Machteld Marcelis

Urbanization and psychosis: a study of 1942-1978 birth cohorts in The Netherlands.

BACKGROUND Urban birth is associated with later schizophrenia. This study examined whether this finding is diagnosis-specific and which individuals are most at risk. METHODS All live births recorded between 1942 and 1978 in any of the 646 Dutch municipalities were followed-up through the National Psychiatric Case Register for first psychiatric admission for psychosis between 1970 and 1992 (N = 42115). RESULTS Urban birth was linearly associated with later schizophrenia (incidence rate ratio linear trend (IRR), 1.39; 95% confidence interval (95% CI), 1.36-1.42), affective psychosis (IRR, 1.18; 95% CI, 1.15-1.21) and other psychosis (IRR, 1.27; 95% CI, 1.24-1.30). Individuals born in the highest category of the three-level urban exposure were around twice as likely to develop schizophrenia. Associations were stronger for men and for individuals with early age of onset. The effect of urban birth was also stronger in the more recent birth cohorts. CONCLUSIONS There are quantitative differences between diagnostic categories in the strength of the association between urban birth and later psychiatric disorder. High rates of psychosis in urban areas may be the result of environmental factors associated with urbanization, the effect of which appears to be increasing over successive generations.

Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis ? A psychosis proneness-persistence model

BACKGROUND Research suggests that low-grade psychotic experiences in the general population are a common but transitory developmental phenomenon. Using two independent general population samples, the hypothesis was examined that common, non-clinical developmental expression of psychosis may become abnormally persistent when synergistically combined with developmental exposures that may impact on behavioural and neurotransmitter sensitization such as cannabis, trauma and urbanicity. METHOD The amount of synergism was estimated from the additive statistical interaction between baseline cannabis use, childhood trauma and urbanicity on the one hand, and baseline psychotic experiences on the other, in predicting 3-year follow-up psychotic experiences, using data from two large, longitudinal, random population samples from the Netherlands [The Netherlands Mental Health Survey and Incidence Study (NEMESIS)] and Germany [The Early Developmental Stages of Psychopathology (EDSP) study]. RESULTS The 3-year persistence rates of psychotic experiences were low at 26% in NEMESIS and 31% in EDSP. However, persistence rates were progressively higher with greater baseline number of environmental exposures in predicting follow-up psychotic experiences (chi2=6.9, df=1, p=0.009 in NEMESIS and chi2=4.2, df=1, p=0.04 in EDSP). Between 21% and 83% (NEMESIS) and 29% and 51% (EDSP) of the subjects exposed to both environmental exposures and psychotic experiences at baseline had persistence of psychotic experiences at follow-up because of the synergistic action of the two factors. CONCLUSION The findings suggest that environmental risks for psychosis act additively, and that the level of environmental risk combines synergistically with non-clinical developmental expression of psychosis to cause abnormal persistence and, eventually, need for care.

The effects of FreeSurfer Version, workstation type, and Macintosh Operating System Version on anatomical volume and cortical thickness measurements.

FreeSurfer is a popular software package to measure cortical thickness and volume of neuroanatomical structures. However, little if any is known about measurement reliability across various data processing conditions. Using a set of 30 anatomical T1-weighted 3T MRI scans, we investigated the effects of data processing variables such as FreeSurfer version (v4.3.1, v4.5.0, and v5.0.0), workstation (Macintosh and Hewlett-Packard), and Macintosh operating system version (OSX 10.5 and OSX 10.6). Significant differences were revealed between FreeSurfer version v5.0.0 and the two earlier versions. These differences were on average 8.8±6.6% (range 1.3–64.0%) (volume) and 2.8±1.3% (1.1–7.7%) (cortical thickness). About a factor two smaller differences were detected between Macintosh and Hewlett-Packard workstations and between OSX 10.5 and OSX 10.6. The observed differences are similar in magnitude as effect sizes reported in accuracy evaluations and neurodegenerative studies. The main conclusion is that in the context of an ongoing study, users are discouraged to update to a new major release of either FreeSurfer or operating system or to switch to a different type of workstation without repeating the analysis; results thus give a quantitative support to successive recommendations stated by FreeSurfer developers over the years. Moreover, in view of the large and significant cross-version differences, it is concluded that formal assessment of the accuracy of FreeSurfer is desirable.

