[Show abstract][Hide abstract] ABSTRACT: The increasingly recognised role of inflammation in the pathogenesis and prognosis of depression has led to a renewed focus on the immunomodulatory properties of compounds with antidepressant action. Studies have so far explored such properties in human blood samples and in animal models. Here we used the more relevant model of human hippocampal progenitor cells exposed to an inflammatory milieu, induced by treatment with IL-1β. This increased the levels of a series of cytokines and chemokines produced by the cells, including a dose- and time-dependent increase of IL-6. We investigated the immunomodulatory properties of four monoaminergic antidepressants, venlafaxine, sertraline, moclobemide and agomelatine, and two omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA). We found that venlafaxine and EPA were anti-inflammatory: venlafaxine decreased IL-6, with a trend for decrease of IL-8 and IP-10, while EPA decreased the levels of IL-6, IL-15, IL-1RA, and IP-10. These effects were associated with a corresponding decrease in NF-kB activity. Unexpectedly, sertraline and DHA had pro-inflammatory effects, increasing IFN-α and IL-6, and IL-15, IL-1RA, IFN-α and IL-6, respectively, though these changes were also associated with a decrease in NF-kB activity, suggesting distinct modes of action. Agomelatine and moclobemide had no effect on IL-6 secretion. These observations indicate that monoaminergic antidepressants and n-3 PUFAs have distinctive effects on immune processes in human neural cells. Further characterisation of these actions may enable more effective personalisation of treatment based on the inflammatory status of patients.
The International Journal of Neuropsychopharmacology 10/2014; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Children with externalising problems are at risk of developing internalising problems as they grow older. The pathways underlying this developmental association remain to be elucidated. We tested two processes that could explain why some children with externalising problems develop internalising symptoms in preadolescence: a mediation model whereby the association between early externalising and later new internalising symptoms is explained by negative experiences; and a genetic model, whereby genes influence both problems.Methods
We used data from the Environmental Risk (E-Risk) Study, a 1994–1995 birth cohort of 2,232 twins born in England and Wales. We assessed externalising and internalising problems using combined mothers’ and teachers’ ratings at age 5 and 12. We measured bullying victimisation, maternal dissatisfaction and academic difficulties between age 7 and 10 and used linear regression analyses to test the effects of these negative experiences on the association between early externalising and later internalising problems. We employed a Cholesky decomposition to examine the genetic influences on the association.ResultsChildren with externalising problems at age 5 showed increased rates of new internalising problems at age 12 (r = .24, p < .001). Negative experiences accounted for some of the association between early externalising and later internalising problems. Behavioural-genetic analyses indicated that genes influencing early externalising problems also affected later internalising problems.Conclusions
Our findings highlight the role of genetic influences in explaining why some children with externalising problems develop internalising symptoms in preadolescence. Negative experiences also contribute to the association, possibly through gene–environment interplay. Mental health professionals should monitor the development of internalising symptoms in young children with externalising problems.
Journal of Child Psychology and Psychiatry 10/2014; · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The study of resilience may lead to the identification of new targets for prevention and intervention, yet there has been little research on why some people, but not others, show resilience after facing stressful life events. New research in this issue shows that resilience is equally explained by genetic and environmental influences, and that individual experiences and situational factors are both important in shaping resilient responses to stress. These findings could inform the development of interventions that enhance psychiatric resilience after exposure to adversity.
The British journal of psychiatry: the journal of mental science 10/2014; 205(4):281-2. · 6.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We conducted a meta-analysis to investigate the HPA axis response to social stress in studies that used the Trier Social Stress Test (TSST), or comparable distressing paradigms, in individuals with either depression or schizophrenia. Sample size-adjusted effect sizes (Hedge'sg statistic) were calculated to estimate the HPA axis stress response to social stress. We used a meta-regression model to take into account the moderating effect of the baseline cortisol level. Participants with depression show an activation pattern to social stress similar to that of healthy controls. Despite a normal cortisol production rate, individuals with schizophrenia have lower cortisol levels than controls both in anticipation and after exposure to social stress. Participants with depression and higher cortisol levels before the task have an increased cortisol production and reached higher cortisol levels during the task. This may be explained by the presence of an impaired negative feedback. The activation pattern present in schizophrenia may explain the reduced ability to appropriately contextualize past experiences shown by individuals with psychosis in social stressful situation.
