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

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

Gender differences of patients at-risk for psychosis regarding symptomatology, drug use, comorbidity and functioning - Results from the EU-GEI study.

BACKGROUND: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis. METHODS: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews. RESULTS: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing. CONCLUSIONS: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful.

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders.

BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

[The Association between the Extended Psychosis Phenotype and COMT val158met and BDNF val66met polymorphisms]. / Genis Psikoz Fenotipinin COMT val158met ve BDNF val66met Polimorfizmleri ile Iliskisi.

OBJECTIVE: Psychotic disorders were previously associated with catechol- O-methyltransferase (COMT) val158met (rs4680) and brain-derived neurotrophic factor (BDNF) val66met (rs6265) polymorphisms. This article evaluates the association between COMT/BDNF polymorphisms and the extended psychosis phenotype which covers not only schizophrenia but also subclinical expressions of psychotic experiences. METHOD: The participants of this study were part of the TürkSch (Izmir Mental Health Survey for Gene-Environment Interaction in Psychoses), a longitudinal study Psychotic experiences and disorders were screened 437. The extended psychosis phenotype was grouped into four: (1) no psychotic experiences (n: 194), (2) subclinical psychotic experiences (n: 87), (3) clinically relevant psychotic experiences (n: 104), and (4) schizophrenia-like disorders (n: 52). BDNF rs6265 was genotyped occurred in every participant whereas COMT rs4680 genotyping could be done on 366 individuals. RESULTS: There was no association between the extended psychosis phenotype and BDNF rs6265/COMT rs4680 polymorphisms. The frequency of met carriers in the BDNF rs6265genotype was slightly higher in individuals with subclinical psychotic experiences than in the group with no psychotic experiences, which was just below the significance level (p=0.08). CONCLUSION: The lack of an association between different expression levels of the extended psychosis phenotype and the BDNF rs6265/ COMT rs4680 polymorphism might be related to sample characteristics, underlying gene-gene, gene-environment and gene-environment-gene interactions.

Differential Time Course of Microstructural White Matter in Patients With Psychotic Disorder and Individuals at Risk: A 3-Year Follow-up Study.

BACKGROUND: Although widespread reduced white matter (WM) integrity is a consistent finding in cross-sectional diffusion tensor imaging (DTI) studies of schizophrenia, little is known about the course of these alterations. This study examined to what degree microstructural WM alterations display differential trajectories over time as a function of level of psychosis liability. METHODS: Two DTI scans with a 3-year time interval were acquired from 159 participants (55 patients with a psychotic disorder, 55 nonpsychotic siblings and 49 healthy controls) and processed with tract-based spatial statistics. The mean fractional anisotropy (FA) change over time was calculated. Main effects of group, as well as group × region interactions in the model of FA change were examined with multilevel (mixed-effects) models. RESULTS: Siblings revealed a significant mean FA decrease over time compared to controls (B = -0.004, P = .04), resulting in a significant sibling-control difference at follow-up (B = -0.007, P = .03). Patients did not show a significant change over time, but their mean FA was lower than controls both at baseline and at follow-up. A significant group × region interaction (χ2 = 105.4, P = .01) revealed group differences in FA change in the right cingulum, left posterior thalamic radiation, right retrolenticular part of the internal capsule, and the right posterior corona radiata. CONCLUSION: Whole brain mean FA remained stable over a 3-year period in patients with psychotic disorder and declined over time in nonaffected siblings, so that at follow-up both groups had lower FA with respect to controls. The results suggest that liability for psychosis may involve a process of WM alterations.

Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction.

No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of cAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is.

Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders.

Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand-activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.

¿Media la dopamina los efectos psicóticos del Cannabis? Revisión e integración de los hallazgos a través de disciplinas / Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines

Los estudios epidemiológicos efectuados en la población general han demostrado sistemáticamente que el consumo de Cannabis aumenta de modo dependiente de la dosis el riesgo de desarrollar trastornos psicóticos. Aunque los indicios epidemiológicos entre el consumo de Cannabis y las psicosis han obtenido una atención considerable, apenas se conoce el mecanismo biológico mediante el que esta droga aumenta el riesgo de psicosis. La investigación en estudios efectuados en animales sugiere que el delta- 9-tetrahidrocanabinol (THC, el componente psicoactivo principal del Cannabis) aumenta los niveles de dopamina en diversas regiones del cerebro, incluido el núcleo estriado y el área prefrontal. Dado que se ha formulado la hipótesis de que la dopamina representa una vía final común decisiva entre la biología del cerebro y la experiencia real de psicosis, inicialmente prestar atención a este neurotransmisor podría ser productivo en el examen de los efectos psicotomiméticos del Cannabis. Por consiguiente, en la presente revisión se examinan las pruebas concernientes a las interacciones entre el THC, los endocanabinoides y la dopamina en la región tanto cortical como subcortical implicadas en las psicosis, y se consideran los posibles mecanismos por los que una disregulación de la dopamina inducida por el consumo de Cannabis podría dar lugar a delirios y alucinaciones. Se concluye que podrían emprenderse productivamente estudios adicionales sobre los mecanismos subyacentes que relacionan el consumo de Cannabis y las psicosis desde una perspectiva de una sensibilización progresiva del desarrollo, como consecuencia de interacciones genes-ambiente (AU)

General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9- tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions (AU)

All-cause mortality and medication risk factors in schizophrenia: a prospective cohort study.

