Decreased oxytocin plasma levels and oxytocin receptor expression in borderline personality disorder.

INTRODUCTION: Borderline personality disorder (BPD) is characterized by intense affective reactions with underlying social and interpersonal cognitive deficits. Oxytocin has largely been associated with both stress regulation and social cognition in psychiatric patients and in non-clinical populations in previous studies. Finally, abnormal oxytocin levels have been preliminary reported in BPD patients. METHODS: 53 patients with moderate-severe BPD and 31 healthy control subjects were investigated for plasma levels of oxytocin and protein expression of oxytocin receptor in blood mononuclear cells. Clinical assessments were made for severity, functionality, and comorbidity with axis I and II conditions. RESULTS: Oxytocin plasma levels were significantly lower in BPD patients compared with controls. In addition, protein expression of oxytocin receptor was significantly reduced in the BPD group. A positive correlation was found between plasma oxytocin levels and the activity index score of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). Oxytocin receptor protein expression, on the contrary, had a negative correlation with the ZKPQ sociability index score. CONCLUSIONS: Results support the evidence of a dysfunction of the oxytocin system in borderline personality disorder, which could be involved in emotional dysregulation and interpersonal disturbances in these patients.

Differences in the regulation of inflammatory pathways in adolescent- and adult-onset first-episode psychosis.

A precise description of the inflammatory response in first-episode psychosis (FEP) by age of onset does not exist. We explored baseline and 6-month follow-up differences in the pro/anti-inflammatory balance in plasma and peripheral blood mononuclear cells in adolescent-onset FEP (≤ 18 y.o., N = 27) and adult-onset FEP (≥ 25 y.o., N = 43) using non-parametric 1-category ANCOVA, with age group as an independent variable and values of pro- and anti-inflammatory markers at baseline and at follow-up as dependent variables. We used a non-parametric repeated-measures mixed-effects model to explore the baseline/6-month change in pro- and anti-inflammatory markers within adolescent- and adult-onset groups, exploring differential trajectories of change by means of the interaction of time by age-of-onset group. Levels of the nuclear transcription factor (NFκB), a master regulator of the inflammatory and oxido/nitrosative status of cells, were higher in adolescent-onset FEP both at baseline and after 6 months. During follow-up, we found further increases in levels of soluble inflammatory markers (PGE2 and NO2-) only in adolescent-onset FEP. In contrast, in adult-onset FEP, the expression of inducible NO synthase (iNOS), which is also pro-inflammatory, tended to decrease, with no further increase in other pro-inflammatory markers. Significant differences in the direction of change by age-of-onset cohort exist only for NFκB (F = 4.165, df = 2, 70.95, p = 0.019). Our results support the existence of changes in the pro/anti-inflammatory balance in FEP depending on the neurodevelopmental stage at illness onset. These results also suggest that inflammation may be a potential therapeutic target in adolescent-onset FEP.

Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress.

BACKGROUND: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. METHODS: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. RESULTS: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. CONCLUSIONS: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies.

Transdiagnostic inflammatory and oxidative biomarkers with predictive capacity of self-injurious behavior in impulsive and unstable disorders.

INTRODUCTION: Alterations in inflammatory processes have previously been reported in impulsive and unstable disorders, as well as in other psychiatric conditions. In order to investigate transdiagnostic biomarkers associated with various phenotypic features of these disorders, this study is designed to identify biomarkers of inflammatory and oxidative endophenotypes related to autolytic behavior. METHODS: Peripheral blood mononuclear cells were collected from 35 patients with borderline personality disorder (BPD), 29 patients with restrictive eating disorder (rED), 21 patients with purging eating disorder (pED) and 23 control subjects. Plasma levels of different inflammatory and oxidative factors were measured by ELISA and the expression of selected proteins was by Western Blot. Principal component analysis (PCA) was performed to categorize the different inflammatory factors. Additionally, Ancova was performed to observe the differences in the principal components among the different groups and logistic regression analysis was conducted to assess the predictive capacity of these components for autolytic behaviors. RESULTS: We found two inflammatory/oxidative components were associated with BPD, characterized by high levels of JNK and ERK and low levels of GPx, SOD and Keap1; and two other inflammatory/oxidative components were linked to pED, associated with more JNK, TBARS and TNF-α and less GPx and SOD. Two components, with more JNK and ERK and less GPx, SOD and Keap1, predicted non-suicidal self-injury and three components, with higher JNK, TBARS and TNF-α levels and lower GPx, SOD and iNOS levels, predicted suicide attempts. CONCLUSIONS: These results strongly support the endophenotypic characterization of impulsivity and the identification of transdiagnostic inflammatory/oxidative biomarkers relevant to autolytic behavior in impulsive and unstable disorders. These dates lay the groundwork for developing of screening tests for these biomarker components to rapidly detect biological risk factors for specific impulse control disorders and future self-injurious behaviors.

