[show abstract][hide abstract] ABSTRACT: There is genetic evidence that schizophrenia is a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) of schizophrenia have had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood of schizophrenia patients and controls. We examined the 6192 single-nucleotide polymorphisms (SNPs) with significance threshold at P<0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n=437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set of schizophrenia cases and controls (n=202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5, TRIM26 and HLA-DRB3) coincided with the direction expected from meta-analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region in schizophrenia susceptibility.
European journal of human genetics: EJHG 03/2012; 20(9):1004-8. · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background:The term psychosis refers to a combination of symptoms, without pointing to the origin of these symptoms. In a subset of psychotic patients, symptoms are attributable to an organic disease. It is important to identify these organic causes of psychosis early, as urgent treatment of the primary disease may be required. Some of these underlying organic disorders can be identified on magnetic resonance imaging (MRI) scans. Whether routine screening for all psychotic patients should therefore include MRI scans is still a matter of debate.Methods:This study investigated the prevalence of clinically relevant abnormalities detected on MRI scans from psychotic patients and a matched control group. We could include MRI scans from 656 psychotic patients and 722 controls. The standard radiological reports of these scans were classified as normal, as a nonrelevant abnormality or as a clinically relevant brain abnormality by means of consensus, blind to diagnosis.Results:A normal aspect of the brain was reported in 74.4% of the patients and in 73.4% of the controls. We found clinically relevant pathology in 11.1% of the patients and in 11.8% of the controls. None of the neuropathological findings observed in the patients was interpreted as a possible substrate for organic psychosis. Brain abnormalities that were classified as not clinically relevant were identified in 14.5% of the patients and in 14.8% of the controls.Conclusions:This suggests that MRI brain scans are not an essential part of routine screening for psychotic patients.
[show abstract][hide abstract] ABSTRACT: To investigate familial clustering of schizophrenia, bipolar disorder, and major depressive disorder.
Combining data from a psychiatric case registry and Statistics Netherlands provided information on 4,673 affected probands and 18,692 matched population controls.
Probands with schizophrenia had relative risks (RRs) for having a sibling with schizophrenia of 3.77 (95% confidence interval (CI): 2.60-5.46) and with bipolar disorder of 1.79 (95% CI: 0.64-4.96) as compared with a reference proband. Probands affected with bipolar disorder have an RR of 6.51 (95% CI: 2.60-16.29) for having a sibling with bipolar disorder and of 1.71 (95% CI: 0.71-4.14) for having a sibling with schizophrenia as compared with a reference proband. Probands affected with major depressive disorder also have increased risk for having a sibling with schizophrenia (RR: 2.04, 95% CI: 1.54-2.72) as compared with a reference proband, which was similar to the risk for having a sibling with major depressive disorder (RR: 1.91, 95% CI: 1.63-2.24) or bipolar disorder (RR: 2.06, 95% CI: 1.18-3.60).
Our findings suggest, as previous studies have, that risk across schizophrenia and bipolar disorder is considerably lower (twofold) than within diagnostic entities, whereas for major depressive disorder risk is similar within and across diagnostic entities.
Genetics in medicine: official journal of the American College of Medical Genetics 03/2012; 14(3):338-41. · 3.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Little is known about how the biological stress response systems--the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system--function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.
[show abstract][hide abstract] ABSTRACT: Volumetric differences of the hypothalamus and/or the pituitary gland tend to support involvement of the HPA axis in psychotic disorders. These structures were manually outlined in 154 schizophrenia patients and 156 matched healthy comparison subjects by MRI brain images. Linear regression analyses were performed to investigate differences in volume between groups. Moreover, the effects of illness duration and type of medication were investigated. No significant differences were found between patients and healthy controls in volumes of the hypothalamus and pituitary gland. In addition, there were no differences in volumes between patients with short and long illness duration. There was a trend towards patients receiving typical antipsychotic medication at the time of scanning having larger pituitary volumes than patients receiving atypical medication. These findings indicate that volume decreases in brain structures important for the normal functioning of the HPA axis are not present, either in recent-onset or chronically ill patients.
The International Journal of Neuropsychopharmacology 02/2012; 15(02):281 - 288. · 5.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evidence indicates involvement of the endocannabinoid (eCB) system in both the pathophysiology of schizophrenia and working memory (WM) function. Additionally, schizophrenia patients exhibit relatively strong WM deficits. These findings suggest the possibility that the eCB system is also involved in WM deficits in schizophrenia. In the present study, we examined if perturbation of the eCB system can induce abnormal WM activity in healthy subjects.
A pharmacological functional magnetic resonance imaging study was conducted with a placebo-controlled, cross-over design, investigating effects of the eCB agonist Δ9-tetrahydrocannabinol on WM function in 17 healthy volunteers, by means of a parametric Sternberg item-recognition paradigm with five difficulty levels.
