Predictive value of cardiometabolic biomarkers and depressive symptoms for symptom severity and quality of life in patients with psychotic disorders.

BACKGROUND: Patients with psychotic disorders show higher rates of the metabolic syndrome (MS) between the cluster of severe mental illnesses. Depressive symptoms can worsen outcomes of individuals with psychotic disorders. However, research on the association between MS and depression in psychotic disorders and their relevance to outcomes is lacking. METHODS: We investigated the association between depression and cardiometabolic biomarkers in psychotic disorders and the predictive value of depressive symptoms on psychopathological severity and quality of life (QoL). 406 patients with psychotic disorders were recruited as part of the Improving Physical Health and Reducing Substance Use in Severe Mental Illness randomised controlled trial. Depression, psychotic symptoms, QoL, waist circumference, triglycerides, high-density lipoprotein cholesterol (HDL-C), blood pressure, and fasting glucose of patients were assessed at baseline and 12 months. Sensitivity analyses were conducted to test the effect of treatment. RESULTS: More severe baseline symptoms of depression significantly predicted worse 12-month psychotic symptoms and lower mental health related QoL at 12 months. These associations held after controlling for alcohol use, gender, ethnicity, education, and mental health related QoL Baseline. Depressive symptoms also correlated with waist circumference at both baseline and 12 months, after controlling for multiple testing. CONCLUSION: Individuals with psychotic disorders experiencing more severe depressive symptoms are more likely to have larger waist circumference contemporaneously and 12 months later, as well as more severe psychotic symptoms and worse QoL at follow-up. This highlights the need for evaluation of strategies to address depression in the management of psychotic disorders.

Social disadvantage, linguistic distance, ethnic minority status and first-episode psychosis: results from the EU-GEI case-control study.

BACKGROUND: Ethnic minority groups in Western countries face an increased risk of psychotic disorders. Causes of this long-standing public health inequality remain poorly understood. We investigated whether social disadvantage, linguistic distance and discrimination contributed to these patterns. METHODS: We used case-control data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, carried out in 16 centres in six countries. We recruited 1130 cases and 1497 population-based controls. Our main outcome measure was first-episode ICD-10 psychotic disorder (F20-F33), and exposures were ethnicity (white majority, black, mixed, Asian, North-African, white minority and other), generational status, social disadvantage, linguistic distance and discrimination. Age, sex, paternal age, cannabis use, childhood trauma and parental history of psychosis were included as a priori confounders. Exposures and confounders were added sequentially to multivariable logistic models, following multiple imputation for missing data. RESULTS: Participants from any ethnic minority background had crude excess odds of psychosis [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.69-2.43], which remained after adjustment for confounders (OR 1.61, 95% CI 1.31-1.98). This was progressively attenuated following further adjustment for social disadvantage (OR 1.52, 95% CI 1.22-1.89) and linguistic distance (OR 1.22, 95% CI 0.95-1.57), a pattern mirrored in several specific ethnic groups. Linguistic distance and social disadvantage had stronger effects for first- and later-generation groups, respectively. CONCLUSION: Social disadvantage and linguistic distance, two potential markers of sociocultural exclusion, were associated with increased odds of psychotic disorder, and adjusting for these led to equivocal risk between several ethnic minority groups and the white majority.

Assessing cross-national invariance of the Community Assessment of Psychic Experiences (CAPE).

BACKGROUND: The Community Assessment of Psychic Experiences (CAPE) is a 42-item self-report questionnaire that has been developed and validated to measure the dimensions of psychosis in the general population. The CAPE has a three-factor structure with dimensions of positive, negative and depression. Assessing the cross-national equivalence of a questionnaire is an essential prerequisite before pooling data from different countries. In this study, our aim was to investigate the measurement invariance of the CAPE across different countries. METHODS: Data were drawn from the European Union Gene-Environment Interaction (EU-GEI) study. Participants (incident cases of psychotic disorder, controls and siblings of cases) were recruited in Brazil, France, Italy, the Netherlands, Spain and UK. To analyse the measurement invariance across these samples, we tested configural invariance (i.e. identical structures of the factors), metric invariance (i.e. equivalence of the factor loadings) and scalar invariance (i.e. equivalence of the thresholds) of the three CAPE dimensions using multigroup categorical confirmatory factor analysis methods. RESULTS: The configural invariance model fits well, providing evidence for identical factorial structure across countries. In comparison with the configural model invariance, the fit indices were very similar in the metric and scalar invariance models, indicating that factor loadings and thresholds did not differ across the six countries. CONCLUSION: We found that, across six countries, the CAPE showed equivalent factorial structure, factor loadings and thresholds. Thus, differences observed in scores between individuals from different countries should be considered as reflecting different levels of psychosis.