[Show abstract][Hide abstract] ABSTRACT: The aim of this systematic review is to appraise existing literature on the effects of treatments for antenatal depression on the neurodevelopment outcomes of the offspring. We conducted a systematic review of the literature to identify studies on different kinds of treatments for antenatal depression (antidepressants and alternative therapies) and their effects on infants' neurodevelopment. After reading the title, abstract, or full text and applying exclusion criteria, a total of 22 papers were selected. Nineteen papers studied the effects of antidepressant drugs, one on docosahexanoic acid (DHA) (fish oil capsules) and two on massage therapy; however, no studies used a randomized controlled design, and in most studies, the control group comprise healthy women not exposed to depression. Comparisons between newborns exposed to antidepressants in utero with those not exposed showed significant differences in a wide range of neurobehavioral outcomes, although in many cases, these symptoms were transient. Two studies found a slight delay in psychomotor development, and one study found a delay in mental development. Alternative therapies may have some benefits on neurodevelopmental outcomes. Our review suggests that antidepressant treatment may be associated with some neurodevelopmental changes, but we cannot exclude that some of these effects may be due to depression per se.
Archives of Women s Mental Health 09/2014; · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interferon-α (IFN-α) is the standard treatment for chronic hepatitis C virus infection, which causes high rates of depression. However, little is known about the transcriptional impact of IFN-α in vivo and its relationship to behavioural changes. The study aims at investigating whether IFN-α administration caused alterations in the expression of inflammatory, stress and neuroplasticity genes in patients with and without IFN-α-induced-depression. We recruited 48 HCV patients (mean ± SEM age: 43.3 ± 1.6) undergoing IFN-α therapy. The Mini International Neuropsychiatric Interview (MINI) was administered at baseline (treatment week (TW) 0), throughout the treatment and at follow-up for diagnosis of depression. Blood samples were collected using PAXgene Blood RNA Tubes at TW0 and at TW4. For gene expression we selected the inflammatory candidate genes interleukin-1β (IL-1β), IL-6 receptor (R) and IL-18; brain-derived neurotrophic factor (BDNF) as indicator of neuroplasticity; and the glucocorticoid receptor (NR3C1), related to stress. When comparing TW4 with TW0, IL-1β levels decreased in both depressed and non-depressed groups (−38% and −44%, respectively), and the same was observed for IL-6R levels (−48% and −32%, respectively). Contrarily, IL-18 significantly increased in depressed (+31%), but not in non-depressed (+0.9%). BDNF expression did not change within both groups (−0.3% vs. −0.1%), however NR3C1 decreased significantly in non-depressed (−13%), when compared with depressed (−0.7%). Our findings show a relationship between dysregulation in the expression of inflammatory genes and IFN-α-induced depression.
Brain Behavior and Immunity 09/2014; 40:e3. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interferon-α (IFN-α) is used for the treatment of Chronic Hepatitis C Viral infection, however it causes as side effect the development of depression in about the 30–40% of patients. Here we aimed at identify putative biological processes underlying depression development. We recruited 54 HCV patients undertaking IFN-α treatment. Blood was collected using PAXgene Blood RNA Tubes at baseline, TW4, 12 and 24 and depression was diagnosed using the M.I.N.I. We conducted microarray gene expression analyses in the blood of patients at week 0, 4 and 12/24. Statistical analyses, to identify genes and pathways differentially modulated by IFN-α treatment and in relation to depression development, were conducted by Partek Genomic Suite and Ariadne Pathway Software. Atotal number of 754 genes was modulated in the whole sample of patients (p < 0.001, 1.4 < FC < −1.4). Further analyses were performed by comparing the transcriptomic profile of patients that developed depression versus patients that did not develop depression, at treatment week 4 versus baseline, in order to identify genes and pathways modulated by IFN-α in relation with depression development. We found that, at week 4, 489 genes were modulated by IFN-α only in patients that developed depression, 57 genes were modulated by IFN-α only in patients without IFN-α-induced depression and 258 genes were in common between the two groups of patients. A pathway analyses revealed a down-regulation of the notch and neurotrophin signaling, and an up-regulation of natural killer cells mediated cell cytotoxicity and toll like receptor pathways. This study suggests that patients developing IFN-α induced depression have an immune system more reactive to the effect of the treatment and support the involvement of neuroplastic and inflammatory system as processes underlying depression development.
