Environmental Risk Factors For Schizophrenia Research Articles

Neurodevelopment, GABA system dysfunction, and schizophrenia.

The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and environmental risk factors that predispose to schizophrenia disrupt the development and normal functioning of the GABAergic system.

Population impact of familial and environmental risk factors for schizophrenia: A nationwide study

Although several studies have examined the relative contributions of familial and environmental risk factors for schizophrenia, few have additionally examined the predictive power on the individual level and simultaneously examined the population impact associated with a wide range of familial and environmental risk factors. The authors present rate ratios (IRR), population-attributable risks (PAR) and sex-specific cumulative incidences of the following risk factors: parental history of mental illness, urban place of birth, advanced paternal age, parental loss and immigration status. We established a population-based cohort of 2,486,646million persons born in Denmark between 1 January 1955 and 31 December 1993 using Danish registers. We found that PAR associated with urban birth was 11.73%; PAR associated with one, respectively 2, parent(s) with schizophrenia was 2.67% and 0.12%. PAR associated with second-generation immigration was 0.70%. Highest cumulative incidence (CI=20.23%; 95% CI=18.10–22.62) was found in male offspring of 2 parents with schizophrenia. Cumulative incidences for male offspring or female offspring of a parent with schizophrenia were 9.53% (95% CI=7.71–11.79), and 4.89%, (95% CI 4.50–5.31). The study showed that risk factors with highest predictive power on the individual level have a relatively low population impact. The challenge in future studies with direct genetic data is to examine gene-environmental interactions that can move research beyond current approaches and seek to achieve higher predictive power on the individual level and higher population impact.

Schizophrenia and Its Association with Biological and Environmental Factors: A Community Based Study

Aims: The aim of this study was to examine the proportion of probable schizophrenia in Arab population visiting primary health care centers and investigate its associated biologic and environmental factors. Study Design: Cross sectional study. Place and Duration of Study: Primary Health Care (PHC) centres, Supreme Council of Health, Qatar, between January 2009 to December 2010. Subjects: Of 1491 Arab patients approached, 1148 patients agreed to participate in the study (77%). Methods: The study was based on a face to face interview with a designed questionnaire including socio-demographic, biologic and environmental factors. A diagnostic screening questionnaire which consisted of 6 questions about the symptoms of schizophrenic disorders was used for the diagnosis of schizophrenia. Results: Of the studied subjects, 11.7% of them were diagnosed with schizophrenia. A significant association was observed between schizophrenic and non-schizophrenic Research Article British Journal of Medicine & Medical Research, 4(1): 202-214, 2014 203 patients in terms of age group (p=0.048), BMI (p=0.019), gender (p=0.027), ethnicity (p=0.008), marital status (p=0.001), occupation (p<0.001), household income (p<0.001) and place of residence (p=0.039). Obstetric complications were significantly higher in schizophrenic patients with a higher frequency of pregnancy stress (31.3%; p<0.001) and diabetes (20.1%; p=0.008). Among the obstetric complications, Rhesus incompatibility (OR 2.74; 95% CI (1.16-6.47); P=0.021) and pregnancy stress (OR 2.51; 95% CI (1.60-3.94); P<0.001) were the major predictors for the development of schizophrenia. Delivery complications of asphyxia (17.9%; p=0.003), uterine atony (10.4%; p=0.028) and emergency caesarean section (17.2%; p=0.024) were significantly higher in mothers of the patients. Urban upbringing (OR 1.60; 95% CI (1.02 2.50); P<0.037) and social isolation (OR 1.72; 95% CI (1.06-2.74); P<0.027) were the main significant environmental risk factors for schizophrenia. Conclusion: An increasing schizophrenia risk with obstetric complications was observed in the study sample. Rhesus incompatibility and pregnancy stress were the main predictors for schizophrenia.

Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia

Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.

Stress-Induced Dopamine Response in Subjects at Clinical High Risk for Schizophrenia with and without Concurrent Cannabis Use

Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [(11)C]-(+)-PHNO positron emission tomography scans, while performing a Sensorimotor Control Task (SMCT) and a stress condition (Montreal Imaging Stress task). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BPND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST)), globus pallidus (GP), and substantia nigra (SN). Changes in BPND, reflecting alterations in synaptic dopamine (DA) levels, were tested with analysis of variance. SMCT BPND was not significantly different between groups in any brain region (p>0.21). Although stress elicited a significant reduction in BPND in the CHR group, CHR-CU group exhibited an increase in BPND. Stress-induced changes in regional BPND between CHR-CU and CHR were significantly different in AST (p<0.001), LST (p=0.007), SMST (p=0.002), SN (p=0.021), and whole striatum (p=0.001), with trend level in the GP (p=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (p=0.001) following the stress task. Our results suggest altered DA stress reactivity in CHR subjects who concurrently use cannabis, as compared with CHR subjects. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced DA (stress) response in addiction.

