Screening Human Embryos for Polygenic Traits Has Limited Utility.

The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.

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.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability.

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.

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.

The factors associated with the presence of psychotic symptoms in the HELIAD Greek community study of older adults.

BACKGROUND: The prevalence and associated factors related to psychotic symptoms in older adults are understudied. The objectives were to assess the prevalence, incidence and factors associated with psychotic symptoms in a representative Greek sample of community living older adults. METHODS: The sample includes n = 1,904 residents of the cities of Larissa and Maroussi in Greece participating in the Hellenic Longitudinal Investigation of Aging and Diet study with available data at baseline and n = 947 individuals at the 3-year follow-up. Past-month presence of delusions and hallucinations was assessed on the grounds of the 17 symptoms of the Columbia University Scale for Psychopathology in Alzheimer's Disease and 14 symptoms of the Neuropsychiatric Inventory Questionnaire. A comprehensive neuropsychological assessment for probable diagnosis of dementia and physical comorbidity was carried out by neurologists. Penalized logistic regression analyses were used to assess the socio-economic and clinical factors associated with psychotic symptoms. RESULTS: Past-month prevalence of psychotic symptoms was 1.9% and 1.0% when excluding cases of dementia. The prevalence of any delusion and hallucination was 0.8% and 0.3% when excluding dementia. The incidence of psychotic symptoms without dementia was 1.3%. Recent widows and farmers/breeders/craftsmen, versus public servants/teachers/executives, had both six times the odds of experiencing psychotic symptoms without dementia. Hearing impairment and the number of health conditions also increased the odds while increased age was protective. CONCLUSION: Psychotic symptoms unrelated to dementia constitute a considerable mental health problem in old age. Paranoid delusions were the most prevalent. Socio-economic and health status factors are significant predictors of psychotic symptoms.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

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.

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.

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.

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.

Does accumulating exposure to illicit drugs bring forward the age at onset in schizophrenia?

OBJECTIVE: Whilst cannabis has been associated with an earlier age at onset in schizophrenia, the impact of amphetamine and/or cocaine plus cannabis consumption on age at onset remains unclear. The present study was designed to test the hypothesis that consumption of amphetamine and/or cocaine in addition to cannabis would lead to an earlier age at onset of schizophrenia than that seen for cannabis consumption alone. A secondary objective was to determine what kind of effect additional substance use exerted (e.g. additive, multiplicative). METHOD: Patients with a diagnosis of schizophrenia were recruited from consecutive admissions to the inpatient and outpatient services of a large psychiatric hospital in Perth, Australia and 167 participants were assessed using the Diagnostic Interview for Psychosis, which included detailed inquiry into illicit drug use in the 12 months prior to the onset of psychiatric symptoms. Participants were categorized into four groups: no illicit substance use (n = 65), cannabis use (n = 68), cannabis plus amphetamine use (n = 25), and cocaine plus cannabis/cocaine plus cannabis plus amphetamine use (n = 9). Analysis of variance was performed to detect trends, and linear regression used to analyze the consumption of each additional substance as a predictor of age at onset. RESULTS: We observed a linear trend for mean age at onset: 23.34 (SD = 6.91) years for no illicit substance use, 22.51 (SD = 5.27) years for cannabis use, 20.84 (SD = 3.48) years for cannabis plus amphetamine use, and 19.56 (SD = 3.54) years for cocaine plus cannabis/cocaine plus cannabis plus amphetamine use; the variation in the means between groups was statistically significant: F(1,163) = 5.66, p = 0.008, Cohen's d = 0.38. For the consumption of each additional substance, age at onset was earlier by 1.2 years: R (2) = 0.034, F(1,165) = 5.72, p = 0.018. CONCLUSIONS: Whilst preliminary, these findings suggest that additional consumption of each substance predicted an earlier age at onset by approximately 1 additional year.

Investigating environmental parameters involved in psychosis etiopathology. Translation and test-retest reliability of four scales.

First Episode Psychosis (FEP) emergence and clinical outcome might be attributed to various parameters, wherein gene - environment interaction plays a pivotal role in. Four specified psychometric tools, that have been used for the evaluation of possible environmental, social and psychological parameters involved in the etiopathology and clinical course of psychosis are the following: Social Environment Assessment Tool (SEAT), Discrimination (DISC), Brief Core-Schema Scales (BCSS) and Life-Threatening Events-Brief Life-Events Questionnaire (LTE-Q). These tools were used in the Athens-FEP Study assessment schedule, which investigates the gene-environment interaction among patients presenting with FEP. The goal of the present study is to present them in regard to their content, their use in international literature, their translation in Greek, and their test-retest reliability. SEAT, DISC and BCSS were provided to the Athens FEP Study by the European Network of National Schizophrenia Network studying Gene-Environment interactions (EUGEI) research project. LTE-Q was already translated into Greek and was selected as befitting the purposes of the FEP-Study. The EUGEI instruments were translated into Greek language by two independent translators for each instrument. All translators were qualified in the administration of the English version of the scales after being trained online through a comprehensive work-package training set provided by the EUGEI. The principal investigator of the Athens-FEP project checked and approved the final versions of the questionnaires. The four tools were administered to 32 subjects, all diagnosed with FEP, participating in the Athens-FEP project. Intraclass correlation coefficients (ICCs) were used to assess the agreement between scores of the four questionnaires after first and second administration. The scales were administered to our subjects twice, with an intermediate period of three weeks between the first and second administrations, by three qualified researchers. There was a statistically significant agreement for almost all measurements of the four questionnaires, except for the frequency dimension of DISC. Agreement between those measurements was very high (ICCs>0.8). Our study is an indication that the Greek versions of the psychometric tools are reliable, although a more thorough test of their psychometric properties is needed. All four questionnaires have unique properties that differentiate them from other similar tools. Moreover, the DISC is the only discrimination scale translated into Greek. More importantly, the translated questionnaires are part of a broad, well-established research package of psychometric tools, suitable for the evaluation of environmental risk factors potentially involved in early psychosis, which might represent a valuable scientific resource in the Greek research field.

