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Background: Shortening the duration of untreated psychosis (DUP) - with the aim of improving the prognosis of psychotic disorders - requires an understanding of the causes of treatment delay. Current findings concerning several candidate risk factors of a longer DUP are inconsistent. Our aim was to identify factors contributing to DUP in a large sample that represents the treated prevalence of non-affective psychotic disorders.Method: Patients with a non-affective psychotic disorder were recruited from mental health care institutes from 2004 to 2008. Of the 1120 patients enrolled, 852 could be included in the present analysis. Examined candidate factors were gender, educational level, migration status, premorbid adjustment and age at onset of the psychotic disorder. DUP was divided into five ordinal categories: less than one month, one month to three months, three months to six months, six months to twelve months and twelve months and over. An ordinal logistic regression analysis was used to identify the risk factors of a longer DUP.Results: Median DUP was less than one month (IQR 2). The factors migration status (p = 0.028), age at onset of the psychotic disorder (p = 0.003) and gender (p = 0.034) were significantly associated with DUP in our analysis.Conclusion: First generation immigrant patients, patients with an early onset of their psychotic disorder and male patients seem at risk of a longer DUP. These findings can assist in designing specific interventions to shorten treatment delay. (C) 2014 Elsevier B.V. All rights reserved.

Background Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals. In this context, an extensively studied psychosis vulnerability gene is catechol-methyl-transferase ( COMT ). Therefore, we aimed to examine whether the COMT Val 158 Met polymorphism (rs4680) moderates the interaction between childhood maltreatment and cannabis use on psychotic symptoms in the general population. Method The discovery sample consisted of 918 individuals from a cross-sectional study. For replication we used an independent sample of 339 individuals from the general population. Results A significant three-way interaction was found between childhood maltreatment, cannabis use, and the COMT genotype (rs4680) in the discovery sample (P = 0.006). Val-homozygous individuals displayed increased psychotic experiences after exposure to both cannabis use and childhood maltreatment compared to Met-heterozygous and Met-homozygous individuals. Supportive evidence was found in the replication sample with similar effect and direction even though the results did not reach statistical significance (P = 0.25). Conclusions These findings suggest that a functional polymorphism in the COMT gene may moderate the interaction between childhood maltreatment and cannabis use on psychotic experiences in the general population. In conclusion, the COMT Val 158 Met polymorphism may constitute a genetic risk factor for psychotic symptoms in the context of combined exposure to childhood maltreatment and cannabis use.

Kurt Schneider defined 'first rank symptoms' (FRS) of psychosis. Previous research found two clusters of FRS: 'loss of ego bound' symptoms (e.g., delusions of external control) and auditory hallucinations (e.g, commenting voices). In patients with a psychosis we investigated whether FRS are a separate cluster within the group of positive symptoms, consisting of two underlying factors that are stable over time. We conducted a principal axis factor analysis (PAF) at baseline (n = 857) and a confirmative factor analysis (CFA) at three-year follow-up (n = 414) on (FRS) symptom score. Also, we investigated the stability of the two-factor structure of FRS over the interval. PAF on 16 items representing positive symptoms at baseline revealed two factors with eigenvalues > 1. FRS-delusional self experience (thought withdrawal, thought broadcasting, thought insertion, and beliefs that impulses and/or actions are controlled by an outside force) clustered in one factor and FRS-auditory hallucinations (auditory hallucinations, conversational voices, and voices commenting on one's actions) in the second factor. Furthermore, CFA on the FRS-items at follow-up confirmed the two-factor structure of FRS. FRS delusional self experience and FRS-auditory hallucinations at baseline were significantly associated with the same factors at three-year follow-up (FRS-delusional self experience: r = 0.38; FRS-auditory hallucinations r = 0.47). Hence, our findings confirm a two-factor structure of first rank symptoms, i.e. FRS-delusional self experience and FRS-auditory hallucinations, with a moderate to large internal coherence within each factor and relative stability over time. Future studies on self-processes may contribute to our understanding of the pathophysiology of first rank symptoms.

