Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Gradual Increase in Inflammation-Linked Glycoproteins and a Proatherogenic Lipoprotein Profile in the Early Stages of Psychosis as Characterized by 1H NMR Blood Analysis.

Minimally invasive prognostic markers of inflammation and dyslipidemia in individuals with a risk of psychosis, also called "at-risk mental state" (ARMS), or in the first episode of psychosis (FEP) are of utmost clinical importance to prevent cardiovascular disorders. We analyzed the plasma concentration of inflammation-linked glycoproteins (Glycs) and lipoprotein subclasses by proton nuclear magnetic resonance (1H NMR) in a single acquisition. Study participants were healthy controls (HCs, N = 67) and patients with ARMS (N = 58), FEP (N = 110), or early psychosis diagnosis with ≥2 episodes (critical period (CP), N = 53). Clinical biomarkers such as high-sensitivity C-reactive protein, interleukin 6, fibrinogen, insulin, and lipoproteins were also measured. Although all participants had normal lipoprotein profiles and no inflammation according to conventional biomarkers, a gradual increase in the Glyc 1H NMR levels was observed from HCs to CP patients; this increase was statistically significant for GlycA (CP vs HC). In parallel, a progressive and significant proatherogenic 1H NMR lipoprotein profile was also identified across stages of psychosis (ARMS and CP vs HC). These findings highlight the potential of using 1H NMR Glyc and lipoprotein profiling to identify blood changes in individuals with ARMS or FEP and pave the way for applications using this technology to monitor metabolic and cardiovascular risks in clinical psychiatry.

The relationship between sex, personality traits, and the hypothalamic-pituitary-adrenocortical axis.

The aim of our study was to examine whether there are sex-based differences in the relationship between personality traits and hypothalamic-pituitary-adrenal (HPA) axis measures. A total of 106 healthy volunteers (56.6% women; age: 48.0 ± 15.8 years) were studied. The revised temperament and character inventory (TCI-R) and the Childhood Trauma Questionnaire (CTQ) were administered. HPA axis function was assessed using three dynamic measures: the cortisol awakening response (CAR), the diurnal cortisol slope, and the cortisol suppression ratio with 0.25 mg of dexamethasone (DSTR). Female sex was associated with an increased CAR and a more flattened diurnal cortisol slope, although a negative significant interaction between harm avoidance and female sex was found. Regarding the DSTR, perseverance was associated with increased cortisol suppression after dexamethasone; sex did not affect this association. Our study suggests that the relationship between specific personality traits (harm avoidance) and HPA axis measures (CAR, diurnal slope) differs according to sex.

Sleep disturbances in obsessive-compulsive disorder: influence of depression symptoms and trait anxiety.

BACKGROUND: Sleep disturbances have been reported in obsessive-compulsive disorder (OCD) patients, with heterogeneous results. The aim of our study was to assess sleep function in OCD and to investigate the relationship between sleep and the severity of obsessive-compulsive (OC) symptoms, depressive symptoms and trait anxiety. METHODS: Sleep quality was measured in 61 OCD patients and 100 healthy controls (HCs) using the Pittsburgh Sleep Quality Index (PSQI). Multiple linear regression was conducted to explore the association between sleep and psychopathological measures; a mediation analysis was also performed. RESULTS: OCD patients showed poor sleep quality and more sleep disturbances compared to HCs. The severity of depression, trait anxiety and OC symptomatology were correlated with poor sleep quality. Multiple linear regression analyses controlling for potential confounders revealed that the severity of depression and trait anxiety were independently related to poor sleep quality in OCD. A mediation analysis showed that both the severity of trait anxiety and depression mediate the relationship between the severity of OC symptoms and poor sleep quality among patients with OCD. CONCLUSIONS: Our findings support the existence of sleep disturbances in OCD. Trait anxiety and depression play a key role in sleep quality among OCD patients.

Acute exposure of rats to a severe stressor alters the circadian pattern of corticosterone and sensitizes to a novel stressor: Relationship to pre-stress individual differences in resting corticosterone levels.

