Diminished social motivation in early psychosis is associated with polygenic liability for low vitamin D.

Insufficiency of vitamin D levels often occur in individuals with schizophrenia and first-episode psychosis (FEP). However, it is unknown whether this represents a biological predisposition, or it is essentially driven by illness-related alterations in lifestyle habits. Lower vitamin D has also been associated with adverse neurodevelopmental outcomes and predominant negative psychotic symptoms. This study aimed to investigate the contribution of polygenic risk score for circulating 25-hydroxyvitamin D concentration (PRS-vitD) to symptom presentation among individuals with FEP enrolled in the Athens First-Episode Psychosis Research Study (AthensFEP n = 205) and the Psychosis Incident Cohort Outcome Study (PICOS n = 123). The severity of psychopathology was evaluated using the Positive and Negative Syndrome Scale at baseline and follow-up assessments (AthensFEP: 4-weeks follow-up, PICOS: 1-year follow-up). Premorbid intelligence and adjustment domains were also examined as proxy measures of neurodevelopmental deviations. An inverse association between PRS-vitD and severity of negative symptoms, in particular lack of social motivation, was detected in the AthensFEP at baseline (adjusted R2 = 0.04, p < 0.001) and follow-up (adjusted R2 = 0.03, p < 0.01). The above observation was independently validated in PICOS at follow-up (adjusted R2 = 0.06, p < 0.01). No evidence emerged for a relationship between PRS-vitD and premorbid measures of intelligence and adjustment, likely not supporting an impact of lower PRS-vitD on developmental trajectories related to psychotic illness. These findings suggest that polygenic vulnerability to reduced vitamin D impairs motivation and social interaction in individuals with FEP, thereby interventions that encourage outdoor activities and social engagement in this patient group might attenuate enduring negative symptoms.

Stress, Environment and Early Psychosis.

Existing literature provides extended evidence of the close relationship between stress dysregulation, environmental insults, and psychosis onset. Early stress can sensitize genetically vulnerable individuals to future stress, modifying their risk for developing psychotic phenomena. Neurobiological substrate of the aberrant stress response to hypothalamic-pituitary-adrenal axis dysregulation, disrupted inflammation processes, oxidative stress increase, gut dysbiosis, and altered brain signaling, provides mechanistic links between environmental risk factors and the development of psychotic symptoms. Early-life and later-life exposures may act directly, accumulatively, and repeatedly during critical neurodevelopmental time windows. Environmental hazards, such as pre- and perinatal complications, traumatic experiences, psychosocial stressors, and cannabis use might negatively intervene with brain developmental trajectories and disturb the balance of important stress systems, which act together with recent life events to push the individual over the threshold for the manifestation of psychosis. The current review presents the dynamic and complex relationship between stress, environment, and psychosis onset, attempting to provide an insight into potentially modifiable factors, enhancing resilience and possibly influencing individual psychosis liability.

Role of Clinical Insight at First Month in Predicting Relapse at the Year in First Episode of Psychosis (FEP) Patients.

INTRODUCTION: Clinical insight constitutes a useful marker of the progress and outcome of the First Episode of Psychosis (FEP), and lack of insight has been associated with more severe psychopathology, treatment non-adherence, and rehospitalization/relapse. In this study, we aimed to further investigate the possible role of insight as a predictor of relapse, its relation to diagnosis, and other parameters of positive psychotic symptomatology (delusions, hallucinations, and suspiciousness). METHODS: The Athens FEP study employed a prospective, longitudinal cohort design in which consecutive newly diagnosed patients with psychosis were interviewed and asked to voluntarily participate after completing informed consent. A total of 88/225 patients were examined at three different time points (baseline, month, and year). Their scores in the relevant items of the Positive and Negative Syndrome Scale (PANSS) were compared (G12 for insight, P1 for delusions, P3 for hallucinations, and P6 for suspiciousness), and they were further associated to diagnosis and the outcome at the end of the year (remission/relapse). RESULTS: In total, 22/88 patients with relapse at the year had greater scores in G12 for both the month and the year, and this finding was corroborated after adjusting the statistical analysis for demographics, diagnosis, social environment, and depression via multiple logistic regression analysis. Moreover, delusions and suspiciousness were significantly higher in patients diagnosed with non-affective psychosis compared to those diagnosed with affective psychosis (p < 0.001) at the first month. CONCLUSIONS: Lack of insight at the first month may serve as a predictor of relapse at the year.

Association between exposome score for schizophrenia and functioning in first-episode psychosis: results from the Athens first-episode psychosis research study.