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.

Patient-reported needs predict perceived psychosocial disability and quality of life beyond symptom severity in schizophrenia.

PURPOSE: We examined whether patient-rated or clinician-rated needs are more strongly associated with perceived psychosocial disability (PPD) and subjective quality of life (SQOL) of schizophrenia patients, beyond symptom severity. METHODS: Hierarchical regression analyses were computed to test patient and clinician-rated unmet and met needs (estimated by eighty-two patient-clinician pairs) as predictors of PPD and SQOL above and beyond demographics and psychopathology. Needs, symptomatology, PPD and SQOL were estimated using Camberwell Assessment of Need (CAN), PANSS, WHODAS 2.0 and WHOQOL-BREF respectively. RESULTS: Needs were significantly associated with all WHODAS 2.0 and WHOQOL-BREF domains above and beyond demographics and PANSS variables. Clinician-rated needs were better predictors of only one WHODAS 2.0 domain, while patient-rated needs were better predictors of all other WHODAS 2.0 and WHOQOL-BREF domains. Patient-rated unmet needs were more strongly than met needs associated with the most WHODAS 2.0 and WHOQOL-BREF subscores. CONCLUSION: This study offers the first evidence that patient-rated needs, especially unmet needs, are strongly associated, above and beyond symptomatology, with global and domain-specific PPD of schizophrenia patients. Accordingly, strong relations of patient-rated needs with SQOL emerged. Identifying and addressing patient-reported needs could facilitate PPD and SQOL improvement more effectively than interventions confined solely to symptom remission.IMPLICATIONS FOR REHABILITATIONSchizophrenia is associated with poor rehabilitation and recovery outcomes, i.e., perceived psychosocial disability (PPD) and subjective quality of life (SQOL).Assessment of patients' needs constitutes the basis of determining treatment goals and planning tailor-made interventions to achieve crucial rehabilitative outcomes.Higher levels of patient-reported unmet needs are associated with poorer SQOL and higher global and domain-specific PPD of schizophrenia patients, above and beyond symptom severity.Addressing patient-reported needs through personalized interventions can facilitate more effectively PPD and SQOL improvement, than treatment confined to symptomatic alleviation.

Comprehensive Evaluation of Psychotic Features and Their Clinical Correlates in Early Parkinson's Disease.

BACKGROUND: Some reports suggest that psychotic features may occur in the early stages of Parkinson's disease (PD), but sensitive tools have not been utilized. OBJECTIVE: The aim was to evaluate the presence of psychotic symptoms using detailed scales and to assess the association with clinical characteristics. METHODS: Healthy controls and patients within three years of PD onset were recruited. Participants were examined for psychotic symptoms using two different instruments: the Comprehensive Assessment of At-Risk Mental States (CAARMS) and a 10 question PD specific psychosis severity scale (10PDQ). In the PD group, medication use, motor and non-motor symptoms were documented. RESULTS: Based on CAARMS and 10PDQ scales, psychotic features were present in 39% (27/70) of patients and 4% (3/74) of controls. The prevalence of passage hallucinations and illusions was significantly higher in PD compared to the control group. The presence of PD-associated psychotic features was not significantly affected by medication, motor severity or global cognitive status. Higher prevalence of overall non-motor manifestations, REM sleep behavior disorder (RBD) and depressive symptoms was significantly associated with the manifestation of psychotic features in PD [(adjusted OR:1.3; 95% CI:1.1-1.6; p = 0.003), (adjusted OR:1.3; 95% CI:1.0-1.6; p = 0.023), and (adjusted OR:1.2; 95% CI:1.0-1.4;p = 0.026)]. CONCLUSIONS: Psychotic phenomena mainly of minor nature are highly common in early PD. Cumulative non-motor symptoms, RBD and depressive features are associated with the presence of psychotic symptoms in this non-demented, early-stage PD population. More studies are needed to clarify the mechanisms that contribute to the onset of psychotic features in early PD.

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.

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.

Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST).

BACKGROUND: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. METHODS: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. FINDINGS: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. INTERPRETATION: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. FUNDING: Lundbeck and Otsuka.