Traumatic events have been proposed to be associated with hypo-activity of the hypothalamic-pituitary-adrenal (HPA) axis, but data in animal models exposed to severe stressors are controversial and have important methodological concerns. Individual differences in resting or stress levels of corticosterone might explain some of the inconsistencies. We then studied this issue in male rats exposed to 2 h immobilization on boards (IMO), a severe stressor. Thirty-six rats were blood sampled under resting conditions four times a day on three non-consecutive days. Then, they were assigned to control (n = 14) or IMO (n = 22) to study the HPA response to IMO, the stressor-induced alterations in the circadian pattern of corticosterone (CPCORT), and the behavioral and HPA responsiveness to an open-field. Individual differences in pre-IMO resting corticosterone were inconsistent, but averaging data markedly improved consistency. The CPCORT was markedly altered on day 1 post-IMO (higher trough and lower peak levels), less altered on day 3 and apparently normal on day 7. Importantly, when rats were classified in low and high resting corticosterone groups (LCORT and HCORT, respectively), on the basis of the area under the curve (AUC) of the averaged pre-IMO data, AUC differences between LCORT and HCORT groups were maintained in controls but disappeared in IMO rats during the post-IMO week. Open-field hypo-activity and corticosterone sensitization were similar in LCORT and HCORT groups nine days after IMO. A single IMO exposure causes long-lasting HPA alterations, some of them dependent on pre-stress resting corticosterone levels, with no evidence for post-IMO resting corticosterone hypo-activity.

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.

We assessed the utility of raloxifene (60 mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight began the clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann-Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60 mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect.ClinicalTrials.gov Identifier: NCT01573637.

Exploring the relationship of insight with psychopathology and gender in individuals with schizophrenia spectrum disorders with structural equation modelling.

To model the influence of psychopathology on insight deficits in schizophrenia spectrum patients with a gender-stratified analysis. Five hundred sixteen patients (65.1% men) with schizophrenia spectrum disorders were evaluated in four centres of the metropolitan area of Barcelona (Catalonia). Psychopathological assessment was performed using different PANSS factors. Insight and its three main dimensions were assessed by means of the Scale of Unawareness of Mental Disorder: awareness of the disease (SUMD-1), of the effect of medication (SUMD-2) and of the social consequences of the disease (SUMD-3). Structural equation models (SEMs) were used to fix the model in the total sample and by gender. Additional analyses included age, duration of illness (DOI) and education status (ES). There were no significant differences between men and women in the three main dimensions of insight. The SEMs in the total sample showed a modest fitting capacity. Fitting improved after a gender-stratified analysis (particularly in women). In men, positive and excited symptoms were associated with poorer insight in all SUMD dimensions, whereas depressive symptoms were associated with better insight. ES in men was also associated with better SUMD-2 or SUMD-3. In contrast, in women, symptoms did not have a negative effect on SUMD-1 or SUMD-2. However, positive symptoms were associated with a poorer SUMD-3, whereas depressive symptoms were associated with better SUMD-3. Moreover, education level was also associated with a better SUMD-3. A gender approach improved the comprehension of the model, supporting the relevance of gender analysis in the study of insight.

Plasma prolactin levels are associated with the severity of illness in drug-naive first-episode psychosis female patients.

Patients with schizophrenia frequently present hyperprolactinemia as a consequence of antipsychotic treatment. However, an increase in circulating prolactin levels has also been shown in patients without previous treatment. Our objective was to compare prolactin levels between antipsychotic-naive first-episode psychosis (AN-FEP) patients and healthy controls (HC). As part of an FEP program (Programa Asistencial Fases Iniciales de Psicosis [PAFIP]), 270 AN-FEP patients and 153 HC were eligible for this study. Serum prolactin levels were measured by an automated immunochemiluminescent assay. Subjects' sex and having an AN-FEP diagnosis both had an effect on prolactin levels, with higher levels in women than in men, and in AN-FEP patients than in HC. Moreover, plasma prolactin levels showed a negative correlation with the SAPS scores in AN-FEP female patients. AN-FEP patients have increased levels of prolactin, which might be stress-induced. This, together with the association of higher prolactin with a lower severity of the disease, suggests that prolactin might play a neuroprotective role, especially in women.

