Search

Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia. Secondary analyses determined whether this relationship differed according to antipsychotic treatment response. The sample consisted of 79 patients with schizophrenia, of whom 40 were rated as antipsychotic responders and 39 as antipsychotic non-responders. Brain glutamate levels were assessed in the anterior cingulate cortex (ACC) and caudate using proton magnetic resonance spectroscopy ( 1H-MRS) and blood samples were collected for cytokine assay on the same study visit (IL-6, IL-8, IL-10, TNF- α and IFN-γ). Across the whole patient sample, there was a positive relationship between interferon-gamma (IFN-γ) and caudate glutamate levels (r = 0.31, p = 0.02). In the antipsychotic non-responsive group only, there was a positive relationship between interleukin-8 (IL-8) and caudate glutamate (r = 0.46, p = 0.01). These findings provide evidence to link specific peripheral inflammatory markers and caudate glutamate in schizophrenia and may suggest that this relationship is most marked in patients who show a poor response to antipsychotic treatment.

Current lines of research into mood disorders indicate that immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain functions, even when these mediators are produced in peripheral tissues. Elevated levels of circulating immune molecules have been consistently associated with depressive symptoms in a number of clinical populations and experimental models, to the extent that major depressive disorder (MDD) is now seen, at least in part, as a disorder of immunity. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy with the hope to improve treatment efficacy, particularly in those cohorts that do not respond well to standard medication. Such new practice requires the availability of biomarkers to tailor these new therapies to those most likely to benefit but also clear mechanisms of action describing the interaction between peripheral immunity and brain function. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease through peripherally induced sickness behaviour as the model for immune-induced MDD. After an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we propose a modified model of periphery-brain interaction that goes beyond the currently established view of interaction between peripheral cytokines and microglia cells as the driver of depression. Instead, we suggest that brain barriers are primary actors in the communication between body and brain and, as a consequence, in the pathophysiology of the disease. This model suggests novel biomarkers, novel targets for therapies as well as a novel mechanism for resistance to standard treatments.

Orexin-A levels are reportedly increased in antipsychotic (APD)-treated patients with schizophrenia compared to healthy controls and have been associated with metabolic abnormalities. It is not clear whether the orexin-A elevation is related specifically to the drug (APDs) effect, which should be clarified by including a drug-free group for comparison, or related to drug-induced metabolic abnormalities.Blood orexin-A levels and metabolic profiles were compared between 37 drug-free, 45 aripiprazole-treated, and 156 clozapine-treated patients with schizophrenia. The association between orexin-A and metabolic outcomes were examined. We explored the effects of APDs treatment and metabolic status on orexin-A levels by linear regression.Patients under APDs treatment had increased orexin-A levels compared to drug-free patients, with aripiprazole-treated group having higher orexin-A levels than clozapine-treated group. Higher orexin-A levels reduced the risks of metabolic syndrome (MS) and type 2 diabetes mellitus, indicating a relationship between orexin-A levels and metabolic problems. After adjusting the effect from metabolic problems, we found APD treatment is still associated with orexin-A regulation, with aripiprazole more significantly than clozapine.With the inclusion of drug-free patients rather than healthy controls for comparison, we demonstrated that orexin-A is upregulated following APD treatment even after we controlled the potential effect from MS, suggesting an independent effect of APDs on orexin-A levels. Furthermore, the effect differed between APDs with dissimilar obesogenicity, i.e. less obesogenicity likely associated with higher orexin-A levels. Future prospective studies exploring the causal relationship between APDs treatment and orexin-A elevation as well as the underlying mechanisms are warranted.

BACKGROUND. The Identifying Depression Early in Adolescence Risk Score (IDEA-RS) has been externally assessed in samples from four continents, but North America is lacking. Our aim here was to evaluate the performance of the IDEA-RS in predicting future onset of Major Depressive Disorder (MDD) among adolescents from the United States of America. METHODS. We applied the intercept and weights of the original IDEA-RS model developed in Brazil to the Great Smoky Mountains Study (GSMS) sample to generate individual probabilities for each participant at age 15 (N = 1029). We then evaluated the performance of such predictions against the diagnosis of MDD at age 19 using simple, case-mix corrected and refitted models. Furthermore, we compared how prioritizing the information provided by parents or by adolescents affected performance. RESULTS. The IDEA-RS exhibited a C-statistic of 0.63 (95% CI 0.53–0.74) to predict MDD in the GSMS when applying uncorrected weights. Case-mix corrected and refitted models enhanced performance to 0.69 and 0.67, respectively. No significant difference was found in performance by prioritizing the reports of adolescents or their parents. CONCLUSION. The IDEA-RS was able to parse out adolescents at risk for a later onset of depression in the GSMS cohort with above chance discrimination. The IDEA-RS has now showed above-chance performance in five continents.