Hyperprolactinaemia in first episode psychosis - A longitudinal assessment.

Little is known about hyperprolactinaemia (HPL) in first episode psychosis (FEP) patients. We investigated longitudinal changes in serum prolactin in FEP, and the relationship between HPL, and antipsychotic medication and stress. Serum prolactin was recorded in FEP patients at recruitment and again, 3 and 12months later. HPL was defined as a serum prolactin level >410mIU/L (~19.3ng/ml) for males, and a serum prolactin level >510mIU/L (~24.1ng/ml) for females. From a total of 174 people with serum prolactin measurements at study recruitment, 43% (n=74) had HPL, whilst 27% (n=21/78) and 27% (n=26/95) had HPL at 3 and 12months respectively. We observed higher serum prolactin levels in females versus males (p<0.001), and in antipsychotic treated (n=68) versus antipsychotic naïve patients (p<0.0001). Prolactin levels were consistently raised in FEP patients taking risperidone, amisulpride and FGAs compared to other antipsychotics. No significant relationship was observed between perceived stress scores (ß=7.13, t=0.21, df=11, p=0.0.84 95% CI -72.91-87.16), or objective life stressors (ß=-21.74, t=-0.31, df=8, p=0.77 95% CI -218.57-175.09) and serum prolactin. Our study found elevated rates of HPL over the course of the first 12months of illness. We found no evidence to support the notion that stress is related to elevated serum prolactin at the onset of psychosis.

Bridging the gap between research into biological and psychosocial models of psychosis.

SUMMARY: Paul Bebbington's recent Special Article provides an excellent synthesis of recent advances in psychosocial research on psychosis. However, we doubt that a model based solely on social epidemiology and cognitive theory can totally describe psychosis, and to be fair, Bebbington does not suggest that it does. A complete model must also incorporate what we have learned from non-social epidemiology, neuroscience, and genetics. Evidence indicates that both the social risk factors that interest Bebbington and biological risk factors, such as abuse of stimulants and cannabis, can provoke psychotic symptoms by dysregulating striatal dopamine. The role of neurodevelopmental deviance also needs to be considered in the etiology of schizophrenia-like psychosis. Moreover, the striking advances in our understanding of the genetic architecture of psychosis open an exciting door into studies examining gene-environment correlation and gene-environment interaction. In short, Bebbington demonstrates the value of cognitive and social researchers talking to each other, but the occasional chat with the more biologically inclined could produce a more comprehensive model.

Improving physical health and reducing substance use in psychosis--randomised control trial (IMPACT RCT): study protocol for a cluster randomised controlled trial.

BACKGROUND: Cardiovascular morbidity and mortality is increased in individuals with severe mental illnesses.We set out to establish a multicentre, two arm, parallel cluster randomized controlled trial (RCT) of a health promotion intervention (HPI), IMPACT Therapy. The patient-tailored IMPACT Therapy aims to target one or more health behaviours from a pre-defined list that includes cannabis use; alcohol use; other substance use; cigarette smoking; exercise; diet and diabetic control, prioritising those identified as problematic by the patient, taking a motivational interviewing and CBT approach. METHODS: Impact therapy will be delivered by care coordinators in the community to the treatment group and will be compared to treatment as usual (TAU). The main hypothesis is that the addition of IMPACT Therapy (HPI) to TAU will be more effective than TAU alone in improving patients' quality of life as measured by the Short Form-36, including mental health and physical health subscales on completion of the intervention at 12 months post randomisation. A subsidiary hypothesis will be that addition of IMPACT Therapy (HPI) will be more cost-effective than TAU alone in improving health in people with SMI 12 months from baseline. The IMPACT therapy patient groups' improvement in quality of life, as well as its cost effectiveness, is hypothesised to be maintained at 15 months. Outcomes will be analyzed on an intention-to-treat (ITT) basis. DISCUSSION: The results of the trial will provide information about the effectiveness of the IMPACT therapy programme in supporting community mental health teams to address physical comorbidity in severe mental illness. TRIAL REGISTRATION: ISRCTN58667926.

Is neuregulin 1 involved in determining cerebral volumes in schizophrenia? Preliminary results showing a decrease in superior temporal gyrus volume.

BACKGROUND/AIMS: Reduced left superior temporal gyrus (STG) volume is one of the most replicated imaging findings in schizophrenia. However, it remains unclear whether genes play any role in our understanding of such structural alteration. It has been proposed that Neuregulin 1 (NRG1) might be a promising gene involved in schizophrenia, because of its role in neurodevelopment and neuroplasticity. In this study, the association between NRG1 and STG anatomy in patients with schizophrenia was explored for the first time. METHODS: We investigated a 1-year treated prevalence cohort of patients with schizophrenia in contact with the South Verona Community-Based Mental Health Service. A blood sample was collected for DNA extraction and brain structure was assessed with an MRI scan. A total of 27 subjects with schizophrenia underwent both assessments and were included in the study. RESULTS: We investigated the association between the polymorphism SNP8NRG222662 (rs4623364) of NRG1 and volume of the STG. We found that patients homozygous for the C allele had reduced left STG gray and white matter volumes in comparison to those homozygous for the G allele (p < 0.01 and p < 0.001, respectively). CONCLUSIONS: This exploratory study suggests that NRG1 may be involved in determining STG size in schizophrenia, and may play a role in the neurogenetic basis of the language disturbances seen in this disorder. However, due to our small sample size, the results should be regarded as preliminary and replicated in a larger sample.

Assessment of posttraumatic symptoms in patients with first-episode psychosis.

Posttraumatic stress disorder is common among patients with psychotic disorders. The present study examined the internal reliability and comparability of the Impact of Event Scale (IES) in a sample of 38 patients with first-episode psychosis and 47 controls exposed to severe physical and/or sexual abuse. The IES total score and both subscales showed high internal consistency in both groups (Cronbach's alpha coefficients of approximately 0.9 or higher). Given their equivalent trauma reporting, the lack of differences in IES scores between patients and controls seems to indicate that patients are likely to report accurately and neither exaggerate nor minimize their posttraumatic symptoms. Overall, the findings suggest that the IES can be used to assess symptoms of posttraumatic stress in patients with psychotic disorders as in other populations.

The economic cost of pathways to care in first episode psychosis.

Few studies have examined the economic cost of psychoses other than schizophrenia and there have been no studies of the economic cost of pathways to care in patients with their first episode of psychosis. The aims of this study were to explore the economic cost of pathways to care in patients with a first episode of psychosis and to examine variation in costs. Data on pathways to care for first episode psychosis patients referred to specialist mental health services in south-east London and Nottingham between 1997-2000. Costs of pathway events were estimated and compared between diagnostic groups. The average costs for patients in south-east London were £54 (CI £33-£75) higher, compared to patients in Nottingham. Across both centres unemployed patients had £25 (CI £7-£43) higher average costs compared to employed patients. Higher costs were associated with being unemployed and living in south-east London and these differences could not be accounted for by any single factor. This should be considered when the National Health Service (NHS) is making decisions about funding.

Increased inferior frontal activation during word generation: a marker of genetic risk for schizophrenia but not bipolar disorder?

During verbal-fluency tasks, impairments in performance and functional abnormalities in the inferior frontal cortex have been observed in both schizophrenia patients and their unaffected relatives. We sought to examine whether such functional abnormalities are a specific marker of genetic vulnerability to schizophrenia. We studied a sample of 132 subjects, comprising 39 patients with schizophrenia, 10 unaffected monozygotic (MZ) cotwins of schizophrenia probands, 28 patients with bipolar disorder, 7 unaffected MZ cotwins of bipolar disorder probands and 48 healthy controls. Blood oxygen level-dependent response was measured using functional magnetic resonance imaging during the performance of an overt verbal-fluency task with two levels of task difficulty, in a cytoarchitectonic region of interest encompassing Brodmann areas 44 and 45 bilaterally. Patients with schizophrenia and the unaffected MZ cotwins of schizophrenia probands showed increased activation in the inferior frontal cortex relative to healthy controls and bipolar patients. Increased engagement of the inferior frontal cortex during verbal-fluency may thus be a marker of genetic vulnerability to schizophrenia.