Background: Monitoring patients' experiences with antipsychotics may help to improve medication adherence and outcome. We aimed to develop a shorter version of a comprehensive 74-item self-report questionnaire suitable for routine monitoring of desired and undesired effects of antipsychotics.Methods: Included were patients with psychotic disorders from seven mental health care organizations in The Netherlands, using antipsychotic medication, who completed the Subjects' Response to Antipsychotics (SRA-74). Exploratory factor analysis (EFA) and similarity analysis based on mutual information were used to identify the latent factor structure of the SRA. Items were reduced according to their metric properties and clinical relevance upon consensus by an expert panel, using a Delphi procedure of three rounds. We determined the internal consistency of the shorter version using Cronbach's alpha.Results: SRA data of N = 1478 patients (mean age of 40 years, 31% females) were eligible for analysis. EFA extracted thirteen factors from the SRA-74, including four factors for desired effects (e. g. recovery of psychosis, cognition and social functioning) and nine factors for undesired effects (e. g. weight gain, flattened affect and increased sleep). Based on this solution 12 items were eliminated for statistical reasons. The expert panel eliminated another 28 items with redundant content, resulting in a 34-item version. The SRA-34 includes 10 desired and 24 clinically relevant undesired effects. Both the subscales for desired and undesired effects have a Cronbach's alpha coefficient of 0.82.Conclusions: The SRA-34 can be used to evaluate desired and undesired effects of antipsychotics in routine clinical practice and research. (C) 2013 Elsevier B. V. All rights reserved.

Background: Auditory hallucinations are experienced by 60-80% of all patients diagnosed with a schizophrenia spectrum disorder. However, in this patient group, the prevalence of hallucinations in multiple sensory modalities, i.e. multimodal hallucinations (MMHs), is unknown.Aims: To assess the prevalence of MMHs in patients diagnosed with a schizophrenia spectrum disorder, data were analyzed from 750 patients who participated in the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study.Method: We drew on the section of the CASH (Comprehensive Assessment of Symptoms and History) that probes into the lifetime presence of auditory, visual, somatic/tactile, and olfactory hallucinations.Results: A lifetime prevalence of 80% was found in this group for hallucinations in any of these modalities. Within the whole group, 27% of the participants reported unimodal hallucinations and 53% MMHs. There were no significant differences in prevalence rate for Dutch versus migrant participants from Morocco, Turkey, Surinam or the (former) Dutch Antilles.Conclusion: We conclude that MMHs, rather than auditory hallucinations, are the most frequent perceptual symptom of patients diagnosed with a schizophrenia spectrum disorder. Our data also suggest that hallucinations experienced in a single sensory modality (notably auditory ones) stochastically increase the risk for more sensory modalities to join in. We recommend that future studies take into account all 14 sensory modalities in which hallucinations can be experienced. For this we provide a classification of MMHs that allows characterization of their serial versus simultaneous occurrence and their congruent versus incongruent nature. (C) 2016 The Authors. Published by Elsevier B.V.

Cannabis use has been associated with favorable outcomes on metabolic risk factors. The cause of this relation is still unknown. In this study we investigated whether this effect is mediated by the AKT1 gene, as activation of the related enzyme by cannabis may cause metabolic changes.Six Single Nucleotide Polymorphisms (SNPs) of the AKT1 gene (rs1130214, rs1130233, rs2494732, rs2498784, rs3730358, and rs3803300) of patients with psychotic disorders (n = 623) were related to Body Mass Index (BMI), levels of glycosylated hemoglobin (HBA(1c)) and total metabolic risk. Next, mediation analysis was performed with BMI as outcome, cannabis as predictor, and AKT1 as mediator. Cannabis use was inversely related to BMI but not with levels of HBA(1c) and totalmetabolic risk. Moreover, out of 6 AKT1 SNPs, rs2494732 was associated with cannabis use, but AKT1 did not mediate the effect of cannabis on BMI.In conclusion, cannabis use is likely to be associated with a lower BMI in patients with a psychotic disorder. Moreover, AKT1 risk alleles may increase the incidence of cannabis use in patients with a psychotic disorder, but AKT1 does not appear to mediate the effect of cannabis on BMI. (C) 2016 Elsevier B.V. All rights reserved.

A recent study found genome-wide significant association between common variation in the gene neurocan (NCAN, rs1064395) and bipolar disorder (BD). In view of accumulating evidence that BD and schizophrenia partly share genetic risk factors, we tested this single-nucleotide polymorphism for association with schizophrenia in three independent patient-control samples of European ancestry, totaling 5061 patients and 9655 controls. The rs1064395 A-allele, which confers risk for BD, was significantly over-represented in schizophrenia patients compared to controls (p=2.28x10(-3); odds ratio=1.11). Follow-up in non-overlapping samples from the Schizophrenia Psychiatric GWAS Consortium (5537 patients, 8043 controls) provided further support for our finding (p=0.0239, odds ratio=1.07). Our data suggest that genetic variation in NCAN is a common risk factor for BD and schizophrenia. (C) 2012 Elsevier B.V. All rights reserved.