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 (β = 0.915, 95% confidence interval: 0.062–1.769) and daily stressors (β = 0.379, 95% confidence interval: 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 (β = 0.743, 95% confidence interval: 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.

Introduction Although the aetiology and pathophysiology of depression are multifactorial, to date most studies have examined either biological or environmental mechanisms without looking at the integration of both; with most studies conducted in high-income countries (HICs). Therefore, we conducted a systematic review of worldwide studies investigating the relationship between biological and environmental stress risk factors for major depressive disorder (MDD) in adolescence. Methods We searched MEDLINE (via Ovid), PsycINFO, Cochrane Database of Systematic Reviews, Web of Science (Core Collection), Lilacs, African Journals Online and Global Health for prospective and cross-sectional studies that examined the association between biological markers and environmental stress risk factors in MDD during adolescence. Findings Of 11,089 articles identified, 21 were included, with only two from middle-income countries. Increased inflammation, telomere length and brain abnormalities, including blunted reward-related activity, white matter disruptions, and altered volume of limbic brain regions, were associated with increased risk for MDD mainly in the context of early life adversity. There is little evidence suggesting that the neurobiological changes investigated were associated with MDD in the context of recent life stress. Interpretation The developmental trajectory of depression appears to start with early life adversities and occurs in the context of immune and brain abnormalities. Understanding these biopsychosocial processes will help to improve our ability to detect individuals at risk of developing depression in adolescence. However, generalizability is limited by few studies examining both biological and environmental stress risk factors and a lack of studies on adolescents and young adults in low-and-middle-income countries (LMICs).

The relationship between peripheral and central immunity and how these ultimately may cause depressed behaviour has been the focus of a number of imaging studies conducted with Positron Emission Tomography (PET). These studies aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood–brain barrier and ultimately depressive behaviour. However, studies conducted so far using PET radioligands targeting the neuroinflammatory marker 18 kDa translocator protein (TSPO) in patient cohorts with depression have demonstrated mild inflammatory brain status but no correlation between central and peripheral immunity. To gain a better insight into the relationship between heightened peripheral immunity and neuroinflammation, we estimated blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies, one large cross-sectional study of neuroinflammation in normal and depressed cohorts (N = 51 patients and N = 25 controls) and a second study where peripheral inflammation in N = 7 healthy controls was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with c-reactive protein P (CRP), and radiotracer perfusion into and from the brain parenchyma and CSF. Importantly, there was no association of this effect with the marker of BBB leakage S100β, that was unchanged. These results suggest a different model of peripheral-to-central immunity interaction whereas peripheral inflammation may cause a reduction in BBB permeability. This effect, on the long term, is likely to disrupt brain homeostasis and induce depressive behavioural symptoms.

Highlights • Global experts ranked biopsychosocial risk factors for adolescent depression • Risk factors include female sex, family history, physical illness, bullying • Mood changes and loss of interest are measurable early signs of adolescent depression • Culture influences the types and specificity of adolescent depression risk factors, Background Adolescence represents a vulnerable period for the onset of depression. Globally, there is a need to better understand risk factors for adolescent depression to inform policies for effective prevention initiatives. Methods A Delphi consensus study was conducted on risk factors, early signs, and detection strategies for adolescent depression in global settings. Over 3 survey rounds, global experts formulated and ranked these variables for (1) specificity for adolescent depression and (2) feasibility of measurement (round 1, n=21 participants; rounds 2 and 3, n=17). We calculated Smith's salience index as a measure of consensus. Interviews were conducted with 10 participants to elicit qualitative reflections on the ranking results, and on the influence of cultural and contextual factors on depression risks. Results Thirty-one risk factors for adolescent depression were generated. Panelists ranked three as highly specific and highly feasible to measure: family history of depression, exposure to bullying, and a negative family environment. Six were ranked as modestly specific and highly feasible: physical illness or disability, female sex, bereavement, trauma exposure, substance abuse, and low self-esteem. An additional 5 items were modestly specific and modestly feasible: social difficulties, academic stress, poverty, loss of family, and cognitive distortions. Five symptoms were at least modestly specific and feasible to measure: mood changes, loss of interest, social isolation, suicidality, and sleep changes. Schools were considered the most feasible place for screening. Limitations The participants were not representative of all countries and cultural regions. Conclusions This study offers a profile of risk factors developed and prioritized by experts to inform a research agenda for risk, identification and prevention of adolescent depression across global settings.