Performance accuracy was significantly reduced after Δ9-tetrahydrocannabinol. In the placebo condition, brain activity increased linearly with rising WM load. Δ9-Tetrahydrocannabinol administration enhanced activity for low WM loads and reduced the linear relationship between WM load and activity in the WM system as a whole and in left dorsolateral prefrontal cortex, inferior temporal gyrus, inferior parietal gyrus, and cerebellum in particular.
Δ9-Tetrahydrocannabinol enhanced WM activity network-wide for low loads, while reducing the load-dependent response for increasing WM loads. These results indicate that a challenged eCB system can induce both abnormal WM activity and WM performance deficits and provide an argument for the possibility of eCB involvement in WM deficits in schizophrenia.
[show abstract][hide abstract] ABSTRACT: Structural brain abnormalities are consistently found in schizophrenia (Sz) and have been associated with the familial risk for the disorder. We aim to define the relative contributions of genetic and nongenetic factors to the association between structural brain abnormalities and Sz in a uniquely powered cohort (Schizophrenia Twins and Relatives consortium).
An international multicenter magnetic resonance imaging collaboration was set up to pool magnetic resonance imaging scans from twin pairs in Utrecht (The Netherlands), Helsinki (Finland), London (United Kingdom), and Jena (Germany). A sample of 684 subjects took part, consisting of monozygotic twins (n = 410, with 51 patients from concordant and 52 from discordant pairs) and dizygotic twins (n = 274, with 39 patients from discordant pairs). The additive genetic, common, and unique environmental contributions to the association between brain volumes and risk for Sz were estimated by structural equation modeling.
The heritabilities of most brain volumes were significant and ranged between 52% (temporal cortical gray matter) and 76% (cerebrum). Heritability of cerebral gray matter did not reach significance (34%). Significant phenotypic correlations were found between Sz and reduced volumes of the cerebrum (-.22 [-.30/-.14]) and white matter (-.17 [-.25/-.09]) and increased volume of the third ventricle (.18 [.08/.28]). These were predominantly due to overlapping genetic effects (77%, 94%, and 83%, respectively).
Some of the genes that transmit the risk for Sz also influence cerebral (white matter) volume.
[show abstract][hide abstract] ABSTRACT: Findings on the impact of cannabis use on the course of schizophrenia are inconsistent and not conclusive.
To study the effect of cannabis use on the course of schizophrenia taking into account the effects of the quantity of cannabis use and important confounders.
Prospective cohort study with assessments of symptoms, confounders and hospitalizations at baseline, 6 month and 12 month follow up.
In a representative cohort of 145 male patients with schizophrenia, 68 (46.9%) used cannabis. Mean age at onset of schizophrenia in cannabis using patients was significantly lower than in non-cannabis using patients. No other cross-sectional demographic or clinical differences were observed between users and non-users. In a series of longitudinal analyses, cannabis use was not associated with differences in psychopathology, but relapse in terms of the number of hospitalizations was significantly higher in cannabis using patients compared to non-cannabis using patients.
Patients with schizophrenia using cannabis are more frequently hospitalized than non-cannabis using patients but do not differ with respect to psychopathology. Possible explanations for these findings are discussed.
Schizophrenia Research 02/2012; 137(1-3):50-7. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) to the temporoparietal region has been proposed as a therapeutic option for auditory verbal hallucinations (AVH). However, most large randomized controlled trials failed to demonstrate a superior effect of rTMS treatment as compared to sham. Previous studies applied daily rTMS sessions for one or more weeks to summate its effects. However, the effect of a single rTMS treatment on AVH-severity has never been studied, making it unclear if there is an initial effect that could be increased by repeated treatment.
In three separate sessions, twenty-four patients with a psychotic disorder received 1-Hz rTMS to the left temporoparietal cortex, its right-sided homologue or a centro-occipital control site. Severity of AVH was assessed before and after each rTMS session and resting-state EEGs were recorded to investigate the neuronal effects of rTMS.
Stimulation of the temporoparietal cortices was not more effective in reducing AVH-severity than control-site stimulation. In addition, EEG-related power and connectivity measures were not affected differently across stimulation sites and changes in neuronal activity did not correlate with changes in AVH-severity.
These results may suggest a placebo effect of a single session of 1-Hz rTMS treatment on AVH-severity.
Schizophrenia Research 01/2012; 137(1-3):174-9. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background:The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations.Methods:We compared dopamine synthesis capacity (using 6-[(18)F]fluoro-L-DOPA [[(18)F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls.Results:There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group.Conclusions:Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.