Biological, life course, and cross-cultural studies all point toward the value of dimensional and developmental ratings in the classification of psychosis.

The diagnostic criteria for schizophrenia in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) are based on the premise that it is a discrete illness entity, in particular, distinct from the affective psychoses. This assumption has persisted for more than a century, even though patients with a diagnosis of schizophrenia show a wide diversity of symptoms and outcomes, and no biological or psychological feature has been found to be pathognomonic of the disorder. However, there has been sustained, and indeed growing, criticism of the concept. For example, writing about the diagnosis of schizophrenia more than a decade ago,2 one of Britain's most sophisticated nosological experts, Ian Brockington, enjoined "It is important to loosen the grip which the concept of 'schizophrenia' has on the minds of psychiatrists. Schizophrenia is an idea whose very essence is equivocal, a nosological category without natural boundaries, a barren hypothesis. Such a blurred concept is 'not a valid object of scientific enquiry'."3 Should Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition(DSM-V), persist with the neo-Kraepelinian concept of schizophrenia with all its defects, or should it deconstruct psychosis into its component dimensions? In this article, we will address the question by considering 2 main themes, firstly, the role of culture and ethnicity in the diagnosis of psychosis, and secondly, a life course approach to understanding psychosis. We will then discuss whether more progress would be achieved in DSM-V by abandoning the familiar categorical system and instead moving to a dimensional system which rates both developmental impairment and symptom factor scores. However, we will begin by briefly reviewing the recent history of the classification of the psychoses.

Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1).

CONTEXT: Second-generation (atypical) antipsychotics (SGAs) are more expensive than first-generation (typical) antipsychotics (FGAs) but are perceived to be more effective, with fewer adverse effects, and preferable to patients. Most evidence comes from short-term efficacy trials of symptoms. OBJECTIVE: To test the hypothesis that in people with schizophrenia requiring a change in treatment, SGAs other than clozapine are associated with improved quality of life across 1 year compared with FGAs. DESIGN: A noncommercially funded, pragmatic, multisite, randomized controlled trial of antipsychotic drug classes, with blind assessments at 12, 26, and 56 weeks using intention-to-treat analysis. SETTING: Fourteen community psychiatric services in the English National Health Service. PARTICIPANTS: Two hundred twenty-seven people aged 18 to 65 years with DSM-IV schizophrenia and related disorders assessed for medication review because of inadequate response or adverse effects. INTERVENTIONS: Randomized prescription of either FGAs or SGAs (other than clozapine), with the choice of individual drug made by the managing psychiatrist. MAIN OUTCOME MEASURES: Quality of Life Scale scores, symptoms, adverse effects, participant satisfaction, and costs of care. RESULTS: The primary hypothesis of significant improvement in Quality of Life Scale scores during the year after commencement of SGAs vs FGAs was excluded. Participants in the FGA arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores. Participants reported no clear preference for either drug group; costs were similar. CONCLUSIONS: In people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than nonclozapine SGAs. Neither inadequate power nor patterns of drug discontinuation accounted for the result.

Altered functional neuroanatomy of response inhibition in adolescent males who were born very preterm.

Event-related functional magnetic resonance imaging (fMRI) was used to investigate the hypothesis that males who were born very preterm may show differences in relative strength of blood oxygen level dependent (BOLD) signals in selective brain areas during performance of a simple response inhibition task compared with term-born controls. Participants were eight males (mean gestational age at birth 28wks, [SD 2]; mean age at testing 16y, [SD 1] and 14 controls matched for sex, age (mean age 17y, [SD 1]), and IQ. A 'go-no-go' task was used to assess response selection and motor response inhibition in response to a visual stimulus. When the 'no-go' condition was contrasted with an attentional control condition, preterm participants showed reduced BOLD signal response bilaterally in the cerebellum, right caudate nucleus, and thalamus, and prefrontal areas including left inferior prefrontal and left anterior cingulate gyri. They also showed increased response mainly in temporal regions. These results suggest that despite good task performance, individuals who were born very preterm exhibit different BOLD signal responses in selective brain areas compared with controls which may underline the use of alternative strategies when challenged with motor response inhibition processing.