Prenatal immune activation interacts with stress and corticosterone exposure later in life to modulate N-methyl-d-aspartate receptor synaptic function and plasticity

Prenatal infection is an environmental risk factor for schizophrenia while later in life, stressful events have been associated with the onset and severity of psychosis. Recent findings on the impact of stress on the N-methyl-d-aspartate receptor (NMDAR), of which hypofunctioning is implicated in schizophrenia, suggest changes in stress-induced regulation of the glutamatergic system may be related to the pathogenesis of schizophrenia. Our study aimed to test whether prenatal immune activation could interact with stress at adolescence to alter NMDAR function. We used offspring from rat dams administered bacterial lipopolysaccharide (LPS) during pregnancy (gestational days 15 and 16), an animal model expressing schizophrenia-related behavioural phenotypes. Using electrophysiological techniques, we investigated effects of stress and the stress hormone corticosterone (Cort) on NMDAR-mediated synaptic function and long-term depression (LTD) in hippocampal CA1 slices from these adolescent (aged 28-39d) male offspring. In prenatal LPS offspring, NMDAR-mediated synaptic function and LTD were reduced and abolished, respectively, compared to prenatal saline controls. Notably, in vivo stress and in vitro Cort treatment facilitated LTD in slices from prenatal LPS rats but not prenatal saline controls. Finally, Cort enhanced NMDAR-mediated synaptic function in slices from prenatal LPS rats only. We conclude that prenatal immune activation results in NMDAR hypofunction in the hippocampus of adolescent rats but also increases responsiveness of NMDAR-mediated synaptic function and LTD towards stress. Prenatal infection could confer susceptibility to schizophrenia through modification of hippocampal NMDAR function, with hypofunction in resting conditions and heightened responsiveness to stress, thus impacting the development of the disorder.

Transient activation of dopaminergic neurons during development modulates visual responsiveness, locomotion and brain activity in a dopamine ontogeny model of schizophrenia

It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the “dopamine ontogeny hypothesis of schizophrenia”. To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia.

Omega-3 fatty acid deficiency disrupts endocytosis, neuritogenesis, and mitochondrial protein pathways in the mouse hippocampus

Omega-3 fatty acid (n-3 FA) deficiency is an environmental risk factor for schizophrenia, yet characterization of the consequences of deficiency at the protein level in the brain is limited. We aimed to identify the protein pathways disrupted as a consequence of chronic n-3 deficiency in the hippocampus of mice. Fatty acid analysis of the hippocampus following chronic dietary deficiency revealed a 3-fold decrease (p < 0.001) in n-3 FA levels. Label free LC-MS/MS analysis identified and profiled 1008 proteins, of which 114 were observed to be differentially expressed between n-3 deficient and control groups (n = 8 per group). The cellular processes that were most implicated were neuritogenesis, endocytosis, and exocytosis, while specific protein pathways that were most significantly dysregulated were mitochondrial dysfunction and clathrin mediated endocytosis (CME). In order to characterize whether these processes and pathways are ones influenced by antipsychotic medication, we used LC-MS/MS to test the differential expression of these 114 proteins in the hippocampus of mice chronically treated with the antipsychotic agent haloperidol. We observed 23 of the 114 proteins to be differentially expressed, 17 of which were altered in the opposite direction to that observed following n-3 deficiency. Overall, our findings point to disturbed synaptic function, neuritogenesis, and mitochondrial function as a consequence of dietary deficiency in n-3 FA. This study greatly aids our understanding of the molecular mechanism by which n-3 deficiency impairs normal brain function, and provides clues as to how n-3 FA exert their therapeutic effect in early psychosis.

Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the “Two Hit” Hypothesis for the Development of Schizophrenia

Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia.

Prediction and prevention of schizophrenia: what has been achieved and where to go next?

