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The 2015 Named Series on "Psychological Risk Factors and Immune System Involvement in Cardiovascular Disease" was conceived with the idea of drawing attention to the interdisciplinary work aimed at investigating the relationships between the heart, metabolic system, brain, and mental health. In this commentary, we provide a brief overview of the manuscripts included in this Named Series and highlight how a better understanding of immune regulation will help us to move forward from the current "dualistic" perspective of the heart as separate from the mind to a more comprehensive understanding of the physiological links between cardiovascular and mental disorders. The manuscripts included in this Named Series range across a wide spectrum of topics, from understanding biological mechanisms explaining comorbidity between cardiovascular disease and psychiatric disorders to new insights into the dysregulation of inflammation associated with cardiovascular risk factors. Clearly, inflammation emerges as a cross-cutting theme across all studies. Data presented in this Series contribute to putting an end to an era in which the heart and the mind were considered to be separate entities in which the responses of one system did not affect the other.

Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus–pituitary–adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD patients with depression had elevated levels of inflammation in the context of HPA axis hypoactivity, GR resistance, and increased activation of the kynurenine pathway. Reduced cortisol bioavailability and attenuated glucocorticoid responsiveness due to decreased expression and sensitivity of GR may lead to insufficient glucocorticoid signaling and thus elevation of inflammation in these patients.

BackgroundPituitary volume enlargements have been observed among individuals with first-episode psychosis. These abnormalities are suggestive of hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, which may contribute to the development of psychosis. However, the extent to which these abnormalities characterize individuals at elevated risk for schizophrenia prior to illness onset is currently unclear, as volume increases, decreases and no volume differences have all been reported relative to controls. The current study aimed to determine whether antipsychotic-naive, putatively at-risk children who present multiple antecedents of schizophrenia (ASz) or a family history of illness (FHx) show pituitary volume abnormalities relative to typically developing (TD) children. An additional aim was to explore the association between pituitary volume and experiences of psychosocial stress.MethodASz (n = 30), FHx (n = 22) and TD (n = 32) children were identified at age 9–12 years using a novel community-screening procedure or as relatives of individuals with schizophrenia. Measures of pituitary volume and psychosocial stress were obtained at age 11–14 years.ResultsNeither ASz nor FHx children showed differences in pituitary volume relative to TD children. Among FHx children only, pituitary volume was negatively associated with current distress relating to negative life events and exposure to physical punishment.ConclusionsThe lack of pituitary volume abnormalities among ASz and FHx children is consistent with our previous work demonstrating that these children are not characterized by elevated diurnal cortisol levels. The findings imply that these biological markers of HPA axis hyperactivity, observed in some older samples of high-risk individuals, may emerge later, more proximally to disease onset.

SummaryIt is well established that the immune system can modulate brain functioning and influence behavioural processes. Awareness of communication between the immune and nervous systems has, over the years, progressively heightened interest in the relationship between psychiatric disorders and immune function. By reviewing findings from studies investigating inflammation in the periphery and in the central nervous systems, we summarise here the evidence linking inflammation to the development of depression, schizophrenia and bipolar disorder. We discuss how a pathophysiological role for inflammation has now been recognised across different psychiatric disorders, at least in a significant subpopulation of patients. Finally, we discuss a possible role for these findings in the development of future diagnostic classifications of psychiatric disorders as well as of new treatment strategies.

In the last few decades there has been a growing interest in the role of psychoneuroimmunological dysfunction in neuropsychiatric disorders. This article presents recent advances in the literature, from preclinical and clinical studies, suggesting that mood and anxiety disorders are, at least in part, conditions in which the inflammatory system is activated. The evidence-base comprises alterations in the peripheral immune systems of patients with mood or anxiety disorders, together with the development of depression- and anxiety-like symptoms induced by inflammatory agents. The reported anti-inflammatory effects of current psychotropic medications as well as the efficacy of anti-inflammatory medications in treating symptoms of depression and anxiety are also reviewed. Finally, potential mechanisms mediating the link between inflammation and symptomatology presented in these neuropsychiatric illnesses are discussed as well. [ Psychiatr Ann . 2015;45(5):240–248.]

Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress.