Reduced Cortical Thickness as an Outcome of Differential Sensitivity to Environmental Risks in Schizophrenia

BACKGROUND The etiology of schizophrenia is thought to involve differential-likely genetically mediated-sensitivity to environmental exposures. However, examination of differential sensitivity in models of psychopathologic constructs is subject to bias because psychopathology itself may distort exposure assessment. The use of neuroimaging phenotypes, conversely, may provide unbiased evidence for differential sensitivity to environmental exposures. This study examined the impact of two environmental exposures associated with both schizophrenia and magnetic resonance imaging (MRI) cerebral alterations in models of cerebral cortical thickness. METHODS T1-weighted MRI scans were acquired from 88 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia, and 87 control subjects. Freesurfer software was used to measure cortical thickness for 68 brain regions. Associations between 1) cortical thickness and 2) cannabis use and developmental trauma were examined. RESULTS A significant group × developmental trauma interaction (χ(2) = 9.65, p = .01), as well as a significant group × cannabis interaction (χ(2) = 6.04, p = .05) was apparent, indicating differential sensitivity of the patient group, which displayed stronger reductions of cortical thickness for both exposures. A similar pattern was found in the sibling-control comparison for cannabis. For developmental trauma, siblings did not differ from control subjects, displaying an increase in cortical thickness with higher levels of trauma. CONCLUSIONS The findings suggest that schizophrenia and its genetic liability are associated with differential cerebral cortical sensitivity to developmental environmental exposures such as cannabis. Gene-environment interactions may underlie some of the brain alterations observed in patients with schizophrenia and their relatives.

Subtle Fluctuations in Psychotic Phenomena as Functional States of Abnormal Dopamine Reactivity in Individuals at Risk

BACKGROUND Subjects at increased risk for psychosis experience continuous variation in the intensity of subtle psychotic experiences in response to minor stressors. It was investigated whether this psychotic reactivity in individuals at risk for psychosis is the exophenotypic expression of an underlying endophenotype characterized by a hyperreactive dopamine (DA) system. METHODS First-degree relatives (n = 47) and control subjects (n = 49) were studied with the Experience Sampling Method (ESM), a structured diary technique assessing current context and psychopathology in daily life, to assess psychotic experiences in response to stress. A metabolic perturbation paradigm (administration of 2-deoxy-D-glucose inducing a mild state of glucoprivation) causing plasma elevation of homovanillic acid (HVA) was used as a proxy of DA reactivity. RESULTS Multilevel regression analyses revealed that the interaction between HVA reactivity and daily stress in their effect on psychotic experiences differed according to underlying vulnerability. In the first-degree relatives, underlying HVA reactivity modified the psychotic experiences to daily stress, whereas no such effect was found in control subjects. CONCLUSIONS These results suggest that psychotic experiences in response to minor stresses in the flow of daily life may be functional states of an underlying abnormal DA reactivity in subjects at risk to develop psychosis. The results add credence to the suggestion that abnormal DA reactivity may be part of the substrate that increases risk for psychotic symptoms in individuals at risk.

Searching for a structural endophenotype in psychosis using computational morphometry

Structural cerebral abnormalities are frequently observed in schizophrenia. These abnormalities may indicate vulnerability for the disorder, as evidenced by reports of familial clustering of measures identified through region-of-interest analyses using manual outlining procedures. We used computational morphometry to detect structural differences within the entire brain to further examine possible structural endophenotypes. Magnetic resonance imaging scans were obtained in 31 psychotic patients, 32 non-psychotic first-degree relatives of psychotic patients and 27 healthy controls. The images were processed using an automated procedure, yielding global grey matter, white matter, CSF and total brain volume. The relative distribution of grey matter was compared between groups on a clustered-voxel basis. Global grey matter and total brain volume did not differ between the groups. White matter volume was significantly higher and CSF volume significantly lower in relatives compared to both cases and controls. The clustered-voxel based group comparison yielded evidence for significant grey matter deficits in fronto-thalamic-cerebellar regions, in psychotic patients, whereas the most prominent deficits in relatives involved the cerebellum. Patients with psychosis and first-degree healthy relatives of patients with psychosis show cerebellar abnormalities, which may constitute a marker of genetic transmission.