BACKGROUND: It is well established that persons with schizophrenia have high mortality rates. There is conflicting evidence that antipsychotic and perhaps other medications routinely used to treat schizophrenia contribute to mortality risk. METHODS: A health insurer database was used to examine schizophrenia diagnosis and mortality in 2008. Information from the period 2006-2008 was used to analyze demographics and medication prescriptions. The risk set composed of patients with schizophrenia using an antipsychotic (n = 7415) and a group of randomly chosen control subjects (n = 97,726). RESULTS: The mortality risk for having a diagnosis of schizophrenia and using an antipsychotic versus the random control group was a hazard ratio (HR) of 2.6; 95% CI, 2.0-3.2. Over the 3-year period, age, receiving a first-generation antipsychotic, and the use of a mood stabilizer were associated with a higher risk of mortality: HR, 1.06; 95% CI, 1.04-1.08; HR, 2.36; 95% CI, 1.38-4.04; and HR, 8.42; 95% CI, 3.06-24.07, respectively. CONCLUSION: Patients with schizophrenia have higher mortality rates than normal controls. The type of antipsychotic and concomitant medication can affect mortality rates in schizophrenia.

Identifying at-risk states beyond positive symptoms: a brief task assessing how neurocognitive impairments impact on misrepresentation of the social world through blunted emotional appraisal / Identificando estados de risco para além dos sintomas positivos: um teste breve que avalia o impacto de disfunções neurocognitivas sobre a interpretação errônea do mundo social resultante de avaliação emocional embotada

OBJECTIVE: Neurocognitive impairments observed in psychotic disorder may impact on emotion recognition and theory of mind, resulting in altered understanding of the social world. Early intervention efforts would be served by further elucidation of this mechanism. METHOD: Patients with a psychotic disorder (n=30) and a reference control group (n=310) were asked to offer emotional appraisals of images of social situations (EASS task). The degree to which case-control differences in appraisals were mediated by neurocognitive alterations was analyzed. RESULTS: The EASS task displayed convergent and discriminant validity. Compared to controls, patients displayed blunted emotional appraisal of social situations (B=0.52, 95 percent CI: 0.30, 0.74, P<0.001; adjusted for age, sex and number of years of education: B=0.44, 95 percent CI: 0.20, 0.68, P<0.001), a difference of 0.88 (adjusted: 0.75) standard deviation. After adjustment for neurocognitive variables, the case-control difference was reduced by nearly 75 percent and was non-significant (B=0.12, 95 percent CI: -0.14, 0.39, P=0.37). CONCLUSIONS: Neurocognitive impairments observed in patients with psychotic disorder may underlie misrepresentation of the social world, mediated by altered emotion recognition. A task assessing the social impact of cognitive alterations in clinical practice may be useful in detecting key alterations very early in the course of psychotic illness.

OBJETIVO: Melhoras neurocognitivas observadas no transtorno psicótico podem ter impacto no reconhecimento de emoções e na teoria da mente, resultando numa alteração na compreensão do mundo social. Esforços para uma intervenção precoce poderiam se beneficiar de uma maior elucidação deste mecanismo. MÉTODO: Pacientes com transtornos psicóticos (n=30) e um grupo controle de referência (n=310) foram convidados a realizar avaliações emocionais de imagens de situações sociais (teste AESS). A relação das diferenças entre casos e controles com as alterações neurocognitivas foi analisada. RESULTADOS: O teste AESS apresentou validade convergente e discriminatória. Quando comparados aos controles, os pacientes apresentaram avaliação emocional embotada das situações sociais (B=0,52, 95 por cento CI: 0,30, 0,74, P<0,001; ajustado para a idade, sexo e número de anos de educação: B=0,44, 95 por cento CI: 0,20, 0,68, P<0001), uma diferença de 0,88 (ajustado: 0,75) desvio-padrão. Após o ajuste para as variáveis neurocognitivas, as diferenças no estudo caso-controle foram reduzidas em quase 75 por cento e deixaram de ser significativas (B=0,12, 95 por cento CI: -0,14, 0.39, P=0,37). CONCLUSÕES: Disfunções neurocognitivas observadas em pacientes com transtornos psicóticos podem ser subjacentes a uma distorção do mundo social, mediada pela alteração no reconhecimento de emoções. Um teste que avalie o impacto social de alterações cognitivas na prática clínica pode ser útil para a detecção das principais alterações nos primeiros estágios de transtornos psicóticos.