Epidemiological and clinical studies have provided evidence for a role of both genetic and environmental factors, such as stressful experiences early in life, in the pathogenesis of Schizophrenia (SZ) and microRNAs (miRNAs) have been suggested to play a key role in the interplay between the environment and our genome.In this study, we conducted a miRNOme analysis in different samples (blood of adult subjects exposed to childhood trauma, brain (hippocampus) of rats exposed to prenatal stress and human hippocampal progenitor cells treated with cortisol) and we identified miR-125b-1-3p as a down-regulated miRNA in all the three datasets. Interestingly, a significant down-regulation was observed also in SZ patients exposed to childhood trauma. To investigate the biological systems targeted by miR-125b-1-3p and also involved in the effects of stress, we combined the list of biological pathways modulated by predicted and validated target genes of miR-125b-1-3p, with the biological systems significantly regulated by cortisol in the in vitro model. We found, as common pathways, the CXCR4 signaling, the G-alpha signaling, and the P2Y Purigenic Receptor Signaling Pathway, which are all involved in neurodevelopmental processes.Our data, obtained from the combining of miRNAs datasets across different tissues and species, identified miR-125b-1-3p as a key marker associated with the long-term effects of stress early in life and also with the enhanced vulnerability of developing SZ. The identification of such a miRNA biomarker could allow the early detection of vulnerable subjects for SZ and could provide the basis for the development of preventive therapeutic strategies.

The role of omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) in the pathogenesis and treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD) is unclear. A systematic review followed by meta-analysis was conducted on: (1) randomized controlled trials (RCTs) assessing the effects of n-3 PUFAs on clinical symptoms and cognition in children and adolescent with ADHD; and (2) case-control studies assessing the levels of n-3 PUFAs in blood and buccal tissues of children and adolescents with ADHD. In seven RCTs, totalling n=534 randomised youth with ADHD, n-3 PUFAs supplementation improves ADHD clinical symptom scores (g=0.38, p

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.

Repeated lipopolysaccharide exposure is often used in longitudinal preclinical models of depression. However, the potential phenotypic differences from acute depression-mimicking effects are rarely described. This study compared chronic lipopolysaccharide administration of doses previously used in depression research to a new mode of escalating dose injections. Adult male BALB/c mice ( n=8/group) were injected intraperitoneally with either a single 0.83 mg/kg dose, a repeated 0.1 mg/kg lipopolysaccharide dose or a dose which escalated weekly from 0.33 to 0.83 mg/kg lipopolysaccharide for six weeks. The escalating lipopolysaccharide group demonstrated most features of sickness behaviour such as weight loss and reduction in food intake every week, whilst this effect was not sustained in other groups. Moreover, only in the escalating lipopolysaccharide group did most peripheral plasma cytokines levels, measured using Luminex multiplex technology, such as interleukin-6, tumour necrosis factor α and interleukin-2 remain over three-fold elevated on the sixth week. In addition, exposure to escalating doses led to a reduction of neuroblast maturation in the dentate gyrus relevant for depression neurobiology. Therefore, this mode of injections might be useful in the studies attempting to replicate neurobiological aspects of the chronic inflammatory state observed in mood disorders.

To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-beta 1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-beta 1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.

BACKGROUND: Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.METHODS: We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen-Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance.RESULTS: A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies).CONCLUSIONS: MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.

Neurogenesis, associated with synaptic plasticity and memory formation, has been linked to the pathogenesis of psychiatric disorders such as depression. Recently, evidence has emerged to suggest that inflammation and the immune system can influence the way neurogenesis occurs in the brain. Specifically, expression levels of cytokines have been shown to modulate cell proliferation, differentiation, and neurogenesis in specific areas of the brain, in particular, the hippocampus. This chapter identifies particular cytokines separately and describes evidence regarding their effects on adult and fetal neurogenesis.