Hypothalamus-Pituitary-Adrenal (HPA) axis dysregulation, inflammation and imbalance of neurotrophins have been suggested in attention deficit hyperactivity disorder (ADHD), but the results have not been conclusive. The aim of this study is to investigate the levels of salivary cortisol across 4-time points during the day, and of morning plasma inflammatory biomarkers and neurotrophins, in youth with ADHD and in typically developing youth (TD), with stratification by age, ADHD subtypes and oppositional defiant disorder (ODD) comorbidity in Taiwan.We conducted a case-control study measuring saliva cortisol levels at 4 different time points during the day (at awakening, noon, 1800 h and bedtime) and morning plasma levels of inflammatory and neurotrophins biomarkers in youth with ADHD (n = 98, age 6-18 years old with mean age 9.32 ± 3.05 years) and TD (n = 21, age 6-18 years old with mean age 9.19 ± 2.96 years) in Taiwan.Our study showed that youth with ADHD had lower levels of bedtime salivary cortisol (effects size (ES) = -0.04, p = .023), with children with the combined form of the disorder (with inattention, hyperactivity and impulsivity all present) having the lowest awakening salivary cortisol levels. ADHD youth also had higher levels of plasma high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 (ES = 0.85-1.20, p .0001), and lower plasma tumor necrosis factor-alpha (ES = -0.69, p = .009) and brain-derived neurotrophic factors (BDNF) (ES = -1.13, p .0001). Both ADHD groups regardless of ODD comorbidity had higher levels of IL-6 (p .0001) and lower levels BDNF (p .0001).The lower bedtime salivary cortisol levels and higher levels of inflammatory biomarkers in youth with ADHD further support the role of abnormal HPA axis and inflammation in ADHD. Moreover, the lower levels of BDNF in ADHD also indicate that BDNF may be a potential biomarker in this disorder that is part of a broader biological dysfunction.

Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline - the Minocycline in Depression (MINDEP) study.The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) ≥ 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Δ- Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP ≥3 mg/L vs. CRP3 mg/L). Additionally, we investigated the role of serum IL-6 in predicting treatment response to minocycline, using sex-specific medians of IL-6, in novel exploratory analyses.Sex differences in Δ-HAMD-17 indicate that only females (F = 10.49, p = 0.005), but not males (F = 1.64, p = 0.22), presented an effect of CRP levels on the response to minocycline. Also, we detected sex differences in the relationship between serum CRP and IL-6 levels: CRP was strongly correlated with IL-6 in females (Spearman's ρ = 0.658, P 0.001) but not in males (ρ = 0.007, p = 0.979). Exploratory analyses found that IL-6 was indeed a better predictor of response than minocycline than CRP, as we found an interaction between study arms and IL-6 groups (above and below the IL-6 sex-specific median) in females (F = 4.435 p = 0.050) and, at trend statistical level, in males (F = 4.258 p = 0.060). Moreover, Δ-HAMD-17 was numerically comparable in the two high-IL-6 group taking minocycline (females, mean 9.20 ± SD 7.80; males, mean 8.80 ± SD 5.97), confirming that high IL-6, differently from high CRP, identified responders to minocycline both in males and females.Our findings highlight the need of sex-specific inflammatory biomarkers in predicting antidepressant response to anti-inflammatories in TRD patients, with the possibility of CRP being a relevant predictor of treatment response only for females, and IL-6 being relevant for both sexes.

