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Rationale Current psychotropic medications have been shown to modulate immune activation. However, the effects of individual psychotropic agents on the immune system and how these might contribute to their efficacy remain largely unclear. Objective This paper aims to review previous literature on the effects of antidepressants and antipsychotics on the immune system, with a systematic review of in vitro findings, and discuss the relevance of these effects for the response to treatment and future drug development. Results Inflammatory markers have been associated with fluctuations in clinical status and with treatment response both in depression and psychosis. The in vitro literature on antidepressants shows that some antidepressants, such as clomipramine and fluoxetine, more consistently decrease pro-inflammatory cytokines (interleukin (IL)-6, interferon (IFN)-γ, tumour necrosis factor (TNF)-α), whilst others (mirtazapine and venlafaxine) tend to increase their levels. However, any overall conclusion is challenged by several inconsistent findings, which appear partly dependent on different methodological approaches used. The in vitro studies on antipsychotics are even less clear-cut showing pro- and anti-inflammatory activity for the same antipsychotic agent (haloperidol, clozapine, risperidone) across different studies. We also noted inconsistencies between in vivo and in vitro literature, which could partly be attributed to the interaction in vivo with various biological systems or lifestyle factors that can modulate the immune system. Conclusions Inflammatory markers seem to hold potential for developing more individualised treatment strategies in the future. In this context, further research disentangling the differential immunomodulatory effects of different drugs could be used for tailoring treatment to specific individuals, according to their immune endophenotypes.

BackgroundMachine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness data, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between the predictions and clinical variables.Methods428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI (sMRI) session and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20484 vertices) were extracted. Supervised (linear Support Vector Machine) classification was used to differentiate FEP from HC, within a repeated nested Cross-Validation (CV) framework through the NeuroMiner software. In both inner and outer CVs, a 10-fold CV cycle was employed. We performed repeated nested CV at the outer cross-validation cycle by randomly permuting the participants within their groups (10 permutations) and repeating the CV cycle for each of these permutations. As feature preprocessing, regression of covariates (age, sex, and site), Principal Component Analysis and Scaling were applied. All preprocessing steps were implemented within the CV. Further analyses were conducted by stratifying the sample for MRI scanner, sex and by performing random resampling with increasingly reduced sample sizes.ResultsVertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy (BAC) of 66.2% and an Area Under the Curve of 72%, compared to a BAC of 59% and an Area Under the Curve of 61% obtained with the ROI-based approach. The two BACs were significantly different based on the McNemar’s Test. By stratifying our sample for MRI scanner, we increased the overall BAC to more than 70% and we also increased generalizability across sites. Temporal areas resulted the most influential regions in the classification. The predictive decision scores presented significant correlations with age at onset, duration of treatment and the presence of affective vs non-affective psychosis.DiscussionCortical thickness could represent a valid measure to classify FEP subjects, showing temporal areas as potential markers in the early stages of psychosis. The assessment of site-dependent variables allowed us to increase the across-site generalizability of the model, thus attempting to address an important machine learning limitation, especially in the framework of large multi-site cohort and big data analysis.

Background People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. Methods/design The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. Discussion The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. Trial registration ISRCTN, ISRCTN12424842 . Registered on 25 February 2015.

Negative symptoms are one of the most incapacitating features of Schizophrenia but their pathophysiology remains unclear. They have been linked to alterations in grey matter in several brain regions, but findings have been inconsistent. This may reflect the investigation of relatively small patient samples, and the confounding effects of chronic illness and exposure to antipsychotic medication. We sought to address these issues by investigating concurrently grey matter volumes (GMV) and cortical thickness (CTh) in a large sample of antipsychotic-naïve or minimally treated patients with First-Episode Schizophrenia (FES). T1-weighted structural MRI brain scans were acquired from 180 antipsychotic-naïve or minimally treated patients recruited as part of the OPTiMiSE study. The sample was stratified into subgroups with ( = 88) or without ( = 92) Prominent Negative Symptoms (PMN), based on PANSS ratings at presentation. Regional GMV and CTh in the two groups were compared using Voxel-Based Morphometry (VBM) and FreeSurfer (FS). Between-group differences were corrected for multiple comparisons via Family-Wise Error (FWE) and Monte Carlo z-field simulation respectively at < 0.05 (2-tailed). The presence of PMN symptoms was associated with larger left inferior orbitofrontal volume ( = 0.03) and greater CTh in the left lateral orbitofrontal gyrus ( = 0.007), but reduced CTh in the left superior temporal gyrus ( = 0.009). The findings highlight the role of orbitofrontal and temporal cortices in the pathogenesis of negative symptoms of Schizophrenia. As they were evident in generally untreated FEP patients, the results are unlikely to be related to effects of previous treatment or illness chronicity.