Emerging evidence suggests a significant role for inflammation and oxidative stress as main contributors to the neuroprogression that is observed in major depressive disorder (MDD), where patients show increased inflammatory and oxidative stress biomarkers. The process of neuroprogression includes stage-related neurodegeneration, cell death, reduced neurogenesis, reduced neuronal plasticity and increased autoimmune responses. Oxidative stress is a consequence of the biological imbalance between reactive oxygen species (ROS) and antioxidants, leading to the alteration of biomolecules and the loss of control of the intracellular redox-related signalling pathways. ROS serve as crucial secondary messengers in signal transduction and significantly affect inflammatory pathways by activating nuclear factor-κB and mitogen-activated protein kinase family stress kinases. When present in excess, ROS inflict damage, affecting cellular constituents with the formation of pro-inflammatory molecules, such as malondialdehyde, 4-hydroxynonenal, neoepitopes and damage-associated molecular patterns promoting immune response, and ultimately leading to cell death. The failure of cells to adapt to the changes in redox homeostasis and the subsequent cell death, together with the damage caused by inflammatory mediators, have been considered as major causes of neuroprogression and hence MDD. Both an activated immune–inflammatory system and increased oxidative stress act synergistically, complicating our understanding of the pathogenesis of depression. The cascade of antioxidative and inflammatory events is orchestrated by several transcription factors, with nuclear factor (erythroid-derived 2)-like 2 and nuclear factor-κB having particular relevance to MDD. This review focuses on potential molecular mechanisms through which impaired redox homeostasis and neuroinflammation can affect the neuronal environment and contribute to depression.

Background: Child maltreatment can have a long-term impact on mental health. Less is known about the consequences of child maltreatment on the next generation’s psychological wellbeing. Aim: This systematic review aimed to synthesise the existing empirical literature on the association between a mother’s history of maltreatment in her own childhood and her children’s experiences of psychopathology, and to characterise potential mediating pathways. Method: Electronic database and hand searches yielded 12 studies, with a combined sample size of 45,723 mother–child dyads, which met criteria for inclusion in the review. Results: There was evidence of an overall positive association between a mother’s history of child maltreatment and her child’s experience of emotional and behavioural difficulties across childhood and adolescence. Maternal psychological distress and poorer parenting practices were found to be key mediating pathways of this association. Conclusion: Children of mothers who were exposed to maltreatment in childhood appear to be at an increased risk for psychopathology. Mothers with traumatic childhood experiences should be offered improved access to psychological therapies and parenting programmes to help mitigate the potential impact of child maltreatment on future generations.

Immunostimulatory insults such as stress and infection are risk factors for the development of several neuropsychiatric disorders characterized by neuroprogression. Inflammatory and neurotoxic molecules in the brain can cause disruptions in neurogenesis, neuronal excitability, synaptic transmission, synaptic plasticity, and neuronal survival - changes that characterize neuroprogression. We draw on recent findings in the immunology literature that peripheral innate immune cells are capable of retaining long-term memory of infectious insults and displaying long-lasting upregulated proinflammatory function in response to repeated infectious insults - a concept known as "innate immune memory." In turn, we hypothesize that microglia, the resident innate immune cells of the brain, are also capable of retaining long-term memory of infectious and noninfectious insults, including stress. Microglia are capable of producing a variety of proinflammatory neurotoxic cytokines and chemokines. Persistent upregulation of microglial proinflammatory function as a result of memory for immunostimulatory insults may therefore contribute to persistent and progressive inflammation in neuropsychiatric illnesses and be an important driver of neuroprogression.

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti‐TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti‐inflammatory drugs (indomethacin, prednisolone, and anti‐TNFα antibody) on the response of human monocyte‐derived macrophages (MDMs) from 6 individuals to LPS or IFN‐α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P