Brain Behavior and Immunity 09/2014; 40:e4. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammation has been recognized as a common link between coronary heart disease (CHD) and depression. One of the important biological factors that regulate inflammation is the glucocorticoid receptor (GR). We investigated inflammatory markers and GR function in CHD patients with (n = 28) and without (n = 55) depression. Serum CRP and plasma VEGF were measured using ELISA. IL-6 gene expression was measured via qPCR. GR sensitivity was evaluated by dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Compared to CHD non-depressed individuals, CHD patients with depression showed higher serum levels of CRP (5.20 vs 3.34 mg/l, p = 0.030), higher gene expression of IL-6 (2.8-fold increase, p = 0.003), and higher plasma levels of VEGF (173.13 vs 94.24 pg/ml, p = 0.028). The depressed group exhibited reduced GR function (IC50: 8.12 vs 7.59[M], p = 0.0031) which was associated with the severity of depression (r = 0.505, p = 0.006). CHD depressed subjects showed an increased in GR sensitivity by the in vitro effect of clomipramine (IC50: 7.54 vs 7.81[M], p = 0.084), citalopram (IC50: 7.57 vs 8.06[M], p = 0.014), and the omega-3 fatty acid EPA (IC50: 7.43 vs 8.61[M], p = 0.006). Our results show that CHD patients with depression exhibited GR resistance in vitro and elevated inflammatory response. This study provides evidence of improvement of GR sensitivity in vitro in response to the effect of antidepressants and omega-3 fatty acids that may lead to a more effective response to the anti-inflammatory and immunosuppressive activities of glucocorticoids.
Brain Behavior and Immunity 09/2014; 40:e4. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interferon-α (IFN-α) used to treat Chronic Hepatitis C Viral (HCV) infection induces fatigue, which can persist up to six months post-treatment. This study examined some putative biological mechanisms underlying the development of such side effect. We recruited 25 patients receiving IFN-α. Blood was collected using PAXgene tubes at baseline and treatment weeks 4, 12 and 24. Fatigue was assessed using the Chalder Fatigue Questionnaire (CFQ) administered at the same time points and six months post-treatment. Patients were stratified according to whether their fatigue levels at follow-up had improved or returned to baseline levels (Resolved Fatigue; RF, n = 15) or worsened (Persistent Fatigue; PF, n = 10). Assessing the effect of IFN-α, we found that at week 4, 663 genes were modulated in both groups, with a further 229 in the RF group, and 556 uniquely modulated in the PF group. Pathway analyses in the PF group reported alterations in IL-15 and Tec Kinase signaling, among others. Molecules of interest within those pathways included BCL2 (fold-change 1.50, p < .005), STAT1 (1.57, p < .0002) and FCER1A (−2.0, p < .0002), previously shown to be relevant to fatigue. Our data shows a differential modulation of inflammatory pathways by IFN-α in patients that develop persistent fatigue, suggesting a possible underlying role in the development of related symptoms.
Brain Behavior and Immunity 09/2014; 40:e3. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Brain-derived Neurotrophic Factor (BDNF) modulates cognitive processes and is associated with increased risk of schizophrenia. Childhood trauma (CT) is frequent in patients with psychosis and severely affects course and outcome.