Sex differences in the relationship between prolactin levels and impaired processing speed in early psychosis.

INTRODUCTION: Hyperprolactinaemia is commonly observed in people with psychotic disorders due to D2 receptor blockade by antipsychotic drugs, although it may also exist in drug-naïve patients with first-episode psychosis. Recent studies suggest that hyperprolactinaemia may have a negative impact on cognitive function in people with early psychosis. We aimed to explore whether there are sex differences in the association between prolactin levels and cognitive performance in early psychosis patients. METHODS: We studied 60 young patients with early psychosis (aged 18-35 years, 35% females) and a sex- and age-matched control group of 50 healthy subjects. Cognitive assessment was performed with the MATRICS Consensus Cognitive Battery. Prolactin, total cortisol, follicular-stimulating hormone, luteal hormone and sex steroids (testosterone in men, oestradiol and progesterone in women) were measured in plasma. Salivary cortisol was measured at different sampling times (awakening response, 10:00 and 23:00). Psychopathological status was assessed, and antipsychotic treatment was registered. Multiple linear regression analyses were used to explore the relationship between prolactin and cognitive tasks while adjusting for covariates. RESULTS: Prolactin levels were associated with impaired processing speed in men, and this association was independent of cortisol and testosterone. In women, prolactin levels were not associated with processing speed tasks, although we observed a negative effect of prolactin on verbal learning and spatial working memory in female healthy subjects. The male-dependent effect maintained its significance after adjusting for education status, antipsychotic treatment and negative symptoms. CONCLUSION: Our study demonstrates that the previously reported association between high prolactin levels and impaired cognitive processes in early psychosis is restricted to men.

Factor Structure of the Spanish Version of the Edinburgh Postnatal Depression Scale.

INTRODUCTION: The Edinburgh Postnatal Depression Scale (EPDS) is considered the gold standard in screening for postpartum depression. Although the Spanish version has been widely used, its factorial structure has not yet been studied . METHODS: A total of 1,204 women completed the EPDS 32 weeks after delivery. To avoid multiple testing, we split the sample into two halves, randomly drawing two subsamples of 602 participants each. We conducted exploratory factor analysis (EFA), followed by an oblimin rotation with the first sub-sample. Confirmatory factor analysis (CFA) was conducted using a Weighted Least Squares Means and Variance (WLSMV) estimation of the data. We explored different solutions between two and four factors. We compared the factors between two groups with depression and non-depression (evaluated with the Diagnostic Interview for Genetic Studies (DIGS) for the DSM-IV). RESULTS: The EFA indicated a three-factor model consisting of anxiety, depression and anhedonia. The results of the CFA confirmed the three-factor model (χ2=99.203, p<0.001; RMSEA=0.06, 90% CI=0.04/0.07, CFI=0.87 and TLI=0.82). Women with depression in the first 32 weeks obtained higher scores for anxiety, depression and anhedonia dimensions (p<0.001). CONCLUSIONS: This is the first study of confirmatory analysis with the Spanish version of EPDS in a large sample of women without psychiatric care during pregnancy. A three-factor model consisting of anxiety, depression and anhedonia was used. Women with depression had a higher score in the three dimensions of the EPDS.

Sex differences in the effect of childhood trauma on the clinical expression of early psychosis.

Childhood trauma, a risk factor of psychosis, is associated the clinical expression of the illness (greater severity of psychotic symptoms; poorer cognitive performance). We aimed to explore whether there are sex differences in this relationship. We studied 79 individuals with a psychotic disorder (PD) with <3years of illness and 59 healthy subjects (HS). All participants were administered the MATRICS Cognitive Consensus Cognitive Battery (MCCB) to assess cognition. Depressive, positive and negative psychotic symptoms, and global functioning were also assessed. History of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Patients reported a greater history of childhood trauma on all CTQ domains (emotional, physical and sexual abuse, and physical and emotional neglect). A poorer cognitive performance was also observed in PD when compared to HS. No sex differences were found in the CTQ scores. In the relationship between childhood trauma and psychopathological symptoms, significant correlations were found between CTQ scores and positive and negative psychotic symptoms, depressive symptoms and poorer functionality, but only in women. Childhood trauma was associated with poorer social cognition in both men and women. Of all CTQ dimensions, emotional neglect and physical neglect were more clearly associated with a more severe psychopathological and cognitive profile. Our results suggest that childhood trauma, particularly emotional and physical neglect, is associated with the clinical expression of psychosis and that there are sex differences in this relationship.