Introduction: Omega-3 polyunsaturated fatty acids (PUFAs) have been proven critical in the development and management of major depressive disorder (MDD) by a number of epidemiological, clinical and preclinical studies, but the molecular mechanisms underlying this therapeutic action are yet to be understood. Although eicosapentaenoic acid (EPA) seems to be the active component of omega-3 PUFAs' antidepressant effects, the biological research about the difference of specific genetic regulations between EPA and docosahexaenoic acid (DHA), the two main components of omega-3 PUFAs, is still lacking in human subjects. Methods: We conducted a 12-week randomized-controlled trial comparing the effects of EPA and DHA on gene expressions of phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX2), serotonin transporter (5HTT), and Tryptophan hydroxylase 2 (TPH-2) in 27 MDD patients. In addition, the erythrocyte PUFA compositions and the candidate gene expressions were also compared between these 27 MDD patients and 22 healthy controls. Results: EPA was associated with a significant decrease in HAM-D scores (CI: − 13 to − 21, p < 0.001) and significant increases in erythrocyte levels of EPA (CI: + 1.0% to + 2.9%, p = 0.001) and DHA (CI: + 2.9% to + 5.6%, p = 0.007). DHA treatment was associated with a significant decrease in HAM-D scores (CI: − 6 to − 14, p < 0.001) and a significant increase in DHA levels (CI: + 0.2% to + 2.3%, p = 0.047), but not of EPA levels. The cPLA2 gene expression levels were significantly increased in patients received EPA (1.9 folds, p = 0.038), but not DHA (1.08 folds, p = 0.92). There was a tendency for both EPA and DHA groups to decrease COX-2 gene expressions. The gene expressions of COX-2, cPLA2, TPH-2 and 5-HTT did not differ between MDD cases and healthy controls. Conclusions: EPA differentiates from DHA in clinical antidepressant efficacy and in upregulating cPLA2 gene regulations, which supports the clinical observation showing the superiority of EPA's antidepressant effects. Trial registration: ClinicalTrials.gov identifier: NCT02615405

Studies over the last 20 years have demonstrated that increased inflammation andhyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are two of the mostconsistent biological findings in major depression and are often associated: but themolecular and clinical mechanisms underlying these abnormalities are still unclear.These findings are particularly enigmatic, especially considering the accepted notionthat high levels of cortisol have an anti-inflammatory action, and therefore the coexistence of inflammation and hypercortisolemia in the same diagnostic group appears counter-intuitive. To celebrate the 2015 Anna-Monika Foundation Award to our laboratory, this review will discuss our own 20 years of research on the clinical andmolecular evidence underlying the increased inflammation in depression, especially inthe context of a hyperactive HPA axis, and discuss its implications for the pathogenesis and treatment of this disorder.Keywords: HPA, cortisol, glucocorticoid receptor, glucocorticoid resistance, childhoodtrauma, inflammation, biomarker, depression, antidepressants, mRNA

Decisions about the use of psychotropic medication in pregnancy are an ongoing challenge for clinicians and women with mental health problems, owing to the uncertainties around risks of the illness itself to mother and fetus/infant, effectiveness of medications in pregnancy and risks to the fetus/infant from in utero exposure or via breast milk. These consensus guidelines aim to provide pragmatic advice regarding these issues. They are divided into sections on risks of untreated illness in pregnancy; general principles of using drugs in the perinatal period; benefits and harms associated with individual drugs; and recommendations for the management of specific disorders.

Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at their first episode of psychosis (FEP) and associated with increased mortality. However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of FEP is understudied. This study aimed 1) to combine metabolic and inflammatory variables in factors accounting for an overall metabolic-inflammatory status in FEP patients; 2) to explore the association between these factors and clinical outcome at 1 year. We recruited 43 FEP patients and 50 healthy controls (HC). At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as inflammatory biomarker, and body mass index (BMI), lipid profile and gluco-metabolic parameters (glycated haemoglobin (HbA1c) and fasting glucose) as metabolic variables. Using a principal component analysis (PCA) we gathered all variables in factors accounting for both inflammation and metabolic status. In patients, we assessed symptoms severity at T1 and after 1-year (T2) as well as T2 treatment response. FEP showed higher HbA1c (p = 0.034), triglycerides (TG) (p = 0.044) and BMI (p = 0.023) than HC. PCA identified 3 factors. Factor 1, accounting for hsCRP, TG and BMI, was associated with T1 negative symptoms severity (p = 0.018) and predicted T2 positive symptoms severity (p = 0.003), overall symptoms severity (p = 0.004), general psychopathology (p = 0.001) and treatment response (p = 0.007). A combined inflammatory-metabolic factor proved to predict the clinical course of psychosis and offer an important target for early interventions.