Decreased oxytocin plasma levels and oxytocin receptor expression associated with aggressive behavior in aggressive-impulsive disorders.

INTRODUCTION: This study aims to enhance the understanding of the association between the phenotypic and endophenotypic characteristics of impulsive-aggressive disorders, through the study of plasma oxytocin (OXT) and oxytocin receptor (OXTR) levels in patients with borderline personality disorder (BPD) and patients with eating disorders (ED), as well as to examine the relationship of OXT system with aggressive behavior in these disorders. METHODS: 68 patients with BPD, 67 patients with ED and 57 healthy control subjects were examined for plasma oxytocin levels and protein expression of OXTR in blood mononuclear cells. Aggressive behavior was assessed using the State-Trait Anger Expression Inventory (STAXI-2). Other self and hetero-aggressive behaviors were also evaluated through interviews. RESULTS: BPD and ED patients exhibited significantly lower plasma oxytocin levels than control subjects. Furthermore, BPD patients demonstrated significantly reduced expression of OXTR compared to controls. Plasma oxytocin levels negatively correlated with verbal aggression, while OXTR expression was inversely associated with the STAXI trait subscale. CONCLUSIONS: The findings validate the existence of oxytocin system dysfunction in impulsive-aggressive disorders. They also support the link between low OXT levels in plasma and OXTR expression and the impulsive-aggressive behavior that characterizes these patients in both state and trait situations.

Neuroimaging revealed long-lasting glucose metabolism changes to morphine withdrawal in rats pretreated with the cannabinoid agonist CP-55,940 during periadolescence.

This study evaluates the long-term effects of a six and 14-week morphine withdrawal in rats pretreated with a cannabinoid agonist (CP-55,940, CP) during periadolescence. Wistar rats (33 males; 32 females) were treated with CP or its vehicle (VH) from postnatal day (PND) 28-38. At PND100, rats performed morphine self-administration (MSA, 15d/12 h/session). Eight groups were defined according to pretreatment (CP), treatment (morphine), and sex. Three [18F]FDG-PET brain images were acquired: after MSA, and after six and 14 weeks of withdrawal. PET data were analyzed with SPM12. Endocannabinoid (EC) markers were evaluated in frozen brain tissue at endpoint. Females showed a higher mean number of self-injections than males. A main Sex effect on global brain metabolism was found. FDG uptake in males was discrete, whereas females showed greater brain metabolism changes mainly in areas of the limbic system after morphine treatment. Moreover, the morphine-induced metabolic pattern in females was exacerbated when CP was previously present. In addition, the CP-Saline male group showed reduced CB1R, MAGL expression, and NAPE/FAAH ratio compared to the control group, and morphine was able to reverse CB1R and MAGL expression almost to control levels. In conclusion, females showed greater and longer-lasting metabolic changes after morphine withdrawal than males, indicating a higher vulnerability and a different sensitivity to morphine in subjects pre-exposed to CP. In contrast, males primarily showed changes in EC markers. Together, our results suggest that CP pre-exposure contributes to the modulation of brain metabolism and EC systems in a sex-dependent manner.

Inflammatory and oxidative endophenotypes in borderline personality disorder: A biomarker cluster analysis.

OBJECTIVES: This study is designed to search for aggrupation of inflammatory/oxidative biomarker alterations in borderline personality disorder (BPD) and their association with phenotypic features. METHODOLOGY: Inflammatory/nitrosative proteins were measures in plasma and peripheral blood mononuclear cells obtained from BPD patients. Patients were assessed on different clinical dimensions of BPD. Oxidative damage was tested by measuring TBARS, nitrites, catalase, GPx and SOD. Protein expression of IκBα, NFκB, iNOS, COX-2, PPARγ, Keap1, NQO1, Nrf2 and α7nAChR was also determined. Western blot and ELISA were used for measurements and a cluster analysis of inflammatory/oxidative biomarkers alterations was performed to investigate subgroups of patients with similar alterations and its relationship with clinical features of BPD. RESULTS: 69 patients were included in the study. Two inflammatory/nitrosative clusters of patients were found: Cluster 1 patients showed significantly higher levels of GPx, IκBα, keap1, NQO1, PPARγ, α7nAChR and Nrf2 than cluster 2 patients. These patients had significantly longer duration of illness, milder anxiety symptoms and lower prescription of antipsychotic drugs than cluster 2. CONCLUSIONS: Two clusters of BPD patients according to the inflammatory/nitrosative profiles were identified. Cluster 1 had increased antioxidant and anti-inflammatory biomarkers and was characterised by greater chronicity of illness but less acute symptomatic severity.

BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year.

Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs.