I don't understand how I feel: mediating role of impaired self-mentalizing in the relationship between childhood adversity and psychosis spectrum experiences.

Introduction: Childhood adversity is associated with the severity of multiple dimensions of psychosis, but the mechanisms underpinning the close link between the two constructs is unclear. Mentalization may underlie this relationship, as impaired mentalizing is found in various stages of the psychosis continuum. Nonetheless, the differential roles of self- and other-mentalizing in psychosis are not well understood. Methods: Parallel multiple mediation was conducted for the relationship between a diverse range of childhood adversity types, including intentional and nonintentional harm, and schizotypy (positive, negative, disorganized), psychotic-like experiences (PLE) and paranoia via self-mentalizing (attention to emotions and emotional clarity) and other-mentalizing in n = 1,156 nonclinically ascertained young adults. Results: Significant parallel multiple mediation models were found for all psychotic outcomes except negative schizotypy. The associations between intentionally harmful childhood adversity and psychotic outcomes were significantly mediated by increased attention to emotions for most models and decreased emotional clarity for some models. No significant mediation was found for parental loss. Paternal abuse was only mediated by attention to emotions whereas the effects of maternal abuse were mediated by attention to emotions and emotional clarity. Other-mentalizing only showed mediating effects on one of thirty models tested. Conclusion: Results highlight the mediating role of impaired self-mentalizing in the association between childhood adversity and psychosis. This is consistent with disturbances of self-concept and self-boundary characterizing, in particular, the positive dimension of psychosis. Maternal versus paternal figures may contribute differentially to the development of mentalizing. These results could inform future preventative interventions, focusing on the development and maintenance of self-mentalizing.

Atypical antipsychotics attenuate MK801-induced social withdrawal and hyperlocomotion in the RHA rat model of schizophrenia-relevant features.

RATIONALE: The administration of NMDA receptor (NMDAR) antagonists constitutes a widely used model that produce both positive (e.g., hyperactivity) and negative (e.g., social withdrawal) symptoms relevant for schizophrenia in rodents. These effects can be reversed with the administration of atypical (second and third generation) antipsychotics. OBJECTIVES: In this study we combined the NMDAR-antagonist model with the Roman High-Avoidance (RHA) strain, a psychogenetically selected model of schizophrenia-relevant features. We also studied whether some atypical antipsychotic drugs (clozapine, ziprasidone, and aripiprazole) would be able to attenuate or reverse the behavioural alterations induced by MK801 and whether such effects might be dependent on the rat strain. METHODS: MK801 dose-response study was conducted in RHA and Roman Low-Avoidance (RLA) male rats. After that, the 0.15 mg/kg MK801 dose was selected to carry out pharmacological studies versus atypical antipsychotics. RESULTS: In the first experiment we establish that MK801 (dizocilpine), a NMDAR antagonist, produces dose-related hyperactivity and social withdrawal, which are more marked in RHA than RLA rats. The administration of the atypical antipsychotics clozapine (2.5 mg/kg) or ziprasidone (2.5 mg/kg) partially reversed or attenuated some of the social behaviour deficits and hyperactivity induced by the administration of MK801. Aripiprazole (3 mg/kg), a third-generation antipsychotic, reversed or attenuated the social preference deficit, the hyperactivity and the impairment of social latency induced by MK801. CONCLUSIONS: These results seem to be in line with previous studies with the NMDAR-antagonist model and add face (MK801-induced social withdrawal and hyperactivity) and predictive (attenuation of MK801-induced effects by atypical antipsychotics) validity to the RHA rat strain as a model of schizophrenia-relevant features.

The moderating role of hair cortisol in the association of early and recent stress with stress-related phenotypes.

Background: Increased hair cortisol concentrations (HCC) have been found in clinical samples of schizophrenia, first episode psychosis and clinical risk for psychosis, but evidence of such is scarce in schizotypy. High HCC are supposed to reflect elevated chronic stress. However, HCC were not directly associated with adversity measures and stress-related phenotypes in previous research. This study tested whether HCC moderated the association between a comprehensive range of psychosocial stressors with several stress-related phenotypes in a sample of nonclinical young adults. It was expected that stressors, either distal (i.e., early-life) or recent, would be associated with subclinical features, particularly for those with elevated HCC, reflecting the effects of a potential biological sensitization to stress. Methods: The sample comprised 132 nonclinical young adults belonging to the Barcelona Longitudinal Investigation of Schizotypy Study (BLISS). Participants completed a questionnaire of childhood adversity and two complementary measures of recent life events, tapping threatening vs. more general life events. Both the frequency and subjective impact (positive vs. negative) of general life events were also assessed. Psychotic (i.e., schizotypy, suspiciousness) and non-psychotic (i.e., depression, anxiety) subclinical features as well as appraisals of perceived stress were examined. Hierarchical linear regressions and simple slope analyses were computed. Results: HCC moderated the effects of both early and recent stress on suspiciousness as well as the effects of recent life events on perceived stress, such that those with higher HCC presented increased suspiciousness and perceived stress at higher levels of stress exposure. Positive, but not negative, recent life events were associated with decreased perceived stress and depression, and these associations were moderated by low HCC, indicating a buffering effect for those with a non-impaired HPA axis. Conclusion: In line with the neural diathesis-stress model, results highlight the role of the interplay between the HPA axis and exposure to stressful experiences in exacerbating psychosis features and extend evidence to the nonclinical expression of the psychosis continuum. In addition, findings support the protective effect of positive experiences in decreasing stress appraisals and affective disturbances, which is consistent with emerging research about the relevance of positive factors in reducing the likelihood of psychopathological outcomes.