BACKGROUND: Evidence suggests that environmental factors not only increase psychosis liability but also influence the prognosis and outcomes of psychotic disorders. We investigated temporal and cross-sectional associations of a weighted score of cumulative environmental liability for schizophrenia - the exposome score for schizophrenia (ES-SCZ) - with functioning in first-episode psychosis (FEP). METHODS: Data were derived from the baseline and 1-month assessments of the Athens FEP Research Study that enrolled 225 individuals with FEP. The Global Assessment of Functioning (GAF) and the Personal and Social Performance Scale (PSP) were used to measure social, occupational, and psychological functioning. The ES-SCZ was calculated based on the previously validated method. RESULTS: ES-SCZ was associated with the total scores of GAF and PSP at baseline and 1-month assessments. These findings remained significant when accounting for several associated alternative explanatory variables, including other environmental factors (obstetric complications, migration, ethnic minority), clinical characteristics (duration of untreated psychosis, symptom severity, previous antipsychotic use), and family history of psychosis, demonstrating that the association between ES-SCZ and functioning is over and above other risk factors and cannot be explained by symptom severity alone. Functioning improved from baseline to 1-month assessment, but no significant ES-SCZ-by-time interaction was found on functioning, indicating that functioning changes were not contingent on ES-SCZ. CONCLUSIONS: Our findings suggest that rather than a predictor of functional improvement, ES-SCZ represents a stable severity indicator that captures poor functioning in early psychosis. Environmental risk loading for schizophrenia (ES-SCZ) can be beneficial for clinical characterization and incorporated into transdiagnostic staging models.

Three scales about childhood trauma, traumatic experiences and bullying: Greek translation, test-retest reliability.

Exposure to traumatic life events is one of the most robust predictors for psychosis. The Childhood Trauma Questionnaire-Short Form (CTQ-SF), a version of Childhood Experience of Care and Abuse (CECAEUGEI) and a version of the Bullying Questionnaire (BQEUGEI) refer to early life adversities, traumatic episodes and bullying. Those scales belong to a battery of psychometric tools detecting environmental and genetic factors associated with First Episode Psychosis (FEP) that was employed in the Athens-FEP study. The goal of this paper is to present those three versions, regarding their content, their use in the international research, their translation in Greek and their test-retest reliability. The three questionnaires were translated by two independent translators, administered twice to 32 subjects with FEP, with a three weeks intermediate period. Intraclass correlation coefficients (ICCs) were used to investigate agreement between scores of the first and second administration. There was a statistically significant agreement for all measurements of the three questionnaires. Cronbach's a were also calculated and were acceptable and over 0.7. Our study is an indication that the translated versions are reliable, although a more thorough test of their psychometric properties is needed. Both might be used in the Greek research field as part of a broad package of psychometric tools, specifically addressed to patients with FEP.

Don't blame psychosis, blame the lack of services: a message for early intervention from the Greek standard care model.

BACKGROUND: Early Intervention Services (EIS) aim to reduce relapse rates and achieve better treatment and functional outcomes for first episode psychosis (FEP) patients. Existing models of services in Greece are still treatment as usual (TAU), however a reform of mental health services is underway and initial steps have been taken to shift standard care towards EIS. The purpose of the study is to address therapeutic gaps by exploring service engagement and relapse rates in the current standard care model for psychosis. METHODS: We examined follow-up and relapse rates one year after initial treatment contact in the first longitudinal FEP study conducted in Greece. 225 patients were enrolled between 2015-2020. Sociodemographic, clinical and functional characteristics were assessed in association with follow-up and relapse rates. RESULTS: Within a TAU follow-up setting, one year attrition rates were high. Only 87 patients (38,7%) retained contact with services after one year and within this time frame, 19 of them (21,8%) experienced a severe relapse requiring rehospitalization. Demographic, clinical and functional contributors failed to predict service engagement and relapse rates, with the exception of treatment adherence. CONCLUSION: Both follow-up and one-year rehospitalization rates in our FEP sample, highlight the need for the implementation of early intervention services, that will aim at engagement maximization and relapse prevention. These indexes also provide a benchmark against which future early intervention services for psychosis in Greece will have to demonstrate superior efficacy.

Tobacco and Alcohol and Cannabis Experience Questionnaires. Greek translation and test-retest reliability.