AimsTo explore the relationship between the menstrual cycle and mental health-related symptoms in women admitted as psychiatric inpatients. To explore the acceptability and feasibility of enquiry. Background: Despite the increasing global burden of mental disorder among women* of reproductive age, there has been little focus in research or clinical practice on the role of reproductive hormones in the pathogenesis, maintenance and treatment of mental disorder in women. Yet a significant proportion of women are vulnerable to fluctuations in sex hormones (for example in the premenstrual or perimenopausal periods).Methods1. 21 patients were asked a series of questions about their menstrual cycle by ward doctors, during their inpatient admission. Descriptive statistics were generated. Data from free text questions were analysed using thematic analysis.2. A focus group was facilitated by the ward occupational therapist on 1st November 2021, involving seven patients.ResultsThe project ran between November 2021 and February 2022. Mean age of respondents was 38 years and 57% (n = 12) were of Black ethnicity. 76% (n = 16) reported having a period in the last 12 months. Of these, 10 women felt their mental health changed throughout the month in relation to their menstrual cycle. Themes elicited from free text questions related to symptoms experienced during the pre-menstrual phase and included increased suicidality, anger, low mood and unusual experiences. Of the seven women who had not had a period in the last 12 months, over half (n = 4) reported menopausal symptoms. During the focus group those women who had gone through the menopause noted they had limited knowledge about it and how it may affect their mental health.With regards to feasibility of enquiry, the focus group indicated that women would like to discuss their menstrual cycle, how it can affect their mood and additional support available. However, they would prefer this took place in a one-to-one setting outside of ward round, ideally with a female doctor.ConclusionA number of female psychiatric inpatients likely experience an increase in mental health-related symptoms pre-menstrually. Enquiry about menstruation is likely to be feasible in the inpatient setting, given it is done sensitively. Such enquiry could provide opportunities to discuss areas of concern to the patient and discuss specific issues such as menopause and pre-menstrual dysphoric disorder. It could also provide data for future research and guide the development of clinical practices that recognise the relationship between the menstrual cycle and women's mental health.

Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups—a ‘lower brain volume’ subgroup (SG1) and an ‘higher striatal volume’ subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership (‘None’), and mixed SG1 + SG2 subgroups (‘Mixed’). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of ‘lower brain volume’ in SG1 and ‘higher striatal volume’ (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p  < 0.0001), with SG2 showing higher education but also greater positive psychosis symptoms at first presentation, and an association with symptom remission at 1-year, 5-year, and when timepoints were combined. Neuromorphological subtypes of schizophrenia are already evident at illness onset, separated by distinct clinical presentations, and differentially associated with subsequent remission. These results suggest that the subgroups may be underlying risk phenotypes that could be targeted in future treatment trials and are critical to consider when interpreting neuroimaging literature.

Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease - gyrus rectus - was negatively correlated with the severity of positive and negative symptoms. This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

BackgroundVitamin D is a neuro-steroid hormone important in brain development, maturation and function as it modulates the production of numerous brain growth factors. Indeed insufficient levels seem to compromise brain development and confer an increased risk of developing schizophrenia later on in life. Finally patients with first-episode psychosis tend to have lower levels of vitamin D than healthy controls. We aimed to explore: 1) The association between vitamin levels and brain structure (i.e. cortical thickness and surface area) in FEP individuals; 2) Differences in brain structure (i.e. cortical thickness and surface area) between FEP individuals with optimal and sub-optimal levels of Vitamin D.MethodsSample: 49 patients with first episode of psychosis (mean age: 27.8 SD ± 9.1 years) part of the BRC Psychosis Theme study on Genetics and Psychosis (GAP). Vitamin D: Vitamin D (serum 25-hydroxyvitamin D) levels were determined by immunoassay. Patients were considered to have sub-optimal levels if vitamin D concentration was below 20 ng/ml, with higher concentrations deemed optimal. Twenty patients had sub-optimal levels of Vitamin D whereas 29 had optimal Vitamin D concentration. Brain Structure: 3T MRI scan were used to evaluate the cortical thickness and the surface area in 49 FEP patients. FreeSurfer 5.3.0 was used to correlate Vitamin D levels with both cortical thickness and surface area in a vertex-by-vertex analysis. afterwards differences in cortical thickness and surface area between FEP participants with both optimal and sub-optimal Vitamin D levels were examined using a vertex-by-vertex General Linear Model analysis in FreeSurfer 5.3.0. Results were corrected for multiples comparison with Montecarlo simulation.ResultsVitamin D levels positively correlated with cortical thickness in the left superior-frontal gyrus and surface area in the right peri-calcarine and right inferior-parietal gyrus (all p<0.05 FWE corrected).FEP patients with sub-optimal levels of Vitamin D (below 20 ng/ml) had reduced cortical thickness in the right medial-orbitofrontal gyrus and lingual gyrus compared to those with optimal levels of Vitamin D (all p<0.05 FWE corrected). Additionally, FEP patients with sub-optimal levels of Vitamin D had smaller surface areas in the cuneus, latero-orbitofrontal gyrus, pre- and post central gyri, superio-frontal gyrus, and inferio parietal gyrus in the right hemisphere than those with optimal levels (all p<0.05 FWE corrected).DiscussionVitamin D levels are associated with reduced cortical thickness and smaller surface area in frontal, temporal, parietal and occipital brain regions in individuals with FEP. Interestingly, these areas complete their maturation well into late adolescence, thus potentially being exposed to low Vitamin D levels over a long period of time may contribute to specific brain structure in adulthood. The identification of a specific brain conformation associated to low levels of Vitamin D would promote greater understanding of the interface between physical and mental illness fostering the development of precision psychiatry.