the maintenance of cellular redox homeostasis, have received increasing interest. Among the bioactive dietary compounds considered for cancer prevention and treatment are flavonoids, such as quercetin, carotenoids, such as lycopene, polyphenols, such as resveratrol and stilbenes, and isothiocyanates, such as sulforaphane. In healthy cells, these bioactive phytochemicals exhibit antioxidant, anti-apoptotic and anti-inflammatory properties through intracellular signaling pathways and epigenetic regulation. Short-chain fatty acids (SCFAs), produced by intestinal microbiota and obtained from the diet, also exhibit anti-inflammatory and anti-proliferative properties related to their redox signaling activity-and are thus key for cell homeostasis. There is evidence supporting an antioxidant role for SCFAs, mainly butyrate, as modulators of Nrf2-Keap1 signaling involving the inhibition of histone deacetylases (HDACs) and/or Nrf2 nuclear translocation. Incorporation of SCFAs in nutritional and pharmacological interventions changes the composition of the the intestinal microbiota, which has been shown to be relevant for cancer prevention and treatment. In this review, we focused on the antioxidant properties of SCFAs and their impact on cancer development and treatment, with special emphasis on breast cancer.

Cardiometabolic risk profiles in a Sri Lankan twin and singleton sample.

INTRODUCTION: Prevention of cardiovascular disease and diabetes is a priority in low- and middle-income countries, especially in South Asia where these are leading causes of morbidity and mortality. The metabolic syndrome is a tool to identify cardiometabolic risk, but the validity of the metabolic syndrome as a clinical construct is debated. This study tested the existence of the metabolic syndrome, explored alternative cardiometabolic risk characterisations, and examined genetic and environmental factors in a South Asian population sample. METHODS: Data came from the Colombo Twin and Singleton follow-up Study, which recruited twins and singletons in Colombo, Sri Lanka, in 2012-2015 (n = 3476). Latent class analysis tested the clustering of metabolic syndrome indicators (waist circumference, high-density lipoprotein cholesterol, triglycerides, blood pressure, fasting plasma glucose, medications, and diabetes). Regression analyses tested cross-sectional associations between the identified latent cardiometabolic classes and sociodemographic covariates and health behaviours. Structural equation modelling estimated genetic and environmental contributions to cardiometabolic risk profiles. All analyses were stratified by sex (n = 1509 men, n = 1967 women). RESULTS: Three classes were identified in men: 1) "Healthy" (52.3%), 2) "Central obesity, high triglycerides, high fasting plasma glucose" (40.2%), and 3) "Central obesity, high triglycerides, diabetes" (7.6%). Four classes were identified in women: 1) "Healthy" (53.2%), 2) "Very high central obesity, low high-density lipoprotein cholesterol, raised fasting plasma glucose" (32.8%), 3) "Very high central obesity, diabetes" (7.2%) and 4) "Central obesity, hypertension, raised fasting plasma glucose" (6.8%). Older age in men and women, and high socioeconomic status in men, was associated with cardiometabolic risk classes, compared to the "Healthy" classes. In men, individual differences in cardiometabolic class membership were due to environmental effects. In women, genetic differences predicted class membership. CONCLUSION: The findings did not support the metabolic syndrome construct. Instead, distinct clinical profiles were identified for men and women, suggesting different aetiological pathways.

NRF2: An emerging role in neural stem cell regulation and neurogenesis.

The birth of new neurons from neural stem cells (NSC)s during developmental and adult neurogenesis arises from a myriad of highly complex signalling cascades. Emerging as one of these is the nuclear factor erythroid 2-related factor (NRF2)-signaling pathway. Regulation by NRF2 is reported to span the neurogenic process from early neural lineage specification and NSC regulation to neuronal fate commitment and differentiation. Here, we review these reports selecting only those where NRF2 signaling was directly manipulated to provide a clearer case for a direct role of NRF2 in embryonic and adult neurogenesis. With few studies providing mechanistic insight into this relationship, we lastly discuss key pathways linking NRF2 and stem cell regulation outside the neural lineage to shed light on mechanisms that may also be relevant to NSCs and neurogenesis.