Smaller hippocampal volume has been reported in individuals with post-traumatic stress disorder (PTSD) and dissociative identity disorder (DID), but the regional specificity of hippocampal volume reductions and the association with severity of dissociative symptoms and/or childhood traumatization are still unclear. Brain structural magnetic resonance imaging scans were analyzed for 33 outpatients (17 with DID and 16 with PTSD only) and 28 healthy controls (HC), all matched for age, sex, and education. DID patients met criteria for PTSD (PTSD-DID). Hippocampal global and subfield volumes and shape measurements were extracted. We found that global hippocampal volume was significantly smaller in all 33 patients (left: 6.75%; right: 8.33%) compared with HC. PTSD-DID (left: 10.19%; right: 11.37%) and PTSD-only with a history of childhood traumatization (left: 7.11%; right: 7.31%) had significantly smaller global hippocampal volume relative to HC. PTSD-DID had abnormal shape and significantly smaller volume in the CA2-3, CA4-DG and (pre)subiculum compared with HC. In the patient groups, smaller global and subfield hippocampal volumes significantly correlated with higher severity of childhood traumatization and dissociative symptoms. These findings support a childhood trauma-related etiology for abnormal hippocampal morphology in both PTSD and DID and can further the understanding of neurobiological mechanisms involved in these disorders.

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's g 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.

Background 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. Aims We investigated the hypothesis that BDNF is associated with both CT and cognitive deficits in a sample of first-episode psychosis (FEP) cases and unaffected controls. Method Participants with FEP and healthy controls were recruited between August 2008 and July 2011 from South London, UK. Childhood traumatic events were detected using the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Neuropsychological data were also collected. BDNF plasma levels were measured from fasting blood samples. Results Data were available on 87 FEP patients and 152 controls. Our results showed a significant effect of separation (F = 5.5; df = 1,115; p = .02), physical (F = 4.7; df = 1, 118; p = .03) and sexual abuse (F = 5.4; df = 1,117; p = .02) on BDNF levels with lower levels among those who experienced the traumatic event compared to those who did not. Physical abuse predicted lower plasma levels of BDNF (β = − .30; p = .03) whereas sexual and/or physical abuse showed a trend (β = − .26; p = .06) in FEP patients but not in unaffected controls. No association between BDNF plasma levels and cognitive functions was found among patients with FEP and controls. Conclusion Our findings suggest the possible involvement of BDNF in the onset of first-episode psychosis in individuals exposed to early trauma and propose BDNF as a potential clinical biomarker to detect the detrimental effects of CT on human brain plasticity.

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.

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.

Objective: 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. Methods: Using data from 1683 participants from the MRC NSHD, we investigated associations between affective symptoms at ages 36, 43, 53 and 60–64 years and SBP and DBP at age 60–64. Multivariable linear regression was used to examine the effect on BP of affective symptoms at each age separately and as a categorical cumulative score based on the number of times an individual was classified as a ‘case’. Models were adjusted for sex, BMI, educational attainment, socio-economic position, heart rate, lifestyle factors and antihypertensive treatment. Results: In fully adjusted models, we observed lower SBP in study members with case-level symptoms at one to two time-points [−1.83 mmHg; 95% confidence interval (CI) −3.74 to 0.01] and at three to four time-points (−3.93 mmHg; 95% CI −7.19 to −0.68) compared with those never meeting case criteria suggesting a cumulative inverse impact of affective symptoms on SBP across adulthood (P value for trend 0.022). Sex and BMI had a large impact on the estimates while not other confounders. Potential mediators such as heart rate and lifestyle behaviours had a little impact on the association. SBP at age 36 and behavioural changes across adulthood, as additional covariates, had a little impact on the association. A similar but weaker trend was observed for DBP. Conclusion: A cumulative effect of symptoms of anxiety and depression across adulthood results in lower SBP in late middle age that is not explained by lifestyle factors and antihypertensive treatment. Mechanisms by which mood may impact BP should be investigated.

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.

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.

