Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics.

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-1ß, 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-1ß 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-1ß-dependent pathways, and raised peripheral KYNA might represent a promising indicator of non-response to antipsychotic medication in patients with FEP.

Cognitive Inflexibility Predicts Negative Symptoms Severity in Patients with First-Episode Psychosis: A 1-Year Follow-Up Study.

Negative symptoms and cognitive deficits play a major role in psychosis and significantly influence the functional outcomes of patients, particularly those with a first episode of psychosis (FEP). However, limited research has explored the predictive capacity of cognitive deficits during FEP for subsequent negative symptomatology. Drawing from the Athens FEP research study, we conducted a retrospective longitudinal study in 80 individuals with FEP. All patients were drug naive at admission. Cognitive tests were administered at 1-month and 1-year post-admission, while negative symptomatology was assessed at the same time points using PANSS by trained raters. We considered confounding factors such as age, gender, duration of untreated psychosis (DUP), treatment received, premorbid social adjustment, and premorbid IQ. Univariate regression analysis identified cognitive domains that correlated with negative symptomatology. These, along with the confounders, were incorporated into a multiple regression, with the 1-year PANSS negative scale serving as the dependent variable. Employing the backward elimination technique, we found a statistically significant inverse relationship between the categories completed in the Wisconsin card sorting test (WCST) and the 1-year PANNS negative scale (p = 0.01), beyond the associations with DUP and the 1-month PANSS negative scale. Our results suggest that cognitive flexibility, a key component of executive functions, predicts negative symptom severity one year after FEP.

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.

The relationship between bullying and symptom presentation in first-episode psychosis.

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.

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.

A Missense Variant in CASKIN1's Proline-Rich Region Segregates with Psychosis in a Three-Generation Family.

The polygenic nature of schizophrenia (SCZ) implicates many variants in disease development. Rare variants of high penetrance have been shown to contribute to the disease prevalence. Whole-exome sequencing of a large three-generation family with SCZ and bipolar disorder identified a single segregating novel, rare, non-synonymous variant in the gene CASKIN1. The variant D1204N is absent from all databases, and CASKIN1 has a gnomAD missense score Z = 1.79 and pLI = 1, indicating its strong intolerance to variation. We find that introducing variants in the proline-rich region where the D1204N resides results in significant cellular changes in iPSC-derived neurons, consistent with CASKIN1's known functions. We observe significant transcriptomic changes in 368 genes (padj < 0.05) involved in neuronal differentiation and nervous system development. We also observed nominally significant changes in the frequency of action potentials during differentiation, where the speed at which the edited and unedited cells reach the same level of activity differs. Our results suggest that CASKIN1 is an excellent gene candidate for psychosis development with high penetrance in this family.

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.

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.

The preclinical discovery and development of agomelatine for the treatment of depression.

INTRODUCTION: Under the treatment of commonly used antidepressants, many patients with major depressive disorder (MDD) do not achieve remission. All previous first-line treatments for depression have focused on the enhancement of monoaminergic activity. Agomelatine was the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission. AREAS COVERED: The aim of this case history is to describe the discovery strategy and development of agomelatine. The pharmacodynamic profile of the drug is briefly presented. The article summarizes (a) the preclinical behavioral data on agomelatine's effects on depressive-like behavior, anxiety, and circadian rhythmicity disruptions, and (b) the results of early preclinical studies on safety, efficacy in MDD, and the risk-benefit pharmacological profile. Furthermore, the article examines findings of post-marketing research on safety, efficacy, and cost-effectiveness of the drug. EXPERT OPINION: There is now evidence supporting the clinical efficacy and safety profile of agomelatine in the acute-phase treatment of MDD. Agomelatine may be more effective in specific subgroups of MDD patients, those with severe anxiety symptoms or disturbed circadian profiles. Its antidepressant and anxiolytic activities are due to synergy between its melatonergic and 5-hydroxytryptaminergic effects. Since its discovery, novel compounds acting on the melatonergic system have been under investigation for the treatment of MDD.

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.

An Interleukin-1 beta (IL1B) haplotype linked with psychosis transition is associated with IL1B gene expression and brain structure.

We investigated IL1B genetic variation previously associated with risk for transition to psychosis for its association with gene expression in human post-mortem dorsolateral prefrontal cortex (DLPFC) from 74 (37 schizophrenia, 37 control) individuals and brain structure in 92 (44 schizophrenia, 48 control) living individuals. The IL1B A-G-T 'risk for psychosis transition' haplotype (rs16944|rs4848306|rs12621220) was associated with upregulation of IL1B mRNA expression in the DLPFC as well as reduced total grey matter and left middle frontal volumes and enlarged left lateral ventricular volume. Our results suggest IL1B genetic variation may confer psychosis risk via elevated mRNA expression and/or brain structure abnormalities.

Early psychosis intervention outpatient service of the 1st Psychiatric University Clinic in Athens: 3 Years of experience.

To present the 3-year experience of the early intervention in psychosis (EIP) service implementation of the 1st Psychiatric University Clinic in Athens. An overview of: (1) the purpose of our service, (2) the referral network, (3) the selection criteria, (4) the diagnostic procedures, (5) the therapeutic interventions and (6) the research activities. The service was established in 2012 and developed gradually aiming to provide information, early detection, treatment and support to people aged 15 to 40 years with psychotic manifestations, who are either at increased risk of developing psychosis (at-risk mental state [ARMS]) or with first episode psychosis (FEP). In order to assess individuals with ARMS, we used the comprehensive assessment of at-risk mental states interview and the Social and Occupational Functioning Assessment Scale The duration of untreated psychosis was estimated by using the Nottingham Onset Schedule. So far we have had 65 referrals, of which 26 were ARMS and 17 FEP. Based on the individual needs, they were offered psychotherapeutic and/or pharmacological treatment. After 3 years, the rate of transition to psychosis was 19.2% and the rate of psychosis relapse was 11.7%. The implementation of our service has had positive results, enabling young people with early psychosis to receive prompt and effective care. The rates of transition to psychosis are the first to be published from a Greek EIP service. Further development of our referral network and inter-hospital collaboration will allow us to address the needs of a wider part of the population.

Drugs under early investigation for the treatment of bipolar disorder.

INTRODUCTION: Despite the availability of several treatment options for bipolar disorder (BD), patients suffer from chronic, subsyndromal symptoms, quite frequent polarity shifts, cognitive impairment and poor community function. Overall, the current treatment outcomes for BD highlight the need to develop targeted, more effective and safe treatments. AREAS COVERED: This review focuses on compounds currently under investigation for BD, covering compounds tested through animal studies to those in Phase II clinical trials over the past 5 years. These drugs concern all phases of BD treatment, that is, mania, depression, maintenance, and cognitive dysfunction. EXPERT OPINION: Limitations exist in applying valid preclinical bipolar models and study designs. Research emphasis is given mainly on bipolar depression, with few compounds showing some evidence of efficacy. Non-effectiveness in current studies of mania and maintenance treatment reflects the need for novel compounds. Glycogen synthase kinase 3, casein kinase 1, inositol monophosphatase inhibition, histone deacetylase inhibition pathways are known targets that should proceed from preclinical to the clinical trial level.