Schizophrenia Research 08/2014; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this article, we propose an X-linked hypothesis of brain disorders that postulates a neuronal origin of those neurodegenerative and psychiatric disorders with a greater male prevalence. The hypothesis is based on the accumulated genetics and genomic evidence linking X chromosome genes and transcripts to neuronal cells. The behavioral genetics literature has long pointed to the link between postsynaptic protein complexes coded on chromosome X and mental retardation. More recently, novel genomic evidence has emerged of X-linked mRNA overexpression of neuronal source in the human brain. We review the evidence for this hypothesis and its consistency with the distribution across genders of brain disorders of known aetiology. We then provide examples of the utilization of this hypothesis in the investigation of the pathophysiology of complex brain disorders in both the stratification of disease cohorts and the development of realistic preclinical models. We conclude by providing a general framework for testing its validity, which will be exploited in future studies, and provide future directions for research.
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 08/2014;
[Show abstract][Hide abstract] ABSTRACT: There is a consensus that stress plays a role in the onset of psychosis but the precise underlying mechanism remains unclear. The hypothalamic-pituitary-adrenal (HPA) axis is hypothesised to mediate the relationship between stress and psychosis and evidence indicates a potential role for the stress hormone cortisol as a biomarker of psychosis risk.
Schizophrenia Research 07/2014; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Failure to account for the etiological diversity that typically occurs in psychi-atric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases.This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level. Methods: Two hundred and ninety-one first-episode psychosis cases from South Lon-don, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis. Results: Association at rs1360780 was not detected until the effects of the two environ-mental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23–6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. More-over, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95). Conclusion: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.
[Show abstract][Hide abstract] ABSTRACT: Diurnal rhythms have been observed in human behaviors as diverse as sleep, olfaction, and learning. Despite its potential impact, time of day is rarely considered when brain responses are studied by neuroimaging techniques. To address this issue, we explicitly examined the effects of circadian and homeostatic regulation on functional connectivity (FC) and regional cerebral blood flow (rCBF) in healthy human volunteers, using whole-brain resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). In common with many circadian studies, we collected salivary cortisol to represent the normal circadian activity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Intriguingly, the changes in FC and rCBF we observed indicated fundamental decreases in the functional integration of the default mode network (DMN) moving from morning to afternoon. Within the anterior cingulate cortex (ACC), our results indicate that morning cortisol levels are negatively correlated with rCBF. We hypothesize that the homeostatic mechanisms of the HPA axis has a role in modulating the functional integrity of the DMN (specifically, the ACC), and for the purposes of using fMRI as a tool to measure changes in disease processes or in response to treatment, we demonstrate that time of the day is important when interpreting resting-state data.Journal of Cerebral Blood Flow & Metabolism advance online publication, 18 June 2014; doi:10.1038/jcbfm.2014.109.
[Show abstract][Hide abstract] ABSTRACT: Depression and anxiety are highly prevalent and represent a significant and well described public health burden. Whilst first line psychological treatments are effective for nearly half of attenders, there remain a substantial number of patients who do not benefit. The main objective of the present project is to establish an infrastructure platform for the identification of factors that predict lack of response to psychological treatment for depression and anxiety, in order to better target treatments as well as to support translational and experimental medicine research in mood and anxiety disorders.Methods/design: Predicting outcome following psychological therapy in IAPT (PROMPT) is a naturalistic observational project that began patient recruitment in January 2014. The project is currently taking place in Southwark Psychological Therapies Service, an Improving Access to Psychological Therapies (IAPT) service currently provided by the South London and Maudsley NHS Foundation Trust (SLaM). However, the aim is to roll-out the project across other IAPT services. Participants are approached before beginning treatment and offered a baseline interview whilst they are waiting for therapy to begin. This allows us to test for relationships between predictor variables and patient outcome measures. At the baseline interview, participants complete a diagnostic interview; are asked to give blood and hair samples for relevant biomarkers, and complete psychological and social questionnaire measures. Participants then complete their psychological therapy as offered by Southwark Psychological Therapies Service. Response to psychological therapy will be measured using standard IAPT outcome data, which are routinely collected at each appointment.