Schizophrenia polygenic risk score in psychosis proneness.

Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in the general population often broadly referred to as schizotypy. However, it is still poorly understood how these traits overlap genetically with the disorder. We investigated whether polygenic risk for SZ is associated with these disorder-related phenotypes (schizotypy, psychotic-like experiences, and subclinical psychopathology) in a sample of 253 non-clinically identified participants. Polygenic risk scores (PRSs) were constructed based on the latest SZ genome-wide association study using the PRS-CS method. Their association with self-report and interview measures of SZ-related traits was tested. No association with either schizotypy or psychotic-like experiences was found. However, we identified a significant association with the Motor Change subscale of the Comprehensive Assessment of At-Risk Mental States (CAARMS) interview. Our results indicate that the genetic overlap of SZ with schizotypy and psychotic-like experiences is less robust than previously hypothesized. The relationship between high PRS for SZ and motor abnormalities could reflect neurodevelopmental processes associated with psychosis proneness and SZ.

Examining the Relationship Between Hair Cortisol With Stress-Related and Transdiagnostic Subclinical Measures.

Background: Hair cortisol concentrations (HCC) provide a retrospective examination of long-term cortisol production as a measure of the hypothalamic-pituitary-adrenal (HPA) axis functioning, one of the major neural systems implicated in mediating the effects of stress on mental illness. However, evidence about the relationship between HCC with stressors and symptoms is scattered. In the present study, we aimed to examine the association between HCC and a wide range of stress-related and transdiagnostic subclinical measures in a sample of non-clinical young adults with a wide distribution of schizotypy. Methods: A total sample of 132 non-clinical young adults recruited at college and technical schools oversampled for schizotypy scores were assessed on distal and proximal stressful experiences, appraisals of stress, traits and symptoms of the affective, psychosis and dissociation spectrums, as well as stress-buffering measures, and provided 3 cm-hair samples. Results: No significant associations were found between HCC and any of the stress-related and subclinical measures. Only suspiciousness and disorganization showed a trend for a positive association with HCC but the magnitude was small. Conclusions: The present findings support previous studies indicating an overall lack of concordance between a broad range of stress-related and (sub)clinical phenotypic measures with hair cortisol. This study examined for the first time the relationship of HCC with the non-clinical expression of the psychosis spectrum, that is, schizotypy, which complements previous studies on clinical high risk and established psychosis and offers a promising strategy for studying possible HPA dysfunctions characterizing the subclinical psychosis continuum without the confounds associated to clinical psychosis.

Decreased social interaction in the RHA rat model of schizophrenia-relevant features: Modulation by neonatal handling.

The Roman-Low (RLA) and High-Avoidance (RHA) rat strains have been bidirectionally selected and bred, respectively, for extremely poor vs. rapid acquisition of the two-way active avoidance task. Over 50 years of selective breeding have led to two strains displaying many differential specific phenotypes. While RLAs display anxious-related behaviours, RHA rats show impulsivity, and schizophrenia-like positive and cognitive symptoms or phenotypes. Neonatal handling (NH) is an environmental treatment with long-lasting anxiolytic-like and anti-stress effects. NH also reduces symptoms related to schizophrenia, such as pre-pulse inhibition (PPI) impairment and latent inhibition (LI) deficits, and improves spatial working memory and cognitive flexibility. The present work was aimed at exploring whether RHAs also display negative schizophrenia-like symptoms (or phenotypes), such as lowered preference for social interaction (i.e. asociality), and whether NH would reduce these deficits. To this aim, we evaluated naïve inbred RHA and RLA rats in a social interaction (SI) test after either long- or short-term habituation to the testing set up (studies 1-2). In Study 3 we tested untreated and NH-treated RHA and RLA rats in novel object exploration (NOE) and SI tests. Compared with RHAs, RLA rats displayed increased anxiety-related behaviours in the NOE (i.e. higher behavioural inhibition, lesser exploration of the novel object) and SI (i.e. higher levels of self-grooming) tests which were dramatically reduced by NH treatment, thus supporting the long-lasting anxiolytic-like effect of NH. Remarkably, RHA rats showed decreased social preference in the SI test compared with RLAs, evidencing that RHAs would present a relative asociality, which is thought to model some negative symptomatology (i.e. social withdrawal) of schizophrenia. NH increased absolute levels of social behaviour in both strains, but with a more marked effect in RHA rats, especially in the first 5 min of the SI test. Thus, it is hypothesized that, apart from its effects on anxiety-related behaviours, NH might have long-lasting positive effects on behavioural and neurobiological processes that are impaired in schizophrenia.