Background Pituitary volume (PV) abnormalities, representing one of several markers of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been observed in psychosis, with variable patterns across illness stages. Typically, enlargements characterise first-episode patients, with reductions observed in those with chronic illness relative to healthy controls. Findings in high-risk populations have been inconsistent, highlighting the need for an updated review of the evidence. Methods We searched PubMed, PsycINFO, and EMBASE for studies examining PV in high-risk [clinical high-risk (CHR), family history of psychosis (FHx), schizotypal personality disorder (SPD), and psychotic-experiences (PEs)] and healthy individuals. Random effects models were used to examine group differences in PV (Hedges g) with stratified analyses and meta-regression employed to investigate the effect of high-risk category, transition status, age, sex, and antipsychotic medication. Results Ten studies, yielding 11 effect sizes, were eligible for inclusion. Overall, high-risk individuals had significantly larger PV relative to healthy controls (g = 0.16 [95% CI: 0.01 to 0.32] p = 0.04), despite showing a reduction in whole brain volume (g = −0.17, [95% CI. −0.30 to −0.03] p = 0.020). Individual sub-group analyses for CHR and FHx groups showed no significant differences relative to controls; however, larger PV increases characterised those who later transitioned to psychosis (g = 0.55, [95% CI. 0.06 to 1.04] p = 0.028). Larger effect sizes were positively associated with the proportion of high-risk individuals receiving antipsychotic medication. Conclusions PV enlargements characterise high-risk individuals and are more pronounced among those who later develop psychosis. We provide recommendations for future studies.

BACKGROUND: Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality. However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of these patients has not yet been investigated.OBJECTIVES: The aims of this study were 1) to explore whether, in a sample of patients at their first episode of psychosis (FEP), an overall metabolic-inflammatory status may be measured, by combining metabolic and inflammatory variables in metabolic-inflammatory factors; 2) to explore the association between these factors and clinical outcome at 1-year follow-up (FU), in terms of symptoms severity and treatment response.METHODS: In this longitudinal study we recruited 42 FEP patients and 46 healthy controls (HC) matched with patients for age, gender and ethnicity. At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as biomarker of inflammation, and body mass index (BMI), lipid profile and gluco-metabolic parameters (glycated hemoglobin (HbA1c) and fasting glucose) as metabolic variables. A principal component analysis (PCA) was then used to reduce the dimensionality of the dataset accounting for both inflammation and metabolic status. In FEP patients, we assessed symptoms severity at T1 and at 1-year FU (T2) as well as treatment response to antipsychotics at T2.RESULTS: at T1, FEP showed higher HbA1c (p = 0.034), triglycerides (TG) (p = 0.045) and BMI (p = 0.026) than HC. PCA identified 3 factors: factor 1 accounting for hsCRP, TG and BMI, factor 2 accounting for LDL and cholesterol, and factor 3 accounting for fasting glucose and HbA1c. Factor 1 was associated with T1 negative symptoms severity (p = 0.021) and predicted T2 positive (p = 0.004) and overall symptoms severity (0.001), as well as general psychopathology (p CONCLUSION: In this sample of FEP patients, inflammation and metabolism, closely correlated at the onset of psychosis, proved to play a key role as predictors of the clinical course of psychosis when combined in a single factor. These findings offer an important potential target for early screening and interventions.

Neurological soft signs (NSS) are subtle abnormalities of motor and sensory function that are present in the absence of localized brain pathological lesions. In psychoses they have been consistently associated with a distinct pattern of cortical and subcortical brain structural alterations at the level of the heteromodal cortex and basal ganglia. However, a more specific and accurate evaluation of the cytoarchitecture of the cortical mantle could further advance our understanding of the neurobiological substrate of psychosis. We investigated the relationship between brain structure and NSS in a sample of 66 patients at their first episode of psychosis. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and Freesurfer to explore cortical thickness and surface area. Higher rates of NSS were associated with a reduction of cortical thickness in the precentral and postcentral gyri, inferior-parietal, superior temporal, and fusiform gyri. Higher rates of NSS were also associated with smaller surface areas of superior temporal gyrus and frontal regions (including middle frontal, superior and orbito-frontal gyri). Finally, more sensory integration signs were also associated with larger surface area of the latero-occipital region. We conclude that the presence of NSS in psychosis is associated with distinct but widespread changes in cortical thickness and surface area, in areas crucial for sensory-motor integration and for the fluid execution of movement. Studying these morphological correlates with advanced neuroimaging techniques can continue to improve our knowledge on the neurobiological substrate of these important functional correlates of psychosis.