Relationship between CRP and depression: A genetically sensitive study in Sri Lanka.

BACKGROUND: Previous studies have shown associations between major depression and C-reactive protein (CRP) levels. Few studies have considered the extent to which shared genetic and environmental factors contribute to this association, nor have they considered the relationship outside of European populations. We examined the association between CRP levels and depression and their aetiology in a Sri Lankan population. METHODS: Data were collected from 2577 twins and 899 singletons in Colombo, Sri Lanka. Depression symptoms were assessed using the revised Beck Depression Inventory (BDI-II). High-sensitive CRP blood levels were assessed using immunoturbidimetry. Linear regressions were performed to test the association between CRP and depression. The heritability of CRP levels was estimated using Structural Equation Modelling. RESULTS: CRP was significantly associated with BMI (p < 0.01) but not depression (p > 0.05). In males, variance in CRP levels was explained by shared environment (51% 95%CIs: 13-62) and non-shared environment (45% 95%CIs: 36-54). In contrast, in females, CRP variance was explained by genetic (41% 95%CIs: 10-52) and non-shared environment (56% 95%CIs: 47-67). A genetic correlation between CRP and BMI was observed in females only. LIMITATIONS: CRP level was based on a single data collection point, longer term data collection would give a more accurate picture of an individual's state of inflammation. CONCLUSIONS: The lack of association between depression and CRP strengthens the hypothesis that inflammation might contribute to the development of some, but not all types of depression. CRP levels were moderated by the environment, suggesting interventions aimed at reducing CRP levels and risk for inflammatory conditions, particularly in males.

Cortisol Levels in Childhood Associated With Emergence of Attenuated Psychotic Symptoms in Early Adulthood.

BACKGROUND: In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms. METHODS: A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9-12 years and assessed at age 11-14 years (T1) and 17-21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire. RESULTS: Diurnal cortisol (ß = 0.915, 95% CI: 0.062-1.769) and daily stressors (ß = 0.379, 95% CI: 0.034-0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (ß = 0.743, 95% CI: 0.081-1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased. CONCLUSIONS: Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods.

Increased maternal inflammation and poorer infant neurobehavioural competencies in women with a history of major depressive disorder from the psychiatry research and motherhood - Depression (PRAM-D) study.

INTRODUCTION: Stress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response. METHODS: A prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as 'history-only', and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured. RESULTS: Compared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in thesocial-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months. CONCLUSION: Our study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition.

Short-chain fatty acids as modulators of redox signaling in health and disease.

Short-chain fatty acids (SCFAs), produced by colonic bacteria and obtained from the diet, have been linked to beneficial effects on human health associated with their metabolic and signaling properties. Their physiological functions are related to their aliphatic tail length and dependent on the activation of specific membrane receptors. In this review, we focus on the mechanisms underlying SCFAs mediated protection against oxidative and mitochondrial stress and their role in regulating metabolic pathways in specific tissues. We critically evaluate the evidence for their cytoprotective roles in suppressing inflammation and carcinogenesis and the consequences of aging. The ability of these natural compounds to induce signaling pathways, involving nuclear erythroid 2-related factor 2 (Nrf2), contributes to the maintenance of redox homeostasis under physiological conditions. SCFAs may thus serve as nutritional and therapeutic agents in healthy aging and in vascular and other diseases such as diabetes, neuropathologies and cancer.

Covid-19 and Mental Health: Could Visual Art Exposure Help?

A worldwidemental health crisis is expected, as millions worldwide fear death and disease while being forced into repeated isolation. Thus, there is a need for new proactive approaches to improve mental resilience and prevent mental health conditions. Since the 1990s, art has emerged as an alternative mental health therapy in the United States and Europe, becoming part of the social care agenda. This article focuses on how visual esthetic experiences can create similar patterns of neuronal activity as those observed when the reward system is activated. The activation of the reward structures could have a stress buffering effect, given the interdependence observed between the reward and stress systems. Therefore, could visual esthetic experiences stimulate mental resilience? And if this were the case, could art-based interventions be offered for mental health in the context of COVID-19 and beyond?