The proneness-persistence-impairment (PPI) model states that psychotic experiences are more likely to lead to impairment if their expression becomes persistent. Higher genetic risk for psychosis is known to affect proneness and persistence of subclinical positive symptoms. Less is known about potential effects of genetic risk on the course of subclinical negative symptoms, impairment, and their subsequent associations. The current study examined these issues in a large sample (n=1131), consisting of individuals with higher genetic risk (siblings of patients with psychotic disorders, n=703) and lower genetic risk (controls without a family member with lifetime psychosis, n=428). Psychotic experiences were assessed with the CAPE questionnaire, at two time points three years apart. Participants were allocated to one of four groups representing developmental course: stable low, decreasing, increasing or persisting subclinical positive/negative symptoms. Lifetime clinical psychosis was an exclusion criterion at baseline. Higher genetic risk status was found to be associated with a persisting course of both subclinical positive and negative symptoms, symptom-related distress and functional impairment. There is no evidence for an effect of genetic risk status on the association between developmental course and impairment. The results of the current study underline the importance of assessing psychotic experiences in the context of genetic risk, multidimensional and over time. Additionally, the current findings both underscore and contribute to the PPI model: psychotic experiences are more likely to lead to impairment if their expression becomes persistent, both in individuals with higher and lower genetic risk for psychosis. publisher: Elsevier articletitle: Developmental course of subclinical positive and negative psychotic symptoms and their associations with genetic risk status and impairment journaltitle: Schizophrenia Research articlelink: http://dx.doi.org/10.1016/j.schres.2016.03.028 content_type: article copyright: © 2016 Published by Elsevier B.V. ispartof: Schizophrenia Research vol:174 issue:1 pages:177-182 ispartof: location:Netherlands status: published

Objective: The lack of fit of 25 previously published five-factor models for the PANSS items, can be due to the statistics used. The purpose of this study was to use a 'new' statistical method to develop and confirm an improved five-factor model. The improved model is both complex and stable. Complex means that symptoms can have multiple factor loadings, because they have multiple causes, not because they are ill defined. Stable means that the complex structure is found repeatedly in validations.Methods: A ten-fold cross-validation (10 CV) was applied on a large data set (N = 5769) to achieve an improved factor model for the PANSS items. The advantages of 10 CV are minimal effect of sample characteristics and the ability to investigate the stability of items loading on multiple factors.Results: The results show that twenty-five items contributed to the same factor all ten validations with one item showing a consistent loading on two factors. Three items were contributing to the same factor nine out of ten validations, and two items were contributing to the same factor six to eight times. The resulting five-factor model covers all thirty items of the PANSS, subdivided in the factors: positive symptoms, negative symptoms, disorganization, excitement. and emotional distress. The five-factor model has a satisfactory goodness-of-fit (Comparative Fit Index = .905; Root Mean Square Error of Approximation = .052).Conclusions: The five-factor model developed in this study is an improvement above previously published models as it represents a complex factor model and is more stable. (c) 2006 Elsevier B.V. All rights reserved.

Gray matter brain volume decreases have been found in patients with schizophrenia as compared to healthy control subjects measured by using Magnetic Resonance Imaging (MRI). An association has been suggested between decreased gray matter volume and poor outcome in chronically ill patients with schizophrenia. The present longitudinal multi-center study investigated whether gray matter volume at illness onset can predict poor outcome in recent-onset schizophrenia after a follow-up of approximately 2 years. An MRI calibration study was performed since scans of patients with recent-onset psychosis were conducted at three sites with 1.5 T MR scanners from two different manufacturers. Applying a linear scaling procedure on the histogram improved comparability between volume measurements acquired from images from the different scanners.Brain scans were obtained from 109 patients with recent-onset schizophrenia. Volumes of intracranium, total brain, cerebral gray and white matter, third and lateral ventricles, and cerebellum were measured. After a mean follow-up period of approximately 2 years, measurements of symptoms, functioning, need for care, and illness history variables were assessed. No significant correlations were found between the brain volume measures and any of these measures. Gray matter volume at illness onset does not predict outcome after 2 years in recent-onset schizophrenia. (C) 2003 Elsevier Science B.V. All rights reserved.

Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals. In this context, an extensively studied psychosis vulnerability gene is catechol-methyl-transferase (COMT). Therefore, we aimed to examine whether the COMT Val(158)Met polymorphism (rs4680) moderates the interaction between childhood maltreatment and cannabis use on psychotic symptoms in the general population.The discovery sample consisted of 918 individuals from a cross-sectional study. For replication we used an independent sample of 339 individuals from the general population.A significant three-way interaction was found between childhood maltreatment, cannabis use, and the COMT genotype (rs4680) in the discovery sample (P=0.006). Val-homozygous individuals displayed increased psychotic experiences after exposure to both cannabis use and childhood maltreatment compared to Met-heterozygous and Met-homozygous individuals. Supportive evidence was found in the replication sample with similar effect and direction even though the results did not reach statistical significance (P=0.25).These findings suggest that a functional polymorphism in the COMT gene may moderate the interaction between childhood maltreatment and cannabis use on psychotic experiences in the general population. In conclusion, the COMT Val(158)Met polymorphism may constitute a genetic risk factor for psychotic symptoms in the context of combined exposure to childhood maltreatment and cannabis use.

Background: Longer duration of untreated psychosis (DUP) is associated with poorer outcome in terms of positive symptoms, relapse rate, and time to remission. In contrast, the association with negative symptoms is less consistent. Aims: The study had three aims. First, to arrive at a more precise estimate of the correlation between DUP and negative symptoms than previous reviews, by substantially increasing the amount of available data. Second, to see whether the strength of this correlation attenuated over longer follow-up intervals. Third, to determine whether there is a relationship between DUP and changes in negative symptoms. Method: Relevant databases were searched for studies published between December 1992 and March 2009 that reported data on DUP and negative symptoms. We obtained individual patient data where possible and calculated summary correlations between DUP and negative symptoms for each study at baseline, short and long-term follow-up. We used multilevel regression analysis to examine whether the effect of DUP on negative symptoms was the greatest in the early stages of illness. Results: We included 28 non-overlapping studies from the 402 papers detected by the search strategy. After contacting the authors we obtained individual patient data from 16 of these studies involving 3339 participants. The mean DUP was 61.4 weeks (SD = 132.7, median DUP = 12.0). Shorter DUP was significantly associated with less severe negative symptoms at baseline and also at short (1-2 years) and longer term follow-up (5-8 years) (r = 0.117, 0.180 and 0.202 respectively, p

Background and aims: As part of an RCT in six European sites, the direct mental health care cost for 422 patients with schizophrenia was analysed according to how total and medication costs differed across sites and which variables were likely to predict total or service-specific costs. Method: Service use was recorded continuously during a 12-month follow-up. Prescribed psychotropic medication was recorded at baseline and 12 months later. Service use data were transformed into EURO, log-transformed and analysed using linear regression models. Results: Although samples were homogeneous, large inter-site cost differences were found (annual means ranging from 2958 E in Spain up to 36978 E in Switzerland). Psychopharmacologic costs were much more constant across sites than costs for other services. Total costs were associated more with region or socio-demographic characteristics than with disorder related parameters. Conclusions: The findings confirm remarkable differences in direct costs of patients with schizophrenia across Europe. However, the relative stability of medication costs suggests a need to analyse mechanisms that influence service-specific costs for schizophrenia. (C) 2009 Elsevier B.V. All rights reserved.

Background: Substantial evidence exists about emotion processing (EP) impairments in schizophrenia patients. However, whether these deficits are present primarily during psychosis (i.e., state dependent) or an integral part of the disorder (i.e., trait dependent) remains unclear.Methods: EP was assessed with the degraded facial affect recognition task in schizophrenia patients (N = 521) and healthy controls (N = 312) at baseline (T1) and after a three year follow-up (T2). In schizophrenia patients symptomatic remission was assessed with the Positive and Negative Syndrome Scale (PANSS) remission tool. Patients were divided into four groups: remission T1 and remission T2 (RR); remission T1 and non-remission T2 (RN); non-remission T1 and non-remission T2 (NN) and non-remission T1 and remission T2 (NR). Factorial repeated measures ANCOVA was used to compare EP performance over time between groups. Age, gender and general cognition were included as covariates.Results: Schizophrenia patients performed worse than healthy controls on EP at T1 (p = 0.001). The patients that were in symptomatic remission at both time points (the RR group) performed worse than the healthy controls at T2 (p Conclusion: The results show relatively poor EP performance in schizophrenia patients compared to healthy controls. EP performance in schizophrenia patients was associated with symptomatic remission. The results provide support for the hypothesis that EP deficits in schizophrenia are both state and trait dependent. (C) 2014 Elsevier B.V. All rights reserved.