The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague–Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman’s rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have potentially important consequences in terms of metabolic dysregulation associated with long-term antipsychotic treatment.

IntroductionAbnormalities within hypothalamus-pituitary-adrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adolescence; this is also the period when prodromal and psychotic symptoms occur for the first time. More knowledge about how various stress components interact can advance understanding of the link between psychosis and the HPA axis.MethodWe examined 41 ultra high-risk (UHR) patients and 40 antipsychotic-naïve first-episode schizophrenia (FES) patients and compared them with 47 matched controls. The Perceived Stress Scale and the Recent Life Events Questionnaire were used to assess the stress levels. Day-time saliva samples were taken to measure cortisol. The pituitary gland volume was measured manually on the structural MRI using stereology.ResultsOnly the UHR patients, had a higher cortisol increase just after awakening (p = 0.009) compared to healthy controls. In UHR patients, we found a negative correlation between cortisol increase after awakening and symptom severity (p = 0.008). Pituitary gland volume and diurnal cortisol were not significantly different among the three groups. There was no correlation between pituitary gland volume, perceived stress/recent life events and any of the cortisol measures or symptoms.ConclusionSymptom severity during the very early phase of illness (UHR) seems to be associated with altered cortisol increase. Longitudinal studies in UHR patients would be useful to examine how stress levels affect the course of the illness.

There has been much recent debate concerning the relative clinical utility of symptom dimensions versus conventional diagnostic categories in patients with psychosis. We investigated whether symptom dimensions rated at presentation for first-episode psychosis (FEP) better predicted time to first remission than categorical diagnosis over a four-year follow-up. The sample comprised 193 FEP patients aged 18-65. years who presented to psychiatric services in South London, UK, between 2006 and 2010. Psychopathology was assessed at baseline with the Positive and Negative Syndrome Scale and five symptom dimensions were derived using Wallwork/Fortgang's model; baseline diagnoses were grouped using DSM-IV codes. Time to start of first remission was ascertained from clinical records. The Bayesian Information Criterion (BIC) was used to find the best fitting accelerated failure time model of dimensions, diagnoses and time to first remission. Sixty percent of patients remitted over the four years following first presentation to psychiatric services, and the average time to start of first remission was 18.3. weeks (SD = 26.0, median = 8). The positive (BIC = 166.26), excited (BIC = 167.30) and disorganised/concrete (BIC = 168.77) symptom dimensions, and a diagnosis of schizophrenia (BIC = 166.91) predicted time to first remission. However, a combination of the DSM-IV diagnosis of schizophrenia with all five symptom dimensions led to the best fitting model (BIC = 164.35). Combining categorical diagnosis with symptom dimension scores in FEP patients improved the accuracy of predicting time to first remission. Thus our data suggest that the decision to consign symptom dimensions to an annexe in DSM-5 should be reconsidered at the earliest opportunity.

Highlights • MRI-derived choroid plexus volume is increased in patients with depression as compared to match-controls. • Choroid plexus enlargement is associated with neuroinflammation and reduction of blood–brain barriers permeability in depression. • Imaging transcriptomic CP volume and TSPO PET imaging confirms gene enrichment for several pathways involved in neuroinflammatory response. • Mechanisms choroid plexus volume increase remain unknow and might not be specific to depression., Background Recent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in the interaction between the central and peripheral inflammation. Here we aimed to investigate CP volume alterations in depression and their associations with inflammation. Methods 51 depressed participants (HDRS score > 13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [11C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and CP volume respectively. Results We found a significantly greater CP volume in depressed subjects compared to HCs (t(76) = +2.17) that was positively correlated with [11C]PK11195 PET binding in the anterior cingulate cortex (r = 0.28, p = 0.02), prefrontal cortex (r = 0.24, p = 0.04), and insular cortex (r = 0.24, p = 0.04), but not with the peripheral inflammatory markers: CRP levels (r = 0.07, p = 0.53), IL-6 (r = -0.08, p = 0.61), and TNF-α (r = -0.06, p = 0.70). The CP volume correlated with the [11C]PK11195 PET binding in CP (r = 0.34, p = 0.005). Integration of transcriptomic data from the Allen Human Brain Atlas with the brain map depicting the correlations between CP volume and PET imaging found significant gene enrichment for several pathways involved in neuroinflammatory response. Conclusion This result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component.

