Background: Screening methods for detecting Ultra High Risk status (UHR) or psychosis should be improved, especially in adolescent samples. We therefore tested whether the Child Behavior Checklist ... Show moreBackground: Screening methods for detecting Ultra High Risk status (UHR) or psychosis should be improved, especially in adolescent samples. We therefore tested whether the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) add value to the Prodromal Questionnaire-16 items version (PQ-16) for detecting UHR status or psychosis. Methods: We included help-seeking adolescents who had completed the PQ-16, YSR, CBCL, and a Comprehensive Assessment of an At Risk Mental States (CAARMS) interview, and used independent samples t-tests and binary logistic regression analyses to determine the scales contributing to the prediction of UHR status or of having reached the psychosis threshold (PT). Cutoff scores were determined using ROC analyses. Results: Our sample comprised 270 help-seeking adolescents (mean age 14.67; SD 1.56, range 12-17); 67.8% were girls and 66.3% were of Dutch origin. The Thought Problems syndrome scales of both the YSR and the CBCL best predicted UHR or PT, and had screening values comparable to the PQ-16. Other syndrome scales did not improve screening values. Although combining measures reduced the number of false negatives, it also increased the number of adolescents to be interviewed. The best choice was to combine the YSR Thought Problems scale and the PQ-16 as a first-step screener. Conclusions: Combining measures improves the detection of UHR or PT in help-seeking adolescents. The Thought Problems subscales of the YSR and CBCL can both be used as a first-step screener in the detection of UHR and/or psychosis. Trial registration Permission was asked according to the rules of the Ethics Committee at Leiden. This study is registered as NL.44180.058.13 Show less
A direct comparison of two methods for estimating the treated incidence of schizophrenia: the first-contact design (current standard) vs. an electronic psychiatric case-register (new method). The... Show moreA direct comparison of two methods for estimating the treated incidence of schizophrenia: the first-contact design (current standard) vs. an electronic psychiatric case-register (new method). The assumptions underlying the first-contact design are tested. The causes of 2 to 4-fold difference in estimates are conceptualized in a 3-dimensional model. The model is tested on the Norther European incidence literature. Show less
Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations... Show morePrevious studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities. Show less
In this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was... Show moreIn this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was to determine which predictors and associated factors contributed to the development of certain non-motor symptoms in Parkinson’s disease (PD). Strengths of our cohort study include the length of the follow-up period, broad clinical characterization, limited loss-to-follow-up and the large cohort size. The following non-motor symptoms have been addressed in this thesis: psychosis (hallucinations), dementia, excessive daytime sleepiness (EDS), insomnia, depression and anxiety. We found that while certain non-motor symptoms are inherent components of PD that increase in severity as the disease progresses, others symptoms such as excessive daytime sleepiness are inarguably caused by antiparkinsonian medication. For the future, we hope to see more longitudinal data on the disease progression in PD from large cohorts. Knowledge from longitudinal studies does not only contribute to more insight in the underlying pathobiology of PD, but it could also help the caregiver to monitor patients with particular risk factors more closely and adjust treatment if necessary. Show less
Ziermans, T.; Swaab, J.T.; Stockmann, A.; De Bruin, E.; Rijn, S. van 2017
Schizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was... Show moreSchizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was to identify novel susceptibility genes and pathways for psychosis in a psychostimulant mouse model which is considered a model for psychosis. Genome-wide analysis of transcripts in the hippocampal CA1, driving mesocortical dopaminergic activity, which has a prominent role in schizophrenia, revealed differential expression of target genes of Myocyte Enhancer Factor 2 (MEF2) and Glucocorticoid Receptor (GR). This suggest that this gene network is involved in sensitivity to amphetamine. In primary hippocampal neurons, knockdown of MEF2 reduced the expression of c-Jun and abolished its regulation by GR. Moreover, activation of MEF2 by neuronal depolarization was attenuated by glucocorticoids, suggesting a mutual feedback regulation of these transcription factors. Finally, in vivo MEF2 and GR appeared to be active in the induction phase of amphetamine sensitization. Overall, the findings suggest that in the hippocampus activation of GR can modulate the role of MEF2 target genes in induction of behavioral sensitization. This finding points to the hippocampus as an exciting target for further studies on the role of MEF2 and GR in the precipitation of psychosis susceptibility. Show less