[show abstract][hide abstract] ABSTRACT: Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network.
PLoS ONE 01/2012; 7(6):e39498. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is therefore of interest to investigate how psychiatric drugs are of influence and what the potential is of new epigenetic drugs for psychiatric disorders. With this targeted review we summarize the current state of knowledge in order to provide insight in this developing field. Several traditional psychiatric drugs have been found to alter the epigenome and in a variety of animal studies, experimental compounds with epigenetic targets have been investigated as potential psychiatric drugs. After discussion of the most relevant epigenetic mechanisms we present the evidence for epigenetic effects for the most relevant classes of drugs.
Epigenetics: official journal of the DNA Methylation Society 01/2012; 7(1):20-8. · 4.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia.
PLoS ONE 01/2012; 7(6):e37852. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ~85%), surface area (~85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = -0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization.
PLoS ONE 01/2012; 7(4):e32316. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults.
Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PC(max)) and minimum (PC(min)) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max) = 172 and PC(min) = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations.
In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall.
PLoS ONE 01/2012; 7(2):e30497. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mounting evidence suggests that inflammation is involved in the pathogenesis of schizophrenia. This evidence implies that anti-inflammatory agents are potentially useful therapeutic strategies in schizophrenia. This article quantitatively summarizes the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) to augment antipsychotic treatment to reduce schizophrenia symptom severity.
An electronic search was performed using MEDLINE, Embase, the National Institutes of Health Web site clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. The following basic search terms were used: schizophrenia, nonsteroidal anti-inflammatory drug, and NSAID together with the name of each specific NSAID (ibuprofen, diclofenac, naproxen sodium, and acetylsalicylic acid). We applied no year or language restrictions.
Studies were selected if they met the following inclusion criteria: (1) randomized, double-blind, placebo-controlled trials regarding augmentation of antipsychotic medication with an NSAID, (2) patients included had a diagnosis of a schizophrenia spectrum disorder according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, and (3) studies reported sufficient information to compute common effect size statistics, or corresponding authors could supply these data upon request.
The primary outcome measure was the mean change in total score on the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures included positive and negative symptom subscores of the PANSS.
We could include 5 double-blind, randomized, placebo-controlled trials, reporting on 264 patients. Four studies applied celecoxib, and 1 used acetylsalicylic acid. We found a mean effect size of 0.43, which was significant at P = .02 in favor of NSAIDs on total symptom severity. For positive symptom severity, the mean standardized difference was 0.34 (P = .02). For severity of negative symptoms the mean standardized difference was 0.26 (P = .03).
These results suggest that NSAID augmentation could be a potentially useful strategy to reduce symptom severity in schizophrenia. As these are the first studies on a relatively new strategy and the included sample size is modest, these results should be interpreted with caution. However, augmentation with acetylsalicylic acid may have the additional benefit of reducing cardiac and cancer mortality in schizophrenia. We therefore believe that application of NSAIDs in schizophrenia deserves further investigation as augmentation of antipsychotic treatment and reducing comorbid somatic diseases.
The Journal of Clinical Psychiatry 12/2011; 73(4):414-9. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous research has shown discrepancies between a standard diagnostic interview for schizophrenia (CASH) and a culture sensitive version of this instrument (CASH-CS) in Moroccan patients. More specifically we showed that among Moroccan immigrants the CASH-CS resulted in fewer patients with a diagnosis of schizophrenia compared with diagnoses based on the CASH, whereas for Native Dutch patients there was no difference between the CASH and the CASH-CS. The aim of the current study was to compare the predictive validity of a diagnosis of schizophrenia according to the CASH and CASH-CS.
Thirty months after referral, 26 Moroccan and 26 native Dutch patients with a suspected first psychotic episode were compared with regard to 30-month diagnostic stability, symptom development, psychosocial functioning, medication use and hospitalization using baseline diagnoses based on the two versions of the CASH.
Moroccan patients who were diagnosed with schizophrenia using the standard CASH at baseline had a significantly better 30-month prognosis than native Dutch patients with the same CASH diagnosis. Prognosis of schizophrenia according to the CASH-CS was similar for Moroccans and native Dutch patients. Diagnostic stability according to the CASH was high for native Dutch (92%), but low for Moroccan patients (27%), whereas diagnostic stability according to the CASH-CS was high for both groups (85% and 81%, respectively).
These data raise questions regarding the validity of the standard CASH in Moroccan immigrants in The Netherlands and support the validity of the CASH-CS. As a consequence, there are serious doubts about the validity of previous studies showing an increased incidence of schizophrenia in immigrants using standard diagnostic procedures.
Schizophrenia Research 12/2011; 133(1-3):29-35. · 4.59 Impact Factor