In modern medicine, vigorous efforts are being made in the prediction and prevention of diseases. Mental disorders are suitable candidates for the application of this program. The currently known neurobiological and psychosocial risk indicators for schizophrenia do not have a predictive power sufficient for selective prevention in asymptomatic patients at risk. However, once predictive basic and later pre-psychotic high risk symptoms of psychosis develop into the five-year initial prodrome, the impending outbreak of the disease can be predicted with high accuracy. Research findings suggest a differential strategy of indicated prevention with cognitive behavioral therapy in early initial prodromal states and low dosage atypical antipsychotics in late initial prodromal states. The most important future tasks are the improvement of the predictive power by risk enrichment and stratification, as well as the confirmation of the existing and the development of new prevention strategies, with a stronger focus on the etiology of the disorder. In addition, the prediction and prevention approach would benefit from the inclusion of risk symptoms in the DSM-5 criteria.

Environmental risk factors and their impact on the age of onset of schizophrenia: Comparing familial to non-familial schizophrenia

Background and aims: Several risk factors for schizophrenia have yet been identified. The aim of our study was to investigate how certain childhood and adolescent risk factors predict the age of onset of psychosis in patients with and without a familial component (i.e. a relative with schizophrenia or schizoaffective disorder). Methods: Aside from the age of onset of psychosis, we examined the risk factors for schizophrenia including obstetric complications, birth during winter or spring, behavioral deviances or delayed motor and speech development, exposure to adverse life events and exposure to substance use within a group of 100 patients (45 female, 55 male) with a mean age (± standard deviation) of 35.15 ± 13.21. Results: Birth complications and cannabis abuse are predictors for an earlier onset of schizophrenia in patients with non-familial schizophrenia. No environmental risk factors for an earlier age of onset in familial schizophrenia have been identified. Conclusions: Certain environmental risk factors for schizophrenia seem to have an impact on the age of onset of psychosis in non-familial schizophrenia, they do not seem to have an impact on familial schizophrenia.

194. Modeling an environmental risk factor for schizophrenia and autism in mice leads to permanent immune activation in the offspring

194. Modeling an environmental risk factor for schizophrenia and autism in mice leads to permanent immune activation in the offspring

Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801

The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01 mg/kg/day), or paliperidone (0.01 mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated ( p < 0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01 mg/kg/day postnatal days 35–56) normalized prefrontal cortical basal extracellular glutamate ( p < 0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.

Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation

Aim Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier. We previously described prevention with risperidone of abnormal behavior following neonatal hippocampal lesion. We aimed to extend those findings evaluating risperidone and paliperidone following prenatal immune activation, a developmental model of a schizophrenia risk factor. We evaluated a later developmental time point to determine persistent effects of drug treatment. Methods Pregnant Sprague–Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received risperidone (0.45 mg/kg/d), paliperidone (0.05 mg/kg/d), or vehicle from postnatal days 35–70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following antipsychotic discontinuation. Results Risperidone and paliperidone had persistent effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Risperidone, but not paliperidone, also exerted persistent effects in offspring of saline-treated dams on locomotor response to saline and amphetamine (5 mg/kg) injection. Conclusions Risperidone and paliperidone pre-treatment of poly I:C offspring during peri-pubertal development stabilized response to amphetamine exposure persisting into early adulthood. Prenatal immune activation provides a model for evaluating effects of an environmental risk factor for schizophrenia, and has potential utility for identifying pharmacological approaches to early intervention.

A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring

BackgroundSeveral studies have implicated early infections, including maternal infection with herpes simplex virus 2 (HSV-2), as an environmental risk factor for schizophrenia. MethodsA case–control study nested within the national Danish birth cohort constituted by the PKU Biobank covering all children born in Denmark since 1981. 602 cases of schizophrenia (ICD-10 F20) were ascertained in the Danish Psychiatric Central Register, covering all in- and out-patient contacts in Denmark, and 602 controls were matched individually on gender, exact date of birth and living in Denmark on the date the case became a case.Incidence rate ratio for schizophrenia was estimated using conditional logistic regression. Main exposure was HSV-2 IgG antibody levels. Confounders and potential interacting factors included family history of mental illness, place of birth and gestational age at time of birth. ResultsElevated levels of maternal HSV-2 IgG were associated with schizophrenia risk (IRR 1.56; 95% CI 1.17–2.07, p=0.002). This association was not confounded by a maternal or sibling history of psychiatric illness, place of birth, parental age, gestational age, or immigrant status of the parents. However, adjustment for paternal psychiatric history reduced risk slightly (IRR 1.43; 95% CI 1.06–1.92, p=0.02). ConclusionsThe study replicates an association between maternal HSV-2 IgG levels and schizophrenia risk. Since the confounding by familial risk factors is confined to paternal mental illnesses not belonging to the schizophrenia spectrum, we hypothesize that this confounding may be partly due to other risk factors, e.g., other sexually transmitted infections, rather than reflecting variations in genetic liability to develop schizophrenia.