Coping strategies for postpartum depression: a multi-centric study of 1626 women.

The transition to motherhood is stressful as it requires several important changes in family dynamics, finances, and working life, along with physical and psychological adjustments. This study aimed at determining whether some forms of coping might predict postpartum depressive symptomatology. A total of 1626 pregnant women participated in a multi-centric longitudinal study. Different evaluations were performed 8 and 32 weeks after delivery. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the structured Diagnostic Interview for Genetic Studies (DIGS). The brief Coping Orientation for Problem Experiences (COPE) scale was used to measure coping strategies 2-3 days postpartum. Some coping strategies differentiate between women with and without postpartum depression. A logistic regression analysis was used to explore the relationships between the predictors of coping strategies and major depression (according to DSM-IV criteria). In this model, the predictor variables during the first 32 weeks were self-distraction (OR 1.18, 95 % CI 1.04-1.33), substance use (OR 0.58, 95 % CI 0.35-0.97), and self-blame (OR 1.18, 95 % CI 1.04-1.34). In healthy women with no psychiatric history, some passive coping strategies, both cognitive and behavioral, are predictors of depressive symptoms and postpartum depression and help differentiate between patients with and without depression.

Brain structural imaging correlates of olfactory dysfunction in obsessive-compulsive disorder.

Olfactory dysfunction has been described in obsessive-compulsive disorder (OCD). Brain regions involved in smell processing partially overlap with structures included in the neurobiological models of OCD, although no previous studies have analyzed the neuroanatomical correlates of olfactory dysfunction in this disorder. The aim of our study was to examine the association between regional gray matter volume, as assessed by a voxel-based morphometry analysis of magnetic resonance images (MRI), and olfactory function, as assessed by the Sniffin' Sticks test (SST). Olfactory function was assessed in 19 OCD patients and 19 healthy volunteers. All participants were also scanned in a 1.5-T magnet to obtain T1-weighted anatomical MRIs, which were pre-processed and analyzed with SPM8. Three different correlation models were used to study the association between regional gray matter volumes and olfactory function in the domains assessed by the SST: detection threshold, discrimination, and identification. OCD patients showed a significant impairment in all the domains assessed by the SST. Voxel-based mapping revealed a positive association in healthy controls between detection threshold and the gray matter content of a left anterior cingulate cortex cluster. In OCD patients, a positive correlation was observed between identification errors and the gray matter volume of the left medial orbital gyrus. In a post hoc analysis, these two gray matter regions were shown to be enlarged in OCD patients. Our findings support the idea that olfactory dysfunction in OCD is associated with volumetric changes in brain areas typically implicated in the neurobiology of the disorder.

The Translational Future of Stress Neurobiology and Psychosis Vulnerability: A Review of the Evidence.

Psychosocial stress is a well-established risk factor for psychosis, yet the neurobiological mechanisms underlying this relationship have yet to be fully elucidated. Much of the research in this field has investigated hypothalamic-pituitary-adrenal (HPA) axis function and immuno-inflammatory processes among individuals with established psychotic disorders. However, as such studies are limited in their ability to provide knowledge that can be used to develop preventative interventions, it is important to shift the focus to individuals with increased vulnerability for psychosis (i.e., high-risk groups). In the present article, we provide an overview of the current methods for identifying individuals at high-risk for psychosis and review the psychosocial stressors that have been most consistently associated with psychosis risk. We then describe a network of interacting physiological systems that are hypothesised to mediate the relationship between psychosocial stress and the manifestation of psychotic illness and critically review evidence that abnormalities within these systems characterise highrisk populations. We found that studies of high-risk groups have yielded highly variable findings, likely due to (i) the heterogeneity both within and across high-risk samples, (ii) the diversity of psychosocial stressors implicated in psychosis, and (iii) that most studies examine single markers of isolated neurobiological systems. We propose that to move the field forward, we require well-designed, largescale translational studies that integrate multi-domain, putative stress-related biomarkers to determine their prognostic value in high-risk samples. We advocate that such investigations are highly warranted, given that psychosocial stress is undoubtedly a relevant risk factor for psychotic disorders.