The ecogenetics of schizophrenia : a review

Schizophrenia is generally thought to arise as a result of interactions between genetic vulnerability and environmental risk factors. However, research methods to actually investigate the pattern of hypothesized interactions have only recently been developed. In this article, we review the evidence that genes increase the risk for schizophrenia by making individuals more sensitive to environmental risk factors (genotype-environment interaction), or by making individuals more likely to select high-risk environments (genotype-environment correlation). It is likely that at least some of the impact of genes on the occurrence of schizophrenia is mediated through (sensitivity for) environmental risk factors such as a dysfunctional early family rearing environment, cannabis, viral infections, complications of birth and pregnancy, stressful life events and unknown environmental risk factors associated with urban birth or residence and membership of certain ethnic groups. With the advent of molecular genetics, further knowledge about possible genotype-environment interactions is urgently required in order to develop and improve strategies for the prevention and early treatment of schizophrenia.

FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma

BACKGROUND FK506 binding protein 5 (FKBP5) has repeatedly been shown to be a critical determinant of post-traumatic stress disorder (PTSD) and depression following childhood trauma. AIMS To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype. METHOD In 401 general population twins, four functional polymorphisms were examined in models of psychosis and cortisol, and followed up in models of psychosis in three samples at different familial liability (175 controls, 200 unaffected siblings and 195 patients with a psychotic disorder). RESULTS The most consistent finding was an interaction between childhood trauma and rs9296158/rs4713916 on psychotic symptoms and cortisol in the twin sample, combined with a directionally similar interaction in siblings (rs4713916) and patients (rs9296158), A-allele carriers at both polymorphisms being most vulnerable to trauma. CONCLUSIONS Trauma may increase the risk of psychosis through enduring changes in the cortisol feedback loop, similar to that for PTSD, suggesting comparable biological mechanisms for psychosis across diagnostic boundaries.

Obstetric complications and familial morbid risk of psychiatric disorders

Obstetric complications (OCs) have been found to occur in higher frequency in patients with schizophrenia. One explanation for this finding is that the genes that contribute to the schizophrenia phenotype also influence the likelihood to experience OCs. If this were true, morbid risk of psychiatric illness should be higher in the first-degree relatives of both schizophrenic and control probands exposed to OCs, compared to probands not exposed to OCs. We set out to test this hypothesis. Information on OCs, blind to family history of psychiatric disorder, was collected retrospectively through maternal interview in 151 psychotic patients and 100 controls. Family history (FH) in relatives of cases (n = 600) and controls (n = 461) was assessed with the FH-RDC and through personal interviews. Tests for associations between family history and OCs were conducted using Cox proportional hazard regression. In the cases, familial morbid risk of affective disorder was greater in those with a history of OCs (hazard ratio (HR) = 1.9, P = 0.007). Analyses examining individual complications revealed associations between FH of affective disorder and pre-eclampsia (HR = 2.9, P = 0.003) and FH of affective disorder and breech presentation (HR = 2.8, P = 0.02), especially when family history in the relatives was confined to affective illness in the mother (HR pre-eclampsia = 4.4, P = 0.009; HR breech-presentation = 4.2, P = 0.008). In controls, affective illness in the mother was not only associated with breech presentation (HR = 7.0, P = 0.01) and pre-eclampsia (HR = 4.4, P = 0.03) but also with other complications. Familial morbid risk of schizophrenia and related psychoses was not associated with OCs. The positive associations between OCs and familial morbid risk of affective disorder suggest that the factors that contribute to familial aggregation of affective symptoms in psychotic patients also influence the likelihood to experience OCs. Although the proportion of OCs that could be attributed to these factors was very small, part of the relationship between family history of affective disorder and psychosis may be mediated by OCs.

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.