Fibroblast Growth Factors in Schizophrenia

A large association study by O'Donovan et al recently suggested that genetic variation in fibroblast growth factor receptor (FGFR) 2 increases the risk for developing schizophrenia. Fibroblast growth factors (FGFs) are part of the family of glial growth factors; they control the growth and patterning of specific brain structures and regulate the maintenance and repair of neuronal tissues. In addition, a direct interaction was recently found between FGFRs and adenosine A(2A) receptors, leading to corticostriatal plasticity and antagonizing the signaling pathway of dopamine D(2) receptors. These findings make FGFs plausible candidate genes for schizophrenia. Here, we review the role of FGFs in schizophrenia and combine evidence from studies on variations in FGF genes, RNA expression, protein levels, and FGF administration, as well as the effects of medication and environmental risk factors for schizophrenia. These data suggest that changes in the FGF system contribute to schizophrenia and possibly to a wider range of psychiatric disorders. The role of FGFs in schizophrenia and related disorders needs to be studied in more detail.

Hyperthermia in utero due to maternal influenza is an environmental risk factor for schizophrenia

A hypothesis is presented that the association between maternal influenza and other causes of fever during the second trimester of pregnancy and the subsequent development of schizophrenia in the child is due to the damage caused by hyperthermia to the developing amygdalohippocampal complex and associated structures in the fetal brain. Hyperthermia is a known cause of congenital defects of the central nervous system and other organs after sufficiently severe exposures during early organogenesis. The pathogenic mechanisms include death of actively dividing neuroblasts, disruption of cell migration and arborization and vascular damage. In experimental studies, hyperthermia during later stages of central nervous system development also caused damage to the developing brainstem that was associated with functional defects. This damage usually results in hypoplasia of the parts undergoing active development at the time of exposure. Recent studies have shown no evidence of direct invasion of the fetus by the influenza virus. Factors that might interact with hyperthermia include familial liability to schizophrenia, season of birth, maternal nutrition, severe stress and medications used to alleviate the symptoms of fevers. The time of the development of the fetal amygdalohippocampal complex and the changes found in its structure and associated areas of the brain are compatible with the known effects of hyperthermia.

TC15D HPA AXIS AND THE STRESS RESPONSE IN PSYCHOSIS

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.

Schizophrenia: who is at risk? Who is a case?

It is now almost unanimously acknowledged that schizophrenia is of multifactorial origin (i.e. that the clinical expression of the vulnerability induced by genetic factors depends on the interactions between this genetic liability and environmental risk factors). The list of putative environmental risk factors keeps on lengthening, including perinatal events with potential harmful neurodevelopmental impact, or later risk factors such as substance use or social factors. Although research on genetic and environmental risk factors for schizophrenia is of major importance to elucidate the etiology of the disorder, the usefulness of this body of knowledge with respect to prevention should be considered cautiously. Indeed, there is a huge gap between determining who is at increased risk for the disease and predicting who will actually develop schizophrenia amongst all subjects at increased risk. How a case of schizophrenia is defined is another major issue for etiological research and also for prevention. A growing body of evidence suggests the existence of a symptomatic continuum between subjects from the general population and subjects with clinical psychosis with respect to the occurrence of psychotic experiences. Thus, establishing a boundary between psychosis and normality is, by its very essence, an arbitrary process. Creating a new diagnostic category of ‘prodromal psychosis’ is moving the boundary to include subjects with less severe symptoms. This strategy has major clinical implications because the question ‘who is a case?’ is often equivalent in clinical practice to the question ‘who needs treatment?’.

Environmental risk factors for psychosis

Genetic factors are clearly important in the etiology of schizophrenia, but the environment in which an individual's genes find expression is also crucial to the development of the illness. In this review of environmental risk factors for schizophrenia, we consider risks operating prenatally and perinatally, during childhood, and then later in life prior to illness onset Some of these risk factors have been well documented, for example, early hazards causing fetal growth retardation or hypoxia, and hazards nearer the onset of illness like drug abuse and migration. Others are much less certain. The importance of interaction between genetic and environmental risk is, however, undoubtedly important and there is emerging evidence for this from a range of sources. As the etiology of schizophrenia is unraveled, the picture becomes more complex, but also more obviously relevant to the plight of the individual patient.