Risk factors for postpartum relapse in women at risk of postpartum psychosis: The role of psychosocial stress and the biological stress system.

BACKGROUND: Postpartum psychosis is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high for women with a history of bipolar disorder, schizoaffective disorder or those who have suffered a previous episode of postpartum psychosis. Whilst there is a lot of evidence linking stress to psychosis unrelated to childbirth, the role of stress in the onset of postpartum psychosis has not been fully investigated. METHODS: A prospective longitudinal study of 112 pregnant women, 51 at risk of postpartum psychosis because of a DSM-IV diagnosis of bipolar disorder (n = 41), schizoaffective disorder (n = 6) or a previous postpartum psychosis (n = 4) and 61 healthy women with no past or current DSM-IV diagnosis and no family history of postpartum psychosis. Women were followed up from the third trimester of pregnancy to 4 weeks' post partum. Women at risk who had a psychiatric relapse in the first 4 weeks' post partum (AR-unwell) (n = 22), were compared with those at risk who remained well (AR-well) (n = 29) on measures of psychosocial stress (severe childhood maltreatment and stressful life events) and biological stress (cortisol and inflammatory biomarkers). RESULTS: Logistic regression analyses revealed that severe childhood maltreatment (OR = 4.9, 95% CI 0.5-49.2) and higher daily cortisol in the third trimester of pregnancy (OR=3.7, 95% CI 1.2-11.6) predicted psychiatric relapse in the first 4 weeks' post partum in women at risk of postpartum psychosis after adjusting for clinical and sociodemographic covariates. CONCLUSION: The current study provides evidence for the role of psychosocial stress and the biological stress system in the risk of postpartum relapse in women at risk of postpartum psychosis.

Do different types of stress differentially alter behavioural and neurobiological outcomes associated with depression in rodent models? A systematic review.

Cataloguing the effects of different types of stress on behaviour and physiology in rodent models has not been comprehensively attempted. Here, we systematically review whether chronic exposure to physical stress, psychosocial stress, or both types of stress can induce different behavioural and neurobiological outcomes in male and female rodents. We found that physical stress consistently increased depressive-like behaviour, impaired social interaction and decreased body weight, while psychosocial stress consistently increased both anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity, peripheral inflammation and microglial activation, and decreased hippocampal neurogenesis in male rodents. Moreover, we found that the combined effect of both stress types resulted in a more severe pathological state defined by increased anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity and central inflammation, and reduced hippocampal neurogenesis and neural plasticity in male rodents. Phenotypes for females were less consistent, irrespective of the type of stress exposure, on account of the limited number of studies using females. This review highlights that the type of stress may indeed matter and will help animal researchers to more appropriately choose a stress/depression model that fits their research purposes.

Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice.

Unpredictable chronic mild stress (UCMS) is one of the most commonly used, robust and translatable models for studying the neurobiological basis of major depression. Although the model currently has multiple advantages, it does not entirely follow the trajectory of the disorder, whereby depressive symptomology can often present months after exposure to stress. Furthermore, patients with depression are more likely to withdraw in response to their stressful experience, or as a symptom of their depression, and, in turn, this withdrawal/isolation can further exacerbate the stressful experience and the depressive symptomology. Therefore, we investigated the effect(s) of 6 weeks of UCMS followed by another 6 weeks of social isolation (referred to as UCMSI), on behaviour, corticosterone stress responsivity, immune system functioning, and hippocampal neurogenesis, in young adult male mice. We found that UCMSI induced several behavioural changes resembling depression but did not induce peripheral inflammation. However, UCMSI animals showed increased microglial activation in the ventral dentate gyrus (DG) of the hippocampus and astrocyte activation in both the dorsal and ventral DG, with increased GFAP-positive cell immunoreactivity, GFAP-positive cell hypertrophy and process extension, and increased s100ß-positive cell density. Moreover, UCMSI animals had significantly reduced neurogenesis in the DG and reduced levels of peripheral vascular endothelial growth factor (VEGF) - a trophic factor produced by astrocytes and that stimulates neurogenesis. Finally, UCMSI mice also had normal baseline corticosterone levels but a smaller increase in corticosterone following acute stress, that is, the Porsolt Swim Test. Our work gives clinically relevant insights into the role that microglial and astrocyte functioning, and hippocampal neurogenesis may play in the context of stress, social isolation and depression, offering a potentially new avenue for therapeutic target.