Exposure to childhood trauma has been associated with psychotic symptoms, being at ultra-high risk for psychosis (UHR), and psychotic disorders such as schizophrenia. Negative self-beliefs have been shown to partially mediate the relationship between childhood trauma and paranoia and have been shown to be characteristic of patients with psychosis. However, whether the association between childhood trauma and being at high risk of developing psychosis (e.g., UHR) and paranoia symptoms is mediated by altered cognitive schema is unknown and warrants investigation to inform preventive interventions. Data was collected on 30 UHR patients from Outreach and Support in South London about exposure to childhood trauma, cognitive schema, paranoia and cannabis use. Relative to healthy controls (n = 38), UHR patients were significantly more likely to report exposure to various types of childhood trauma (emotional and sexual abuse, and emotional and physical neglect), had more negative schema and less positive schema about themselves and others, and were more likely to use cannabis more than once a month. Emotional neglect was found to be significantly associated with UHR status even after controlling for the effects of previous exposure to cannabis use (b = 0.262, 95% CI: 0.115–0.408), and this association was partially mediated by negative self-schema (b = 0.045, 95% CI: 0.004–0.159). Similarly, emotional neglect was significantly associated with paranoia (b = 1.354, 95% CI: 0.246-2.462), and this association was partially mediated by negative self-schema (b = 0.988, 95% CI: 0.323-1.895). These findings provide preliminary evidence about the cognitive mechanisms that may underlie the association between childhood trauma and later risk for psychosis.

Background\ud Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses.\ud \ud Methods\ud The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta-analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis.\ud \ud Results\ud PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p < 10−6), but lower in individuals of African ancestry (R2 = 1.1%, p = .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R2 = 9.2%, p = .002).\ud \ud Conclusions\ud PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP.

Evidence suggests there are two treatment-resistant schizophrenia subtypes (i.e. early treatment resistant (E-TR) and late-treatment resistant (L-TR)). We aimed to develop prediction models for estimating individual risk for these outcomes by employing advanced statistical shrinkage methods. 239 first-episode schizophrenia (FES) patients were followed-up for approximately 5 years after first presentation to psychiatric services; of these, n=56 (25.2%) were defined as E-TR and n=24 (12.6%) were defined as L-TR. Using known risk factors for poor schizophrenia outcomes, we developed prediction models for E-TR and L-TR using LASSO and RIDGE logistic regression models. Models' internal validation was performed employing Harrell's optimism-correction with repeated cross-validation; their predictive accuracy was assessed through discrimination and calibration. Both LASSO and RIDGE models had high discrimination, good calibration. While LASSO had moderate sensitivity for estimating an individual risk for E-TR and L-TR, sensitivity estimated for RIDGE model for these outcomes was extremely low, which was due to having a very large estimated optimism. Although it was possible to discriminate with sufficient accuracy who would meet criteria for E-TR and L-TR during the 5-year follow-up after first contact with mental health services for schizophrenia, further work is necessary to improve sensitivity for these models.