Core deficits in people with autisme spectrum disorders (ASD) are difficulties in adapting their behaviour to the social environment which hampers the possibilities to communicate adequately and to... Show moreCore deficits in people with autisme spectrum disorders (ASD) are difficulties in adapting their behaviour to the social environment which hampers the possibilities to communicate adequately and to have reciprocal relationships. These problems have a serious impact on functioning in their daily life. Since ASD are severe and lifelong conditions, it is relevant to examine how children with ASD develop troughout their life and to investigate which factors constitute an unfavourable contribution to their development. This thesis reveals that children with ASD are at specific risk of poor quality of life in adulthood when compared to children with other psychiatric disorders. Secondly, the impact of ASD on specific domains of intellectual functioning is different at different ages, implicating that re-evaluation of cognitive function during development of children with ASD is recommended during their life. Thirdly, children with ASD who are at risk of schizophrenia spectrum pathology, may show negative schizotypal symptoms, but also disorganized and positive symptoms in addition to ASD symptomatology. These symptoms of schizotypy appear to be associated with inhibition problems. We should be aware of inhibition problems in children with ASD because they may be indicators of high risk to schizophrenia spectrum pathology later in life. Show less
During early adolescence, there is no association between internalizing behaviour and cannabis use. There is an association between externalizing behaviour and cannabis use, where externalizing... Show moreDuring early adolescence, there is no association between internalizing behaviour and cannabis use. There is an association between externalizing behaviour and cannabis use, where externalizing behaviour precedes cannabis use rather than the other way around. Secondly, during adolescence, there is an association between psychosis vulnerability and cannabis use, where cannabis use predicts psychosis vulnerability and vice versa, suggesting a bi-directional cascading association. Thirdly, during early adolescence, the social skill “self-control” was (unexpectedly) unrelated to cannabis use. Cooperation and assertiveness are associated with cannabis use during this life phase, where higher levels of cooperation decrease the chance of using cannabis and higher levels of assertiveness increase the chance of using cannabis during early adolescence. Cooperation and assertiveness did not differentiate between early and late onset of cannabis use or predict frequency of use. In addition, compared to non-users, cannabis users experience problems only in motivational inhibitory control, not in cognitive inhibitory control. Also, cannabis users experience problems in behavioural impulsivity, which is related to motivational inhibitory control. Lastly, cannabis users have problems with social perception in comparison to non-using controls, particularly when these social perception skills involve emotion recognition. Also, heavy cannabis users experience significantly more psychological problems when they have relatively poor social perception skills. Future research must determine whether the behavioural and cognitive concepts and constructs examined in this thesis in relation to cannabis use should be incorporated in prevention and intervention programs. Show less
Background: In the present study, we tested both the cumulative stress and the mismatch hypothesis of psychopathology. For this purpose the combined effects of early-life adversity and later-life... Show moreBackground: In the present study, we tested both the cumulative stress and the mismatch hypothesis of psychopathology. For this purpose the combined effects of early-life adversity and later-life stress exposure on behavioral markers of psychosis susceptibility were studied in male Wistar rats.Method: Experiment I: rat pups divided on the basis of the levels of their maternal care experience in low, medium or high maternal care groups, were reared post-weaning in groups (Exp. IA) or in social isolation (Exp. IB) and tested at adulthood under basal conditions or after an acute corticosterone (CORT) administration. Maternal care levels were assessed by measuring the dam's licking and grooming (LG) the first postnatal week of life. Experiment II: rat pups exposed as neonates to daily sessions of 8 h of maternal separation (MS) on postnatal days 3, 4 and 5 either altogether in their home cage (HOME SEP) or alone in a novel environment (NOVEL SEP). were reared post-weaning in groups and tested at adulthood under basal conditions.Adult testing included behaviors marking psychosis susceptibility: apomorphine-induced gnawing (APO-gnawing), acoustic startle response and its modulation by a prepulse stimulus (PPI). The behavior of the Medium LG offspring was used as baseline reference for all the three experiments.Results: Experiment I: Low maternal LG history alone had limited effects on the behavior of Wistar offspring, although increased acoustic startle and increased PPI, at high prepulse intensity levels, were observed. When low maternal LG history was combined with post-weaning social isolation, basal APO-gnawing was decreased and PPI increased, compared to High LG and Med LG offspring. This reflects attenuated psychosis susceptibility. High LG offspring reared in isolation displayed, however, the highest APO-gnawing and the lowest PPI levels among rats reared in social isolation, which is indicative for increased psychosis susceptibility. These findings support the mismatch hypothesis. For demonstration of the cumulative stress hypothesis an injection of CURT in the adult Low LG offspring was required that increased APO-gnawing and reduced PPI. This CURT-induced PPI disruption was greatly enhanced after additional isolation rearing. The High LG group, either socially housed or reared in isolation, was resistant to the acute effects of CORT at adulthood.Experiment II: MS increased psychosis susceptibility only in NOVEL SEP rats that had experienced MS in the context of early social isolation. These individuals displayed increased adult APO-gnawing and reduced PPI, if reared post-weaning in a condition that does not match with their early life social environment (i.e. group housing). This finding supports the mismatch hypothesis.Conclusion: The outcome of environmental manipulations on developmental programming of psychosis susceptibility depends on the interplay of early-life adversity and later-life stressors in a manner that supports the mismatch hypothesis. However, evidence for the cumulative stress hypothesis arises if vulnerable individuals are exposed in later life additionally to excess of the stress hormone CURT. (C) 2012 Elsevier Inc. All rights reserved. Show less
Rietdijk, J.; Hogerzeil, S.J.; Hemert, A.M. van; Cuijpers, P.; Linszen, D.H.; Gaag, M. van der 2011
Rationale Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential... Show moreRationale Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis.Objectives The aim of the current study was to investigate which genes and pathways may contribute to behavioral sensitization in different dopaminergic output areas in the mouse brain.Methods We took advantage of the naturally occurring difference in psychostimulant sensitivity in DBA/2 mice and selected animals displaying extremes in behavioral sensitization to amphetamine. Subsequently, the dopamine output areas, prefrontal cortex, nucleus accumbens, and cornu ammonis 1 (CA1) area of the hippocampus, were isolated by laser microdissection and subjected to DNA microarray analysis 1 h after a challenge dose of amphetamine. Results A large number of genes with differential expression between high and low responders were identified, with no overlap between brain regions. Validation of these gene expression changes with real-time quantitative polymerase chain reaction demonstrated that the most robust and reproducible effects on gene expression were in the CA1 region of the hippocampus. Interestingly, many of the validated genes in CA1 are members of the cAMP response element (CRE) family and targets of the glucocorticoid receptor (GR) and myocyte enhancer factor 2 (Mef2) transcription factors.Conclusion We hypothesize that CRE, Mef2, and GR signaling form a transcription regulating network, which underlies differential amphetamine sensitivity, and therefore, may play an important role in susceptibility to psychosis. Show less
The thesis “Non-motor symptoms in Parkinson’s disease” is part of the PROPARK study, a longitudinal cohort study of approximately 400 patients with Parkinson’s disease (PD), who are profiled on... Show moreThe thesis “Non-motor symptoms in Parkinson’s disease” is part of the PROPARK study, a longitudinal cohort study of approximately 400 patients with Parkinson’s disease (PD), who are profiled on genotype, phenotype, disability, and global outcomes of health, using valid and reliable assessment instruments for PD. The aims of this thesis were to characterize the non-motor domains important in PD such as olfactory, autonomic, sleep, cognitive, and psychiatric problems. Additionally, their relations with other domains of the disease were evaluated on a cross-sectional level, as well as their impact on disability and health-related quality of life. Furthermore, the phenotypic characteristics of mutation carriers in the cohort were evaluated. The most important conclusions from this thesis are: 1. Non-motor symptoms are frequently present in patients with PD 2. Non-motor symptoms are related to each other 3. Non-motor symptoms greatly influence quality of life in patients with PD The results as described in this thesis will serve as guideline for future research which will be aimed at underlying disease mechanisms. Show less
