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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., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Recent evidence indicates that DDR1 participates in myelination and that variants of DDR1 are associated with decreased cognitive processing speed (PS) in schizophrenia (SZ). Here, we explored whether DDR1 variants were associated with PS in subjects diagnosed with an early psychosis (EP), a condition often preceding SZ. Data from two Spanish independent samples (from Reus and Santander) including patients with EP (n = 75 and n = 312, respectively) and healthy controls (HCs; n = 57 and n = 160) were analyzed. The Trail Making Test part A was used to evaluate PS. Participants underwent genotyping to identify DDR1 variants rs1264323 and rs2267641. Cross-sectional data were analyzed with general linear models and longitudinal data were analyzed using mixed models. We examined the combined rs1264323AA-rs2267641AC/CC genotypes (an SZ-risk combination) on PS. The SZ-risk combined genotypes were associated with increased PS in EP patients but not in HCs in the cross-sectional analysis. In the longitudinal analysis, the SZ-risk combined genotypes were significantly associated with increased PS in both HCs and EP patients throughout the 10-year follow-up but no genotype × time interaction was observed. These results provide further evidence that DDR1 is involved in cognition and should be replicated with other samples., Competing Interests: Declaration of conflict of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Our study aimed to explore whether stress-related hormones (hypothalamic-pituitary-adrenal [HPA] axis hormones and prolactin) are associated with poorer cognitive functioning in adolescents with attention deficit and hyperactivity disorder (ADHD) and to test the potential moderating effect of childhood maltreatment. Seventy-six adolescents with ADHD were studied. The ADHD rating scale (ADHD-RS) and Childhood Trauma Questionnaire (CTQ) were administered. Seven cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered, and two cognitive factors (attention and memory as well as executive functioning) were identified by confirmatory factor analysis. Stress-related hormone levels were assessed at the clinic (plasma prolactin and cortisol levels and salivary cortisol levels) before cognitive testing and at home for two consecutive days (cortisol awakening response [CAR] and diurnal cortisol slope). Multiple linear regression analyses were used to explore the association between hormone levels and ADHD severity or cognitive functioning while adjusting for sex and childhood maltreatment. Regarding hormonal measurements obtained at the clinic, female sex moderated the relationship between salivary cortisol levels and executive functioning, whereas childhood maltreatment moderated the relationship between salivary cortisol levels and inattention symptoms of patients with ADHD. Prolactin levels were not associated with cognitive functioning or the severity of ADHD. Regarding HPA axis measurements performed at home, lower cortisol levels at awakening were associated with poorer executive functioning. Neither CAR nor the cortisol diurnal slope were associated with cognitive functioning or ADHD severity. Our study suggests that HPA axis hormone levels are associated with the severity of cognitive and inattention symptoms of patients with ADHD and that childhood maltreatment and sex exert distinct moderating effects depending on the symptom type., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Previous studies in non-clinical populations suggest that obsessive-compulsive symptoms are associated with hypothalamic-pituitary-adrenal (HPA) axis measures and that there are sex differences in these associations. We aimed to replicate these findings in a sample of 57 patients with obsessive-compulsive disorder (OCD) and 98 healthy subjects. Current and lifetime OCD symptom dimensions were assessed with the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS). Depressive symptoms and state and trait anxiety were also assessed. The following HPA axis measures were analysed in saliva: the diurnal cortisol slope (calculated using two formulas: [1] awakening to 11 p.m. [AWE diurnal slope] and [2] considering fixed time points [FTP diurnal slope] from 10 a.m. to 11 p.m.) and the dexamethasone suppression test ratio (DSTR) after 0.25 mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of OCD symptom dimensions to each HPA axis measure while adjusting for age, sex, BMI, smoking, trait anxiety and depressive symptoms. A sex-specific association between current ordering/symmetry symptoms and AWE diurnal cortisol slope (positive association [flattened slope] in men, inverse association [stepper slope] in women) was found. Two similar sex by OCD dimensions interactions were found for lifetime aggressive and ordering/symmetry symptoms and both (FTP, AWE) diurnal cortisol slopes. Current and lifetime hoarding symptoms were associated to a more flattened FTP diurnal cortisol slope in women. The DSTR was not associated with OCD symptoms. The lifetime interference in functionality was associated with a more flattened AWE diurnal cortisol slope. In conclusion, our study suggests that there are sex differences in the association between OCD subtypes and specific HPA axis