Prenatal immune activation in rats and adult exposure to inescapable shocks reveal sex-dependent effects on fear conditioning that might be relevant for schizophrenia.

Prenatal infection is considered a relevant factor for neurodevelopmental alterations and psychiatric diseases. Administration of bacterial and viral components during pregnancy in rodents results in maternal immune activation (MIA), leading to schizophrenia-like neurochemical and behavioral changes. Despite some evidence for abnormal fear conditioning in schizophrenia, only a few animal studies have focused on this issue. Therefore, we addressed the impact of the administration of the viral mimetic polyI:C to pregnant Long-Evans rats on the adult offspring response to inescapable shocks (IS) and contextual fear conditioning. In males, polyI:C induced a greater endocrine (plasma ACTH) response to IS and both polyI:C and IS enhanced fear conditioning and generalization to a completely different novel environment (hole-board), with no additive effects, probably due to a ceiling effect. In contrast, a modest impact of polyI:C and a lower impact of IS on contextual fear conditioning and generalization was observed in females. Thus, the present results demonstrate that polyI:C dramatically affected fear response to IS in adult males and support the hypothesis that males are more sensitive than females to this treatment. This model might allow to explore neurobiological mechanisms underlying abnormal responsiveness to fear conditioning and stressors in schizophrenia.

Lymphocyte-derived and lipoprotein-derived inflammatory ratios as biomarkers in bipolar disorder type I: Characteristics, predictive values, and influence of current psychopharmacological treatments.

PURPOSE OF THIS RESEARCH: The purpose of this research was to investigate peripheral inflammation by analyzing lymphocyte and lipoprotein-derived inflammatory ratios in patients with bipolar disorder type I (BD-I) and healthy controls (HCs), considering mood stabilizer drug treatments, sex and clinical trajectories. METHODS: This was a cross-sectional case-control study of BD-I patients (n=252) and healthy controls (n=62). We investigated peripheral inflammation biomarkers through blood count values (CBCs), lipoproteins and a complex panel of inflammatory ratios, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-HDL ratio (NHR), monocyte-to-HDL ratio (MHR), platelet-to-HDL ratio (PHR) and lymphocyte-to-HDL ratio (LHR). Furthermore, we examined the effects of sex, drug treatment and clinical outcome on the inflammatory profile. RESULTS: We found that the monocyte-to-lymphocyte ratio (MLR) and lipoprotein-derived inflammatory ratio (NHR, MHR, PHR, and LHR) were significantly greater in BD-I patients than in control individuals. The monocyte-to-HDL ratio (MHR) showed acceptable accuracy as a disease predictor. Logistic regression analysis adjusted for sex, age and BMI indicated that the risk of having a BD-I diagnosis was greater for participants with MHR levels in quartiles 3 (OR= 5.2, p=0.001) and 4 (OR=13, p<0.001). There was a strong association between lithium treatment and increased inflammation represented by elevated lymphocyte-derived inflammatory ratios (NLR, MLR, PLR, SII, and SIRI) in lithium-treated BD-I patients compared to those in lithium-free or lithium treatment-naïve BD-I patients. The main limitations are the cross-sectional nature of the study and limited sample size of HCs. MAJOR CONCLUSIONS: Several CBCs, lipoproteins, and a complex panel of inflammatory ratios, including lymphocyte-derived inflammatory ratios (NLR, MLR, PLR, SII, and SIRI) and lipoprotein-derived inflammatory ratios (NHR, MHR, PHR, and LHR), are altered in individuals diagnosed with BD-I. The monocyte-to-HDL ratio (MHR) emerged as a disease predictor in our BD-I sample. A remarkable finding is the association of lithium and valproate treatment with the inflammatory state. Considering the study limitations, our results underscore the importance of pharmacological treatments when researching inflammation markers in mood disorders. Lymphocyte-derived and lipoprotein-derived inflammatory ratios are easy-to-implement and relevant biomarkers in BD-I patients.