[Show abstract][Hide abstract] ABSTRACT: Previous studies testing the hypothesis that symptoms of anxiety and depression increase blood pressure (BP) levels show inconsistent and limited findings. We examined the association between those symptoms across adult life and BP in late middle age.
[Show abstract][Hide abstract] ABSTRACT: In the last few decades, mental health research has increasingly provided evidence supporting the role of inflammation in pathogenesis, course and treatment of mental disorders. With such a steep incline of research, resulting in a wealth of emerged findings, it has become difficult to follow developments within the field. The present review sets out to present the recent developments and to give an overview of the inflammatory profiles of depression, psychosis and bipolar disorder, as well as variations within these disorders. Moreover, mediating factors such as social environment and childhood experience are discussed, both in terms of their potential in elucidating the complex interface between the inflammation and other closely related biological systems, as well as the possibly confounding impact of various lifestyle factors. Whilst many issues in this fascinating area of research remain to be fully understood and elaborated, all current evidence suggests that inflammation plays a key role in mental disorders and may open up novel avenues for clinical treatment.
[Show abstract][Hide abstract] ABSTRACT: Depression in pregnancy (also called 'antenatal depression') is being increasingly recognized as a clinically relevant condition that affects obstetric outcome, maternal behaviour and children's future mental health. The present review focuses on the molecular mechanisms operating in utero that underlie the potential effects of antenatal depression on mothers' and children's behaviour. In particular, I discuss evidence, coming largely from animal and cellular studies, that activation of the main hormonal stress-response system, the HPA (hypothalamic-pituitary-adrenal) axis, in mothers who are depressed during pregnancy may affect maternal care as well as offspring's behaviour and future psychopathology. The evidence summarized in the present review supports the notion that preventing or treating depression in pregnancy will alleviate not only the suffering of mothers, but also the suffering of the next generation.
Biochemical Society Transactions 04/2014; 42(2):582-6. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function are one of the most consistent biological findings across several mental disorders, but many of the mechanisms underlying this abnormality as well as the potential contribution to behavioural phenotypes remain only partially understood. Interestingly, evidence suggests a U-curve, with dysregulation of the HPA axis towards both hyper- or hypoactivity manifesting as a risk to mental wellbeing. This review will elaborate on both the clinical and molecular role of the neuroendocrine stress system in depressive, psychotic and post-traumatic stress disorders and present some of the most recent findings that have shed light on the complex interface between environmental stressors, molecular mechanisms and clinical presentation. Crucially, plasticity of the HPA axis confers both vulnerability to adverse events, particularly so in early developmental stages, as well as hope for the treatment of mental disorder, as evidenced by changes in HPA functioning associated with remission of symptoms.
Current topics in behavioral neurosciences. 03/2014;
[Show abstract][Hide abstract] ABSTRACT: Psychological stress is implicated in the development of schizophrenia, but little is known about experiences of stress among children at elevated risk for the disorder.
To examine stressor exposure and reactivity in children with different vulnerability profiles for schizophrenia: (a) children presenting multiple antecedents of schizophrenia (ASz group), (b) children with a family history of schizophrenia (FHx group) and (c) typically developing low-risk (TD) children.
Ninety-five children (ASz = 29; FHx = 19; ASz+FHx = 5; TD = 42), identified aged 9-12 years using a community-based screening procedure or as relatives of individuals with schizophrenia, completed questionnaires assessing environmental stressors and psychopathology at age 11-14 years.
Relative to their typically developing peers, children in the FHx and ASz groups were exposed to a greater number of negative life events and a higher frequency of daily stressors, respectively; and were more distressed by these experiences.
Stress exposure and reactivity may constitute useful targets of early intervention for psychosis.
The British journal of psychiatry: the journal of mental science 03/2014; · 6.62 Impact Factor