measures., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Studies evaluating leptin levels in patients with first-episode psychoses (FEP) have been inconclusive, and apparently, the high levels of leptin reported in patients with schizophrenia may be associated with weight gain. The aim of this study was to evaluate leptin levels at the early stages of the disease and the relationship between leptin and lifestyle habits, stress-related variables and metabolic parameters., Methods: In total, 14 at-risk mental state (ARMS) patients, 39 FEP patients, 32 psychotic patients in the critical period (CP) and 21 healthy controls (HCs) were assessed. Anthropometric and biochemical parameters, as well as dietary intake, physical activity, stress-related variables and symptomatology, were collected., Results: Leptin levels were higher in the ARMS, FEP and CP patients than in the HCs. After controlling for age, sex, BMI, physical exercise, tobacco use and dietary intake, the highest differences in leptin levels were observed between the ARMS patients and HCs (p = 0.025). In the whole sample, leptin levels were positively correlated with BMI (p < 0.001), waist circumference (p < 0.001), insulin levels (p = 0.020), levels of the inflammatory marker IL-6 (p = 0.007) and energy intake (p = 0.043) and negatively correlated with HDL cholesterol (p = 0.018). Interestingly, energy intake and food craving scores were positively correlated with levels of leptin only in females (p = 0.022 and p = 0.036, respectively)., Discussion: The present study detected increased leptin levels in the early stages of psychosis and significant correlations between leptin levels and anthropometric, lipid, hormone, and cytokine parameters. We found higher leptin levels in women, and we identified dietary intake habits associated with leptin exclusively in females that advocate considering sex in future studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) and obsessive-compulsive disorder (OCD) have both been linked to abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis. Polymorphisms in the genes involved in HPA axis activity, such as FKBP5, and their interactions with childhood trauma have been associated with stress-related mental disorders. Our goal was to study the role of FKBP5 genetic variants in HPA axis negative feedback regulation as a possible risk factor for different mental disorders such as MDD and OCD, while controlling for childhood trauma, anxiety and depressive symptoms. The sample included 266 participants divided into three groups: 1) MDD (n = 89 [n = 73 melancholic; n = 3 atypical]), 2) OCD (n = 51; 39% with comorbid MDD [n = 13 melancholic; n = 7 atypical]) and 3) healthy controls (n = 126). Childhood trauma, trait anxiety and depressive symptoms were assessed. HPA negative feedback was analyzed using the dexamethasone suppression test ratio (DSTR) after administration of 0.25 mg of dexamethasone. Twelve SNPs in the FKBP5 gene were selected for genotyping. Multiple linear regressions, after adjusting for the covariates considered, showed a reduced DSTR in individuals with the rs9470079-A variant that was significant after correction for multiple testing. Childhood trauma did not moderate the association between the rs9470079 and DSTR. Our results support the evidence that FKBP5 genetic variation could lead to abnormal HPA axis negative feedback independent of diagnosis. Therefore, this association can be identified as a transdiagnostic feature, offering an interesting opportunity to identify patients with higher stress vulnerability. Further studies focusing on the influence of FKBP5 on measurable biological endophenotypes are needed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Stress and inflammation are thought to play a role in the risk of developing a psychotic disorder. We aimed to identify stress-related biomarkers for psychosis transition in help-seeking individuals with an at-risk mental state (ARMS). We studied 39 ARMS subjects who were attending an Early Intervention Service. We included a control group of 44 healthy subjects (HS) matched by sex and age. Stressful life events and perceived stress were assessed. Stress-related biomarkers were determined in serum (cortisol, prolactin, C-reactive protein and albumin), plasma (fibrinogen) or saliva (morning cortisol, cortisol awakening response). All ARMS were followed-up at our Unit for at least one year. We divided the ARMS group into two subgroups based on the development of a psychotic disorder (ARMS-P, N = 10) or not (ARMS-NP, N = 29). ARMS-P reported more stressful life events and perceived stress than HS and ARMS-NP groups. In relation to baseline stress biomarkers, ARMS-P subjects had increased prolactin and lower albumin levels in serum, when compared to ARMS-NP and HS groups. These results did not change when repeated in a subsample of antipsychotic-naïve ARMS subjects. We also found significant differences between groups in the cortisol secretion after awakening. In a multinomial logistic regression adjusting for age, sex and life stress, prolactin was a predictor of psychosis transition whereas albumin levels had a protective effect. Our study underscores the role of stress and stress-related biomarkers (cortisol awakening response, prolactin and albumin) in the pathogenesis of psychosis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)