The Sri Lankan twin registry biobank: South Asia's first twin biobank.

Introduction: Biobanks are a valuable resource for creating advancements in science through cutting-edge omics research. Twin research methods allow us to understand the degree to which genetics and environmental factors contribute to health outcomes. Methods: The Sri Lankan Twin Registry biobank (SLTR-b) was established in 2015 as part of Colombo Twin and Singleton Follow-up Study. Venous blood and urine were collected from twins and comparative sample of singletons for clinical investigations and biobanking. Results: The SLTR-b currently houses 3369 DNA and serum samples. Biobank specimens are linked to longitudinal questionnaire data, clinical investigations, anthropometric measurements, and other data. Discussion: The SLTR-b aims to address gaps in health and genetics research. It will provide opportunities for academic collaborations, local and international, and capacity building of future research leaders in twin and omics research. This paper provides a cohort profile of the SLTR-b and its linked data, and an overview of the strategies used for biobanking.

The type of stress matters: repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations.

Chronic stress can alter the immune system, adult hippocampal neurogenesis and induce anxiety- and depressive-like behaviour in rodents. However, previous studies have not discriminated between the effect(s) of different types of stress on these behavioural and biological outcomes. We investigated the effect(s) of repeated injection vs. permanent social isolation on behaviour, stress responsivity, immune system functioning and hippocampal neurogenesis, in young adult male mice, and found that the type of stress exposure does indeed matter. Exposure to 6 weeks of repeated injection resulted in an anxiety-like phenotype, decreased systemic inflammation (i.e., reduced plasma levels of TNFα and IL4), increased corticosterone reactivity, increased microglial activation and decreased neuronal differentiation in the dentate gyrus (DG). In contrast, exposure to 6 weeks of permanent social isolation resulted in a depressive-like phenotype, increased plasma levels of TNFα, decreased plasma levels of IL10 and VEGF, decreased corticosterone reactivity, decreased microglial cell density and increased cell density for radial glia, s100ß-positive cells and mature neuroblasts-all in the DG. Interestingly, combining the two distinct stress paradigms did not have an additive effect on behavioural and biological outcomes, but resulted in yet a different phenotype, characterized by increased anxiety-like behaviour, decreased plasma levels of IL1ß, IL4 and VEGF, and decreased hippocampal neuronal differentiation, without altered neuroinflammation or corticosterone reactivity. These findings demonstrate that different forms of chronic stress can differentially alter both behavioural and biological outcomes in young adult male mice, and that combining multiple stressors may not necessarily cause more severe pathological outcomes.

Differential effect of interferon-alpha treatment on AEA and 2-AG levels.