The Tobacco and Alcohol Questionnaire (TAQ) and the Cannabis Experience Questionnaire (CEQ) are two instruments employed in the evaluation of substance use. The First Episode Psychosis (FEP) study in Athens employed two versions of those questionnaires, as part of a battery of psychometric tools, detecting environmental and genetic factors associated with FEP and addressed specifically to the distinctive characteristics of patients with FEP. The goal of the present study is to present those two versions, regarding their content, their use in international research, their translation in Greek, and their test-retest reliability. The two questionnaires were translated by two independent translators and administered to 32 subjects with FEP twice, in order to be tested for test-retest reliability. Cohen's kappa was used to measure agreement between qualitative variables and ICC between quantitative variables. Significant agreement was found between the two measurements in all items of the TAQ version and almost all items of the CEQ version. Our study is an indication that both translations are reliable, although a more thorough test of their psychometric properties is needed. Both might be used in the Greek research field as part of a broad package of psychometric tools, specifically addressed to patients with FEP.

Prediction of Early Symptom Remission in Two Independent Samples of First-Episode Psychosis Patients Using Machine Learning.

BACKGROUND: Validated clinical prediction models of short-term remission in psychosis are lacking. Our aim was to develop a clinical prediction model aimed at predicting 4-6-week remission following a first episode of psychosis. METHOD: Baseline clinical data from the Athens First Episode Research Study was used to develop a Support Vector Machine prediction model of 4-week symptom remission in first-episode psychosis patients using repeated nested cross-validation. This model was further tested to predict 6-week remission in a sample of two independent, consecutive Danish first-episode cohorts. RESULTS: Of the 179 participants in Athens, 120 were male with an average age of 25.8 years and average duration of untreated psychosis of 32.8 weeks. 62.9% were antipsychotic-naïve. Fifty-seven percent attained remission after 4 weeks. In the Danish cohort, 31% attained remission. Eleven clinical scale items were selected in the Athens 4-week remission cohort. These included the Duration of Untreated Psychosis, Personal and Social Performance Scale, Global Assessment of Functioning and eight items from the Positive and Negative Syndrome Scale. This model significantly predicted 4-week remission status (area under the receiver operator characteristic curve (ROC-AUC) = 71.45, P < .0001). It also predicted 6-week remission status in the Danish cohort (ROC-AUC = 67.74, P < .0001), demonstrating reliability. CONCLUSIONS: Using items from common and validated clinical scales, our model significantly predicted early remission in patients with first-episode psychosis. Although replicated in an independent cohort, forward testing between machine learning models and clinicians' assessment should be undertaken to evaluate the possible utility as a routine clinical tool.

The relationship between early symptom severity, improvement and remission in first episode psychosis with jumping to conclusions.

It is suggested that Jumping To Conclusions (JTC) reasoning bias might contribute to the distortion of external reality. However, the association between psychotic manifestations and JTC is obscure, especially if general intelligence is considered as a mediator. The aim of this study is to investigate the relation between severity, early clinical improvement and remission of symptoms in First Episode Psychosis (FEP) with JTC as an explanatory factor. One hundred seventy-one FEP individuals were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and one month after treatment initiation. Clinical improvement was ascribed as symptom change one-month post-baseline measurements. Symptomatic remission was assessed with the Andreasen severity criteria and JTC with the Beads Task, operationalized through Draws To Decision (DTD) (the lower the number of DTD, the higher the JTC bias). Regarding symptoms severity, total psychotic, total positive psychotic, and hallucinations-item PANSS scores showed a negative association with JTC after controlling for IQ. Regarding early clinical improvement, the association with JTC was non-significant. No significant association was detected between one month remission status of FEP and JTC. Our findings indicate that severity of positive symptoms is not associated with hastiness in decision-making, but rather with a heightened conservatism in terms of increased data gathering. Further research is required to replicate the results and clarify the cognitive processes involved.

Familial and socioeconomic contributions to premorbid functioning in psychosis: Impact on age at onset and treatment response.

BACKGROUND: Premorbid adjustment (PA) abnormalities in psychotic disorders are associated with an earlier age at onset (AAO) and unfavorable clinical outcomes, including treatment resistance. Prior family studies suggest that familial liability, likely reflecting increased genetic risk, and socioeconomic status (SES) contribute to premorbid maladjustment. However, their joint effect possibly indicating gene-environment interaction has not been evaluated. METHODS: We examined whether family history of psychosis (FHP) and parental SES may predict PA and AAO in unrelated cases with first-episode psychosis (n = 108) and schizophrenia (n = 104). Premorbid academic and social functioning domains during childhood and early adolescence were retrospectively assessed. Regression analyses were performed to investigate main effects of FHP and parental SES, as well as their interaction. The relationships between PA, AAO, and response to antipsychotic medication were also explored. RESULTS: Positive FHP associated with academic PA difficulties and importantly interacted with parental SES to moderate social PA during childhood (interaction p = 0.024). Positive FHP and parental SES did not predict differences in AAO. Nevertheless, an earlier AAO was observed among cases with worse social PA in childhood (ß = -0.20; p = 0.005) and early adolescence (ß = -0.19; p = 0.007). Further, confirming evidence emerged for an association between deficient childhood social PA and poor treatment response (p = 0.04). CONCLUSIONS: Familial risk for psychosis may interact with parental socioeconomic position influencing social PA in childhood. In addition, this study supports the link between social PA deviations, early psychosis onset, and treatment resistance, which highlights premorbid social functioning as a promising clinical indicator.