Corrigendum: Psychosocial stress moderates the relationship between cerebrospinal fluid lactate dehydrogenase and the duration of untreated psychosis in first-episode psychosis.

[This corrects the article DOI: 10.3389/fpsyt.2024.1327928.].

Psychosocial stress moderates the relationship between cerebrospinal fluid lactate dehydrogenase and the duration of untreated psychosis in first-episode psychosis.

Introduction: Previous research has shown that lower lactate dehydrogenase (LDH) concentrations in cerebrospinal fluid (CSF) are associated with longer prodromal symptoms in first-episode psychosis (FEP). We aimed to study whether there is a relationship between the duration of untreated psychosis (DUP) and LDH and other CSF biomarkers in FEP and whether stressful life events moderate this association. Methods: Ninety-five inpatients with FEP and with less than 6 weeks of antipsychotic treatment were included in the study. All participants were informed about the nature of the study, which was approved by the local ethics committee, and signed an informed consent form. A lumbar puncture was performed at index admission (baseline) to measure CSF parameters (glucose, total protein, LDH). The DUP was assessed with the Quick Psychosis Onset and Prodromal Symptoms Inventory (Q-POPSI). Stressful life events (SLEs) in the previous 6 months were assessed with the List of Threatening Experiences. We dichotomized the SLE variable into having experienced at least one SLE or no experience of SLEs. Statistical analyses were performed with SPSS v. 25.0. Total protein and LDH concentrations were natural log transformed (ln) to reduce skewness. Multiple linear regression analyses were conducted to explore the association between the DUP and CSF parameters (considered the dependent variable). Age, sex, DUP and SLEs were considered independent variables. We tested the DUP by SLE interaction. Significant interactions were included in the final model. The threshold for significance was set at p<0.05. Results: Fifty-four FEP patients (56.8%) reported an SLE in the previous 6 months. There were no significant differences in the DUP between patients with or without SLEs. There were no significant differences in CSF biomarkers between the SLE groups. In the multiple linear regression analyses, we found a significant DUP by SLE interaction effect on CSF LDH concentrations (standardized beta= -0.320, t= -2.084, p= 0.040). In patients with SLEs, a shorter DUP was associated with higher CSF LDH concentrations and vice versa. No significant associations were found between the DUP or SLEs and other CSF biomarkers (glucose, total proteins). Conclusions: Our study suggests that psychosocial stress moderates the relationship between the onset of psychosis and CSF biomarkers related to bioenergetic systems.

High blood levels of brain-derived neurotrophic factor (BDNF) mRNA in early psychosis are associated with inflammatory markers.

The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism (SNP) rs6265C > T, Val66Met, affects BDNF secretion and has been related to inflammatory processes. Both the rs6265 and BDNF protein levels have been widely investigated in neuropsychiatric disorders with conflicting results. In the present study we examined BDNF mRNA expression in blood considering the SNP rs6265 and its relationship with inflammatory markers in the early stages of psychosis. The rs6265 genotype and blood BDNF mRNA levels were measured in 34 at-risk mental states (ARMS) individuals, 37 patients with first-episode psychosis (FEP) and 42 healthy controls (HCs) by quantitative PCR and reverse transcription (RT)-qPCR using validated TaqMan assays. We also obtained measures of interleukin-6 (IL6) mRNA levels, fibrinogen, neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein. We identified that BDNF mRNA levels were associated with the rs6265 genotype in an allele-dose-dependent manner, with low expression levels associated with the T allele (Met substitution). Thus, we controlled for the rs6265 genotype in all analyses. Blood BDNF mRNA levels differed between diagnostic groups: patients with FEP exhibited higher blood BDNF mRNA levels than ARMS individuals, and the lowest levels were observed in HC. In addition, we observed significant correlations between BDNF mRNA levels and inflammatory markers (IL6 mRNA levels and NLR), controlled by the rs6265 genotype, in ARMS and FEP groups. This exploratory study suggests that the rs6265 genotype is associated with differential blood mRNA expression of BDNF that increases with illness progression and correlated with inflammation in the early stages of psychosis.