The endocannabinoid (eCB) system is one of the key players in immunoregulation, and reduced activity of the eCB system has been linked with depressive-like behaviours in animal studies and depression in clinical samples. There is a well-established link between immune activation and depression, such as following the administration of the pro-inflammatory cytokine, interferon-α (IFN-α), used to treat hepatitis C viral (HCV) infection. However, the role of peripheral endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), following immunotherapy with IFN-α and in IFN-α -induced depression, have not been examined yet. In this study, we investigated whether circulating AEA and 2-AG were modified by treatment with IFN-α and whether they were involved in the development of IFN-α-induced depression. We also explored whether circulating eCBs were associated with peripheral cytokines during and after IFN-α treatment. We measured serum concentrations of AEA and 2-AG using High Performance Liquid Chromatography with Tandem Mass Spectrometry, and serum concentrations of cytokines using Meso Scale Discovery electrochemiluminescence V-PLEX assay, in 70 patients with HCV infection and 41 healthy subjects. We assessed HCV patients at baseline, IFN-α-treatment weeks (TW) 4 and 24, end of treatment (END) and at six months follow-up (FU). We assessed depression using M.I.N.I. International Neuropsychiatric Interview. We found a different pattern of change in peripheral AEA and 2-AG during and after IFN-α treatment. Whilst 2-AG increased earlier in immunotherapy (TW4), remained elevated throughout treatment, and reduced at six months follow-up (FU), AEA increased later in treatment (TW24) and remained elevated six months post-treatment. We also found that baseline levels of AEA were lower in HCV patients compared with healthy controls, whereas there were no differences in 2-AG levels. Interestingly, AEA, but not 2-AG, was significantly, negatively correlated with interleukin (IL)-2 and IL-17a at six months follow-up. We did not find any difference in both eCBs between patients with and without IFN-α-induced depression, at any time point. Our findings suggest that AEA and 2-AG are involved in different stages of immunoregulation following IFN-α treatment, where AEA might be involved in chronic inflammation. Lack of association between peripheral eCBs and IFN-α-induced depression suggests that different biological mechanisms may underpin inflammation-induced depression compared with classic "psychiatric" depression, or that any changes in the eCB system in depression may not be captured by peripheral AEA and 2-AG.

Characterizing anhedonia: A systematic review of neuroimaging across the subtypes of reward processing deficits in depression.

Anhedonia is a key symptom of major depressive disorder (MDD) and comprises behavioural deficits in three reward processing subtypes: reward liking, reward wanting, and reward learning. However, neuroimaging findings regarding the neural abnormalities underpinning these deficits are complex. We have conducted a systematic review to update, reframe and summarize neuroimaging findings across the three subtypes of anhedonia in MDD. Using PubMed, The Cochrane Library, PsycINFO, and Web of Science databases, we identified 59 fMRI studies comparing participants with current or remitted MDD with controls, using reward processing tasks. For reward liking and wanting, striatal hypoactivation was observed, alongside hypoactivation and hyperactivation across frontal regions. For reward learning, blunted frontostriatal sensitivity to positive feedback was observed. These findings highlight the importance of studying anhedonia not only as a clinical manifestation but also as a neurobiological mechanism underlying depressive disorder and other broader psychiatric conditions.

The Anti-Inflammatory Role of Omega-3 Polyunsaturated Fatty Acids Metabolites in Pre-Clinical Models of Psychiatric, Neurodegenerative, and Neurological Disorders.

Inflammation has been identified as one of the main pathophysiological mechanisms underlying neuropsychiatric and neurodegenerative disorders. Despite the role of inflammation in those conditions, there is still a lack of effective anti-inflammatory therapeutic strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) can reduce depressive symptoms and exert anti-inflammatory action putatively by the production of distinct n-3 PUFA-derived metabolites, such as resolvins D (RvD) and E (RvE) series, maresins (MaR) and protectins (PD), which are collectively named specialized pro-resolving mediators (SPMs) and act as strong anti-inflammatory agents. In this review we summarize evidence showing the effects of treatment with those metabolites in pre-clinical models of psychiatric, neurodegenerative and neurological disorders. A total of 25 pre-clinical studies were identified using the PubMed database. Overall, RvD and RvE treatment improved depressive-like behaviors, whereas protectins and maresins ameliorated neurological function. On a cellular level, RvDs increased serotonin levels in a model of depression, and decreased gliosis in neurodegenerative disorders. Protectins prevented neurite and dendrite retraction and apoptosis in models of neurodegeneration, while maresins reduced cell death across all studies. In terms of mechanisms, all SPMs down-regulated pro-inflammatory cytokines. Resolvins activated mTOR and MAP/ERK signaling in models of depression, while resolvins and maresins activated the NF-κB pathway in models of neurodegeneration and neurological disorders. Our review indicates a potential promising approach for tailored therapy with n-3 PUFAs-derived metabolites in the treatment of psychiatric, neurodegenerative, and neurological conditions.

Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.

Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis.