Background Individuals with established psychosis are characterised by a distinct pattern of hypothalamic-pituitary-adrenal (HPA) axis dysfunctions which include both elevated daytime cortisol levels and a blunted cortisol awakening response (CAR). Whilst these patterns of dysfunction have also been observed among those at elevated risk for the disorder, longitudinal studies are scarce. As such, the relevance of these HPA axis abnormalities for the progression of psychopathology in high-risk populations is unknown. Utilising data from a well-characterised, longitudinal cohort of youth at elevated risk for schizophrenia and their typically-developing peers (The Child Health and Development Study), we aimed to investigate the extent to which HPA axis function determined in childhood is a significant predictor of putative prodromal status and psychopathology in late adolescence/early adulthood. Methods The sample comprised high-risk individuals who presented either multiple antecedents of schizophrenia (developmental delays, psychopathology, and psychotic-like experiences: ASz=21) or a family history of illness (FHx=13), and typically-developing youth with neither antecedents nor a family history (TD=36). Participants were recruited at age 9–12 years using a community screening method and assessed biennially throughout adolescence. At the age 11–14 years assessment phase, participants collected salivary cortisol samples in their home environment which were used to determine diurnal cortisol secretion and the CAR. At the age 17–21 years assessment phase, participants completed measures of prodromal symptoms (Prodromal Questionnaire: PQ), depression (Quick Inventory of Depressive Symptomatology questionnaire: QIDS), and anxiety (Social Interaction Anxiety Scale: SIAS). Established PQ thresholds were used to identify participants who met probable prodromal status. Logistic and linear regression analyses were used to examine the extent to which salivary cortisol measures at age 11–14 years predicted probable prodromal status and continuous psychopathology measures at 17–21 years, respectively. Results Relative to the TD group, ASz youth were characterised by higher depression (B=0.24, p=0.05) and disorganised symptoms (B=0.36, p=0.007) at 17–21 years whilst FHx youth obtained higher scores on the PQ general symptoms scale (B=0.24, p=0.048). Analyses performed in the total sample indicated that the CAR was negatively associated with depression symptoms (B=-0.28, p=0.006) and PQ negative symptoms (B=-0.30, p=0.004) at age 17–21 years. Positive associations were observed between diurnal cortisol and positive (B=0.41, p=0.02), disorganised (B=0.30, p=0.04), and general (B=0.29, p=0.03) PQ symptoms. Diurnal cortisol levels were also significantly associated with probable prodromal status at follow-up (OR=1.04, p=0.04). No significant interactions were observed between group status and salivary cortisol levels in any model. After adjustment for potential confounders (age, follow-up time, sex, BMI, and pubertal status), the CAR continued to show significant associations with both depression (p=0.006) and PQ negative symptoms (p=0.007) whilst only a statistical trend was observed for the relationship between diurnal cortisol levels and positive symptoms (p=0.055). Discussion The current study is the first to examine the extent to which HPA axis function can predict development of prodromal symptoms in a high-risk cohort. Our finding that more abnormal HPA axis function (i.e., a decreased CAR and higher diurnal cortisol) at age 11–14 years is associated with both prodromal and depression symptoms at age 17–21 has important implications for aetiological theories and for clinical practice.

Background Psychotic disorders are characterized by large heterogeneity in clinical presentation, response to treatment and cognitive functioning. Indeed, there is evidence of the presence of cognitive subgroups of patients across affective and non-affective psychosis. However, very little is known about these subgroups in first episode psychosis (FEP) and whether they can be informative about course of illness, particularly response to treatment. The aim of this study is to investigate the number and the pattern of cognitive clusters in FEP, their external validity and association with treatment response at 12-week and 1-year follow up. Methods The sample was composed by a total of 212 participants including 105 FEP patients from the South London and Maudsley Foundation Trust and 107 Healthy Controls (HC). All participants underwent a comprehensive clinical and neurocognitive battery. Z-score [mean=0, and standard deviation (SD)=1] were created for the whole sample based on the neurocognitive performance of the HCs. Treatment response at 12-week and 1-year follow-up was used to explore potential utility of subtypes in predicting response to treatment. Hierarchical cluster analysis was carried out to determine the number of cognitive clusters in FEP patients. A series of analyses of variance were carried out to determine if FEP clusters differed among each other in relation to demographic and clinical characteristics, level of functioning and from the HC sample in term of cognitive performance. Logistic regression was used to explore whether cognitive clustering was predictive of treatment response at 12-week and 1-year FU. Results Four cognitive clusters emerged: one with near normal cognition (42.9% of the FEP patients) with a general cognitive score of z=-0.20, one with selected cognitive deficits (14.3%) in the domains of verbal memory, processing speed and executive functions (general cognitive score of z=-0.55); and two severe deficit clusters consisting in one cluster with severe deficits (33.3%; general score of z=-1.48) and the other with a deeply compromised cognitive ability (9.55%; general cognitive score of z=-2.34). There were no significant differences between clusters in terms of clinical features at baseline (including diagnosis, positive and negative symptoms, medication), apart from the level of functioning that was significantly lower in the severely compromised cluster compared to the near normal cognition cluster. It emerged that majority (about 68%) of the patients from the near normal cognition cluster were responsive to treatment, whilst the majority of the selective and severely impaired clusters did not respond to treatment at 12-week follow-up. There were no significant results with regard to treatment response at 1-year FU. Discussion Distinct patterns of cognitive impairments exist within FEP that might be characterized by different response to treatment. Clinical presentation at the onset of the illness is not useful in predicting response to treatment later on in the course of the illness, while cognitive functioning might be a more valid indicator. Cognitive stratification could represent a promising way forward to elucidate pathophysiology of psychosis and to provide tailored interventions.