Background Postpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high in women with a history of bipolar disorder, schizoaffective disorder or in those who have suffered previous episodes of PP. While studies in patients with psychosis not related to the puerperium have demonstrated that abnormalities in stress response are important risk factors for psychosis, it remains unknown whether this is also the case for PP. Methods This study includes 30 postpartum women, assessed, on average, at postpartum week 14.8 ± 10.1 either with a current episode of PP (n = 14), or at-risk of PP because of a history of bipolar/schizoaffective disorder but who were well (n = 16), and a group of healthy women (n = 26). Details about recent stressful life events were obtained using the List of Threatening Experiences questionnaire, while perceived stress was evaluated using the Perceived Stress Scale. We estimated hypothalamic-pituitary adrenal (HPA) activity by measuring salivary cortisol at awakening; at 15, 30, and 60 min after awakening; at noon; and at 8 pm. An Area Under the Curve analysis was performed to assess the awakening response (AUCi) and cortisol levels during the day (AUCg). Immune markers, including high sensitivity C-Reactive Protein (hs-CRP) and Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, Tumor Necrosis Factor (TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF) were evaluated from peripheral blood samples. Results Women with current PP reported more frequent recent stressful life events, and higher perceived stress than healthy women. They also showed an activation of the stress and immune response, with higher levels of cortisol AUCg and hs-CRP (but not of other inflammatory markers) than healthy controls. Women at-risk of PP who remained well had values on these measures that were intermediate between those of women with a current episode of PP and those of healthy women. Stress measures and markers of stress and immune response explained 78 % of the variance of in group status between PP and healthy women, and 46 % of variance of in group status between women at-risk and healthy women. Conclusion These findings suggest that an immune-HPA axis dysregulation, together with current stress may represent an important underlying pathophysiological mechanism in the onset of psychosis after childbirth in vulnerable women.

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.

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.

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.

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.

An increasing body of evidence suggests alterations in immune and inflammatory signaling in depression, with higher levels of pro-inflammatory cytokines in depressed patients as compared with controls. Importantly, we and other groups have also demonstrated an association between high inflammation and poor treatment response. Here we aimed to investigate a broader range of inflammatory genes in a group of depressed patients, who have been characterized for treatment response. Clinical data and blood samples from PaxGene tubes have been collected from 132 patients with depression (36 untreated, 60 treatment resistant and 36 treatment responsive) and from 40 healthy controls, as part of BIODEP, a multicenter study investigating immune biomarkers in depression within the NIMA Consortium. Using qPCR, we have measured mRNA levels of P2X7R and those of other genes involved in inflammation (IL-1b, TNF-alpha, MIF) and stress response (NR3C1, SGK1 and FKBP5). We have found that, compared with controls, untreated and treatment resistant patients had higher levels of P2X7R (+23% and +17%, p

The aim of the study is to investigate the effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation (mainly eicosapentaenoic acid, EPA) on clinical symptoms in youth with attention deficit hyperactivity disorder (ADHD). One hundred and five youth with a DSM-IV diagnosed ADHD were recruited from a medical centre. The youth were randomised into two groups, one group received n-3 PUFAs (1 g EPA) and the other group received placebo (1 g olive oil) for 12 weeks. The youth were assessed for their ADHD symptoms with SNAP-IV scales at baseline, weeks 2, 4, 8 and 12; ninety-eight had completed the study. Overall, there was no difference in symptom reduction between n-3 PUFAs and placebo groups. However, when we analysed the data of 29 youth with ADHD, predominantly inattentive and combined subtypes, without comorbidity such as oppositional defiant disorder, the omega-3 group ( n = 17, age 9.7 + 4.2 years) had a greater reduction in inattention subscale scores and total ADHD scores at week 8 ( p = .003, p = .006) and week 12 ( p = .029, p = .040) than placebo group ( n = 12, age 8.8 + 3.1). In conclusion, n-3 PUFAs supplementation such as EPA, improve attention in a subpopulation of youth with ADHD.

Background—Despite increasing evidence suggesting that childhood maltreatment is significantly associated with psychosis, the specific role of bullying in the onset of psychotic disorders is still unclear. This study aimed to examine whether bullying was more prevalent amongst individuals presenting to services for the first time with a psychotic disorder than in unaffected community controls. Methods—Data on exposure to bullying, psychotic symptoms, cannabis use and history of conduct disorder were collected cross-sectionally from 222 first-presentation psychosis cases and 215 geographically-matched controls. Bullying victimisation was assessed retrospectively as part of the Brief Life Events schedule. Logistic regression was used to examine associations between exposure to bullying and case-control status, while controlling for potential confounders. Results—Psychosis cases were approximately twice as likely to report bullying victimisation when compared to controls. No significant interactions between bullying and either gender or cannabis use were found. Controls reporting being a victim of bullying were approximately twice as likely to also report at least one psychosis-like symptom. Conclusions—Our results extend previous research by suggesting that bullying victimisation may contribute to vulnerability to develop a psychotic disorder in some individuals.