Background: Glucocorticoid resistance-reduced function of the glucocorticoid receptor (GR)-is seen in many depressed patients. It is argued that this resistance to glucocorticoids leads to failure of normal feedback regulation on the immune system. High levels of pro-inflammatory cytokines result. Purpose: We sought to identify evidence supporting or refuting a link between glucocorticoid resistance and immune dysregulation in depression and to summarize retrieved evidence in aggregate form. Methods: We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. These measures included plasma cortisol, the dexamethasone suppression test (DST), GR expression levels, and the results of in vitro assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. Results: After sub-grouping 32 studies by the ratio of cortisol levels in patients compared with controls, we observed a trend for increasing glucocorticoid resistance (i.e., the most hypercortisolemic patients) to be associated with increased production of interleukin (IL)-6 [d = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [d = 0.46; 95% CI (0.12, 0.79)]. We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). This was particularly evident when studies were sub-grouped by source of cytokine-plasma (d = 1.04; 95% CI, 0.57-1.50) versus in vitro (d = 0.24; 95% CI, -0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: d = 1.35; 95% CI 0.53-2.18). Combining our analyses of studies that reported DST results with those that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls (d = 1.02; 95% CI, 0.55-1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. Conclusions: Our work provides some support for a model conceptualizing glucocorticoid resistance as a requisite for increased inflammation in depression. The limited number of studies identified highlights the need for purpose-designed investigations that directly examine the relationship between glucocorticoid resistance and cytokine production in depression.

The role of circulatory systemic environment in predicting interferon-alpha-induced depression: The neurogenic process as a potential mechanism.

Interferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the brain cellular mechanisms underlying these effects are still not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in the blood of depressed versus non-depressed patients. We investigated the in vitro effect of serum from depressed and non-depressed HCV patients (at baseline, before IFN-α; and after four weeks of IFN-α), on the apoptotic and neurogenic processes in a human hippocampal progenitor cells model. Results show that higher apoptosis during proliferation observed upon treatment of cells with baseline serum, and lower neuronal differentiation observed upon treatment with serum after 4 weeks of IFN-α, were predictive of later development of IFN-α-induced depression (odds ratio = 1.26, p = 0.06, and = 0.80, p = 0.01, respectively). While serum after IFN-α increased neurogenesis compared with baseline serum, a lower increase in neurogenesis was also predictive of later development of depression (odds ratio = 0.86; p = 0.006). Our results provide evidence for the fundamental role of the systemic milieu (captured by serum samples) in the regulation of hippocampal neurogenesis by inflammation, a putative mechanism involved in the development of neuropsychiatric conditions.

Cortisol awakening response is decreased in patients with first-episode psychosis and increased in healthy controls with a history of severe childhood abuse.

BACKGROUND: Childhood abuse is highly prevalent in psychosis patients, but whether/how it affects hypothalamic-pituitary-adrenal (HPA) axis at the onset of psychosis remains unclear. We aimed to investigate the effects of severity of childhood abuse on HPA axis activity, in first-episode psychosis (FEP) and healthy controls. METHODS: We recruited 169 FEP patients and 133 controls with different degrees of childhood physical and sexual abuse (i.e. no abuse exposure, non-severe abuse exposure, and severe abuse exposure). Saliva samples were collected to measure cortisol awakening response with respect to ground (CARg), increase (CARi) and diurnal (CDD) cortisol levels. Two-way ANOVA analyses were conducted to test the relationships between severity of childhood abuse and psychosis on cortisol levels in individuals with psychosis and healthy controls with and without childhood abuse history. RESULTS: A statistically significant interaction between childhood abuse and psychosis on CARg was found (F(2,262) = 4.60, p = 0.011, ω2 = 0.42). Overall, controls showed a U-shaped relationship between abuse exposure and CARg, while patients showed an inverted U-shaped relationship. CARg values were markedly different between patients and controls with either no abuse history or exposure to severe childhood abuse. No significant differences were found when looking at CARi and CDD. CONCLUSIONS: Our results show a divergent effect of severe childhood abuse on HPA axis activity in patients with first-episode psychosis and in controls. In the presence of exposure to severe childhood abuse, a blunted CARg and a less reactive HPA axis may represent one of the biological mechanisms involved in the development of psychosis.