BACKGROUND: Cortisol has potent effects on learning and neuroplasticity, but little is known about its effects on negative memory biases in depression. Animal models show that aversive caregiving alters effects of glucocorticoids (primarily corticosterone in rodents; cortisol in primates) on learning and neuroplasticity into adulthood. METHODS: We investigated whether history of childhood emotional abuse (EA) moderated effects of cortisol administration (CORT) vs. placebo on emotional memory formation in depression. Participants included 75 unmedicated women with varying levels of depression severity and/or EA history. In a double-blind crossover investigation, we used fMRI to measure effects of CORT (vs. Placebo) on neural function during emotional memory formation. RESULTS: CORT eliminated the well-known relation between depression severity and negative memory bias, a finding explained by EA severity. For women with history of severe EA, CORT reduced depression-related negative memory bias and normalized recall for pleasant stimuli. EA severity also moderated CORT’s effects on neural function: in women with history of severe EA, CORT increased activation in supplementary motor area (SMA) during unpleasant relative to pleasant pictures. Additionally, SMA activation predicted reduced negative bias for pictures encoded during CORT. CONCLUSIONS: These results suggest that increasing cortisol signaling may be neurocognitively beneficial in depressed women with history of maltreatment. The findings corroborate prior research suggesting that presence or absence of adverse caregiving is etiologically important in depression. The findings suggest potential neurocognitive mechanisms of therapeutics targeting cortisol signaling, which show promise in treating affective disorders.

IntroductionHyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and high cortisol levels have been widely reported in patients with mood disorders but previous clinical trials investigating the efficacy of antiglucocorticoid treatment in this population have reported inconsistent findings. These inconsistencies among these studies may be because not all patients with mood disorders have increased HPA axis activity and therefore might not benefit from antiglucocorticoid treatment. The aim of this meta-analysis was to investigate whether baseline cortisol levels influence influence the efficacy of antiglucocorticoid drugs in patients with mood disorders.MethodsPubMed and Scopus databases were searched systematically up to October 2018. We included studies using metyrapone, ketoconazole or mifepristone in patients with major depressive disorder, bipolar disorder and major depressive disorder with psychotic symptoms. We tested for a difference in cortisol levels between responders (a reduction equal to or greater than 30% on depression scales following antiglucocorticoid treatment) and non-responders (a reduction of less than 30% on depression scales). We performed a meta-analysis to look specifically at differences in cortisol levels in the sample of patients treated with cortisol synthesis inhibitors (metyrapone and ketoconazole) and in those treated with glucocorticoid receptor (GR) antagonist (mifepristone).ResultsWe were able to retrieve data from 11 of the 16 selected studies and to include 9 studies in the meta-analysis. In the overall sample (N = 846), responders had similar baseline cortisol levels compared with non-responders (standardised mean difference, SMD = -0.03, 95% CI [-0.17, 0.12], p = 0.75). In the group of patients treated with cortisol synthesis inhibitors, responders (N = 109) had significantly higher peripheral baseline cortisol levels compared with non-responders (SMD = 0.42, 95% CI [0.01, 0.83], p = 0.047). In the group of patients treated with a GR antagonist (N = 737), both responders and non-responders had similar baseline cortisol levels (SMD= -0.09, 95% CI [-0.25, 0.07], p = 0.26).ConclusionOur data suggest that only patients with higher cortisol levels at baseline benefit from treatment with cortisol synthesis inhibitors and support a potential role for cortisol as a predictive biomarker for treatment with cortisol synthesis inhibitors in patients with mood disorders.