IL RICONOSCIMENTO DELLE EMOZIONI FACCIALI NEI DISTURBI PSICOTICI: UNO STUDIO SUI MECCANISMI GENETICI ED EPIGENETICI

La schizofrenia e altri disturbi psicotici sono disturbi complessi con eziologia multifattoriale che comprende fattori genetici e ambientali. L’architettura genetica di questi disturbi coinvolge numerosi loci implicati nel conferire il rischio di sviluppare la malattia. Inoltre, gli studi che indagano l’eziologia molecolare di questi disturbi hanno mostrato un interesse crescente per le variazioni epigenetiche, specialmente la metilazione del DNA. I disturbi della social cognition, come le difficoltà nel riconoscimento delle emozioni facciali (FER), sono associati con i disturbi psicotici; tuttavia, il loro legame con la genetica e l’epigenetica di questi disturbi sono questioni ancora aperte. I dati utilizzati in questa tesi provengono da due studi: lo studio multicentrico di incidenza e casocontrollo EU-GEI e lo studio di follow-up Sicilian Genetics and Psychosis (SGAP follow-up). Il riconoscimento globale e specifico delle emozioni facciali è stato analizzato attraverso modelli mixed effect tra casi e controlli. Sono stati utilizzati modelli di regressione lineare multipla per studiare l’associazione del FER con il punteggio di rischio poligenico per la schizofrenia (SZ PRS) e, per la prima volta, con i profili di metilazione differenziale del DNA dell’intero genoma (Differentially Methylated Positions – DMPs). In un sottocampione di controlli reclutati a Palermo è stato condotto un follow up a 8 anni ed è stata analizzata la correlazione tra FER a baseline e il cambiamento della sintomatologia subclinica (esperienze simil-psicotiche e schizotipia). I pazienti psicotici presentavano più frequentemente deficit nel riconoscimento delle emozioni facciali rispetto ai controlli, in particolare nel riconoscimento della paura e della rabbia rispetto ai volti felici o neutri. Lo SZ PRS è stato associato a un peggiore riconoscimento globale delle emozioni facciali e in particolare nel riconoscimento della rabbia. Sono state identificate diverse DMPs associate al FER che, sebbene non raggiungessero la soglia di significatività epigenome-wide, erano localizzate in geni espressi a livello del sistema nervoso centrale e già replicati in altri studi di associazione epigenome-wide (EWAS) nella schizofrenia. Infine, compromissioni del riconoscimento delle emozioni negative correlavano con cambiamenti nella schizotipia e nei sintomi subclinici dopo otto anni in un campione della popolazione generale di Palermo. 5 L’analisi EWAS rappresenta una prima indagine esplorativa sul riconoscimento delle emozioni facciali che suggerisce ulteriori sviluppi per la ricerca epigenetica su questo dominio. I risultati sul FER rappresentano ulteriori evidenze riguardo alla compromissione del riconoscimento globale e specifico delle emozioni facciali nel contesto della psicosi, corroborando i precedenti risultati degli studi su familiari e suggerendo come il riconoscimento delle emozioni facciali - in particolare le emozioni negative - possa essere un fenotipo intermedio per la psicosi

A Prediction Modelling and Pattern Detection Approach for the First-Episode Psychosis Associated to Cannabis Use

Over the last two decades, a significant body of research has established a link between cannabis use and psychotic outcomes. In this study, we aim to propose a novel symbiotic machine learning and statistical approach to pattern detection and to developing predictive models for the onset of first-episode psychosis. The data used has been gathered from real cases in cooperation with a medical research institution, and comprises a wide set of variables including demographic, drug-related, as well as several variables specifically related to the cannabis use. Our approach is built upon several machine learning techniques whose predictive models have been optimised in a computationally intensive framework. The ability of these models to predict first-episode psychosis has been extensively tested through large scale Monte Carlo simulations. Our results show that Boosted Classification Trees outperform other models in this context, and have significant predictive ability despite a large number of missing values in the data. Furthermore, we extended our approach by further investigating how different patterns of cannabis use relate to new cases of psychosis, via association analysis and Bayesian techniques

Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of first episode psychosis patients and controls

BackgroundFirst episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups.MethodsWe analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use.ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p 0.5).ConclusionsFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs

Facial Emotion Recognition in Psychosis and Associations With Polygenic Risk for Schizophrenia: Findings From the Multi-Center EU-GEI Case-Control Study

BACKGROUND AND HYPOTHESIS: Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition. STUDY DESIGN: 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD). STUDY RESULTS: A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= -1.5 (0.6), 95% CI -2.7 to -0.3], with evidence for stronger effects on negative emotions (fear [B = -3.3 (1.1), 95% CI -5.3 to -1.2] and anger [B = -2.3 (1.1), 95% CI -4.6 to -0.1]) than on happiness [B = 0.3 (0.7), 95% CI -1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = -3.5 (1.7), 95% CI -6.9 to -0.2]. CONCLUSIONS: Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis

Jumping to conclusions, general intelligence, and psychosis liability: findings from the multi-centre EU-GEI case-control study.

BACKGROUND: The 'jumping to conclusions' (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ. METHODS: A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia. RESULTS: The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn (B = 0.47, 95% CI -0.21 to 1.16, p = 0.17); whereas IQ PRS (B = 0.51, 95% CI 0.25-0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = -1.7, 95% CI -2.8 to -0.5, p = 0.006), but did not relate to delusions in patients. CONCLUSIONS: Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.EU HEALTH-F2-2009-24190

Transdiagnostic dimensions of psychopathology at first episode psychosis: findings from the multinational EU-GEI study.

BACKGROUND: The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment. METHOD: This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions. RESULTS: A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions. CONCLUSIONS: Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

BACKGROUND: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients. METHOD: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses. RESULTS: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use. CONCLUSIONS: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.The work was supported by: Clinician Scientist Medical Research Council fellowship (project reference MR/M008436/1) to MDF; the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust to DQ; DFG Heisenberg professorship (no. 389624707) to UR. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The EU-GEI Project is funded by the European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI). The Brazilian study was funded by the São Paulo Research Foundation under grant number 2012/0417-0

The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'

The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case-control study

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood

The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case-control study

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood