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The tryptophan-metabolizing kynurenine pathway (KP) can be activated by enhanced inflammatory responses and has been implicated in the pathophysiology of schizophrenia. However, there is little evidence for KP dysregulation in the early course of psychotic illness. We aimed to investigate the potential immune-mediated hyperactivity of KP in individuals with first-episode psychosis (FEP) and the relationship with symptom severity and treatment response outcomes. Serum immunoassays were performed to measure peripheral levels of inflammatory cytokines (IL-1β, IL-10, TNF-a), KP rate-limiting enzymes (IDO/TDO), and kynurenic acid (KYNA) metabolite in 104 antipsychotic-naïve patients with FEP and 80 healthy controls (HC). The Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale (GAF) were administered to assess psychopathology and functioning status at admission and following 4-week treatment with antipsychotics. Cytokine and KP components levels were substantially increased in FEP patients compared to HC, before and after antipsychotic treatment. A significant positive correlation between pro-inflammatory IL-1β and KYNA levels was observed among FEP patients, but not in HC. Importantly, within-patient analysis revealed that those with higher baseline KYNA experienced more severe negative symptoms and poorer clinical improvement at follow-up. These findings suggest that KP is upregulated in early psychosis, likely through the induction of IL-1β-dependent pathways, and raised peripheral KYNA might represent a promising indicator of non-response to antipsychotic medication in patients with FEP., (© 2024. The Author(s).)

Multiple recent studies have indicated that adverse psycho-traumatic experiences are particularly significant, if not the most significant, among the environmental factors that participate in the aetiology of schizophrenic spectrum disorders. The prevalence of bullying in the adolescent population has increased dramatically compared to earlier reports. This may be related to the recent development of communication technology and the use of social media, which have expanded the means by which bullying can be practiced. The present study aims to investigate the association between bullying victimisation and psychotic symptoms in First-Episode Psychosis (FEP) patients, hypothesising that patients who have a bullying history may have increased psychotic symptoms and a more unfavourable early trajectory after treatment as usual compared to patients who do not have a bullying history. Research data were collected from a sample of men and women of the Greek general population aged between 16 and 45 (N=225) who experienced a FEP in the context of the Athens First-Episode Psychosis (FEP) Study. The assessment of bullying was performed using the Retrospective Bullying Questionnaire (RBQ). Assessment of positive and negative psychotic symptoms and general psychopathology was performed using the corresponding subscales of the Positive and Negative Syndrome Scale (PANSS) at baseline and after 4 weeks of treatment as usual. Clinical remission was assessed based on the baseline and follow-up values of the PANSS and on Andreasen's symptomatic criteria. Methodologically, Pearson's chi-square test was used to compare the history of bullying between men and women, while linear and logistic regression models were used to check the correlations between history of bullying and symptom severity at baseline and 4-week follow-up, as well as the correlation between history of bullying and remission. The prevalence of bullying history in our sample of patients (N:225) with a FEP was 51.4% (114/225). Bullying was recorded in our study participants with equal frequency in women and men. According to the analysis results, the patients who had experienced bullying did not present at baseline with significantly increased psychotic symptoms compared to the patients who did not have a history of bullying. In addition, bullying was not associated with reduced remission according to Andreasen's criteria. However, the patients who had experienced bullying were found to have significantly increased negative symptoms (B=1.66; SE=0.70; p=0.018) and increased PANSS total score (B=4.81; SE=2.34; p=0.041) at 4-week follow-up. Our results highlight the persistence of negative and overall symptoms as an impact of bullying on the development of the FEP and align with studies that support the consideration of a history of bullying during both the diagnostic and therapeutic processes.

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 R 2  = 0.04, p < 0.001) and follow-up (adjusted R 2  = 0.03, p < 0.01). The above observation was independently validated in PICOS at follow-up (adjusted R 2  = 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., (© 2024. The Author(s).)

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.

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.

Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (CSMD1) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined C4A and CSMD1 mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; n = 73) and mentally healthy volunteers (n = 48). Imputed C4 locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in CSMD1 expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between C4A and CSMD1 mRNA levels in healthy volunteers but not in FEP cases. In addition, C4 copy number variants previously associated with SZ risk correlated with higher C4A mRNA levels in FEP cases, which confirms the regulatory effect of C4 structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher C4A mRNA levels correlated with more severe general psychopathology symptoms and lower CSMD1 mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of CSMD1 in prefrontal-mediated cognitive functioning., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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 Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2019 John Wiley & Sons Australia, Ltd.)

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 (β = -0.20; p = 0.005) and early adolescence (β = -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.

Aims: Diabetic retinopathy (DR) as a common complication of Type 2 Diabetes Mellitus (T2DM) affecting negatively quality of life (QoL). Assessing of QoL in patients with DR is a prerequisite for the evaluation of their needs and for understanding the perception of the patients themselves about their health status and how the disease affects their lives. Additionally, QoL indicators detect individual psychosocial problems that may impact therapeutic response., Materials and Methods: A total of 70 subjects with T2DM and DR as well as 70 T2DM individuals without DR were included. For the evaluation of QoL we used (a) WHO QoL - BREF for the estimation of QoL, (b) Life Satisfaction Scale for the estimation of satisfaction from life, and (c) the special recording document for demographic, socioeconomic, and clinical data. At the same time, blood was collected for the measurement of glucose control and renal function. DR was diagnosed by dilated fundoscopy., Results: Patients with DR had significantly worse scores in all scales of QoL and Life Satisfaction in comparison with those without DR. We found significant impact of the severity of DR in many domains of the QoL and Life Satisfaction. Multivariate logistic regression analysis demonstrated that DR was associated with worse QoL and Life Satisfaction scores as well as lower income, while no significant associations were found with education level, family, insurance and employment status as well as type of residence., Conclusion: DR affects QoL and Life Satisfaction and is associated with lower income., (Copyright © 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background/aim: Indoleamine 2, 3-dioxygenase (IDO) induction has been suggested as a mechanism by which immune activation affects tryptophan metabolism and serotonin synthesis in major depressive disorder (MDD). We investigated IDO and changes in inflammatory mediators in patients with MDD undergoing effective treatment., Patients and Methods: Forty female patients with MDD and 40 controls were recruited. Serum IDO was assessed by enzyme-linked immunosorbent assay (ELISA). We also determined tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), C-reactive protein (CRP) and serotonin concentrations., Results: Patients' baseline concentrations of IDO and immune mediators were higher and serotonin concentrations were lower compared to controls. IDO and TNFα concentrations decreased under treatment and IDO changes were positively correlated with patient improvement. IFNγ and CRP concentrations remained unchanged. Serotonin concentration tended to increase., Conclusion: IDO might play an important role in the pathophysiology of MDD. Moreover, antidepressant therapy might reduce IDO production through an IFNγ-independent pathway. Finally, peripheral concentration of IDO assessed by ELISA might be a useful marker of MDD., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)