Organization framework and preliminary findings from the Athens First-Episode Psychosis Research Study.

AIMS: Athens First-Episode Psychosis (FEP) Research study, aims to explore the potential associations between multiple genetic, environmental and neurometabolic risk factors of psychotic disorders, through the clinical management of FEP patients with minimal exposure (<2 weeks) to antipsychotic treatment at entry. The goal of this paper is to introduce the background, rationale and design of the study and present its preliminary findings. METHODS: We developed a longitudinal cohort study of FEP patients 16-45 years old, presenting at the emergency units of five psychiatric hospitals across Athens, Greece. Research timeline includes baseline, 1-month and 1-year follow-up. Clinical, genetic, environmental, cognitive and biochemical parameters are measured, using psychometric tools, clinical interviews and laboratory tests. A descriptive analysis of baseline and 1-month assessments was performed including demographic characteristics, family history, medication, clinical picture, traumatic experiences, drug use and cognitive functioning. RESULTS: During the last 3 years, 130 subjects have been enrolled in the study. Data so far reveal that, despite the severity of baseline presentation, at 1-month the majority (57.4%) met the Andreasen symptom severity criteria for remission, without the time criterion and showed mild functional improvement. Several environmental adversities and poor cognitive performance were identified, which need to be further elaborated. CONCLUSIONS: Athens FEP Research study is the first gene-environment interaction study in Greece. In this article we introduce the organization and methodological framework of the project, along with its basic initial findings. Future analysis will allow the validation of tractable predictors and risk factors implicated in the development and outcome of psychosis.

Association between serum levels of glutamate and neurotrophic factors and response to clozapine treatment.

Clozapine is the only available therapy for about 30% of schizophrenia patients otherwise refractory to antipsychotics. Unfortunately, the mechanism of action of the drug is still unknown and there are no biomarkers that can predict a positive response to clozapine. We aimed to examine serum neurotrophins and glutamate levels as putative biomarkers for clozapine response based on the hypothesized mode-of-action of the compound. Blood samples of 89 chronic schizophrenia patients maintained on clozapine were analyzed in a cross-sectional design. Serum brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), neurotrophic growth factor (NGF), glial derived neurotrophic factor (GDNF) and glutamate were determined. Differences between responders and non-responders to clozapine and correlation between clinical and biological measures were analyzed. Our sample consisted of 54 (61%) responders and 35 (39%) non-responders. Responders had higher mean BDNF levels than non-responders (2066±814 vs. 1668±820pg/ml, p<0.05. respectively) and higher serum glutamate levels (1.61±2.2 vs. 0.66±0.9pg/ml, respectively, p<0.05). Furthermore, there was a significant correlation between serum glutamate levels and positive symptoms among the clozapine-responder group (rho=0.47, p<0.005). High serum levels of BDNF and glutamate were associated with response to clozapine, while glutamate levels correlated with the psychosis severity in clozapine responders only. Large-scale, prospective longitudinal studies are needed to support these findings and the assumption that serum glutamate and BDNF can discriminate between clozapine responders and non-responders.

A Bayesian model of context-sensitive value attribution.

Substantial evidence indicates that incentive value depends on an anticipation of rewards within a given context. However, the computations underlying this context sensitivity remain unknown. To address this question, we introduce a normative (Bayesian) account of how rewards map to incentive values. This assumes that the brain inverts a model of how rewards are generated. Key features of our account include (i) an influence of prior beliefs about the context in which rewards are delivered (weighted by their reliability in a Bayes-optimal fashion), (ii) the notion that incentive values correspond to precision-weighted prediction errors, (iii) and contextual information unfolding at different hierarchical levels. This formulation implies that incentive value is intrinsically context-dependent. We provide empirical support for this model by showing that incentive value is influenced by context variability and by hierarchically nested contexts. The perspective we introduce generates new empirical predictions that might help explaining psychopathologies, such as addiction.