Chiara Bonetto

Disruption of the neurexin 1 gene is associated with schizophrenia

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels

BACKGROUND Anaphylaxis after Hymenoptera stings has been reported in subjects with mastocytosis, but few data exist regarding disease prevalence in populations allergic to these insects. OBJECTIVE The incidence of clonal mast cell (MC) disorders in subjects with both systemic reactions to Hymenoptera stings and increased serum baseline tryptase (sBT) levels was assessed by using bone marrow (BM) aspirates and biopsy specimens. METHODS Subjects with a history of a systemic reaction caused by a Hymenoptera sting underwent the standard diagnostic work-up for Hymenoptera allergy, and sBT levels were measured. Subjects with an increased sBT level had BM evaluation that included histology/cytology, flow cytometry, and detection of KIT mutations. RESULTS Forty-four (11.6%) of 379 subjects with systemic reactions had increased sBT levels (>11.4 ng/mL), and 31 (70.5%) of these had a history of anaphylaxis. Thirty-four subjects with increased sBT levels underwent a BM analysis. Histology detected diagnostic or subdiagnostic MC infiltrates in 22 (65%) of 34 patients. Abnormal MCs were identified by means of flow cytometry and cytology in 26 (78.8%) of 33 and 20 (58.8%) of 34 subjects, respectively. A KIT mutation was detected in 17 (54.8%) of 31 subjects. The diagnosis was indolent systemic mastocytosis in 21 (61.7%) of 34 subjects and monoclonal MC activation syndrome in 9 (26.5%) of 34 subjects. All subjects with anaphylaxis had one of those 2 disorders. CONCLUSION The concomitant presence of systemic reactions (especially anaphylaxis) after Hymenoptera stings and increased sBT levels strongly suggests that a BM examination is indicated for the diagnosis of clonal MC disease.

Global pattern of experienced and anticipated discrimination reported by people with major depressive disorder: a cross-sectional survey

BACKGROUND Depression is the third leading contributor to the worldwide burden of disease. We assessed the nature and severity of experienced and anticipated discrimination reported by adults with major depressive disorder worldwide. Moreover, we investigated whether experienced discrimination is related to clinical history, provision of health care, and disclosure of diagnosis and whether anticipated discrimination is associated with disclosure and previous experiences of discrimination. METHODS In a cross-sectional survey, people with a diagnosis of major depressive disorder were interviewed in 39 sites (35 countries) worldwide with the discrimination and stigma scale (version 12; DISC-12). Other inclusion criteria were ability to understand and speak the main local language and age 18 years or older. The DISC-12 subscores assessed were reported discrimination and anticipated discrimination. Multivariable regression was used to analyse the data. FINDINGS 1082 people with depression completed the DISC-12. Of these, 855 (79%) reported experiencing discrimination in at least one life domain. 405 (37%) participants had stopped themselves from initiating a close personal relationship, 271 (25%) from applying for work, and 218 (20%) from applying for education or training. We noted that higher levels of experienced discrimination were associated with several lifetime depressive episodes (negative binomial regression coefficient 0·20 [95% CI 0·09-0·32], p=0·001); at least one lifetime psychiatric hospital admission (0·29 [0·15-0·42], p=0·001); poorer levels of social functioning (widowed, separated, or divorced 0·10 [0·01-0·19], p=0·032; unpaid employed 0·34 [0·09-0·60], p=0·007; looking for a job 0·26 [0·09-0·43], p=0·002; and unemployed 0·22 [0·03-0·41], p=0·022). Experienced discrimination was also associated with lower willingness to disclose a diagnosis of depression (mean discrimination score 4·18 [SD 3·68] for concealing depression vs 2·25 [2·65] for disclosing depression; p<0·0001). Anticipated discrimination is not necessarily associated with experienced discrimination because 147 (47%) of 316 participants who anticipated discrimination in finding or keeping a job and 160 (45%) of 353 in their intimate relationships had not experienced discrimination. INTERPRETATION Discrimination related to depression acts as a barrier to social participation and successful vocational integration. Non-disclosure of depression is itself a further barrier to seeking help and to receiving effective treatment. This finding suggests that new and sustained approaches are needed to prevent stigmatisation of people with depression and reduce the effects of stigma when it is already established. FUNDING European Commission, Directorate General for Health and Consumers, Public Health Executive Agency.

Influence of perceived organisational factors on job burnout: survey of community mental health staff

BACKGROUND Staff burnout is a critical issue for mental healthcare delivery, as it can lead to decreased work performance and, ultimately, to poorer treatment outcomes. AIMS To explore the relative weight of job-related characteristics and perceived organisational factors in predicting burnout in staff working in community-based psychiatric services. METHOD A representative sample of 2000 mental health staff working in the Veneto region, Italy, participated. Burnout and perceived organisational factors were assessed by using the Organizational Checkup Survey. RESULTS Overall, high levels of job distress affected nearly two-thirds of the psychiatric staff and one in five staff members suffered from burnout. Psychiatrists and social workers reported the highest levels of burnout, and support workers and psychologists, the lowest. Burnout was mostly predicted by a higher frequency of face-to-face interaction with users, longer tenure in mental healthcare, weak work group cohesion and perceived unfairness. CONCLUSIONS Improving the workplace atmosphere within psychiatric services should be one of the most important targets in staff burnout prevention strategies. The potential benefits of such programmes may, in turn, have a favourable impact on patient outcomes.

At-Risk Variant in TCF7L2 for Type II Diabetes Increases Risk of Schizophrenia

BACKGROUND Schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication. METHODS Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel-Haenszel test. RESULTS One type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01-1.14, p = .033). CONCLUSION The association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity.

Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness

OBJECTIVE Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness. METHOD The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis. RESULTS Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome. CONCLUSIONS These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.

Factor solution of the BPRS-expanded version in schizophrenic outpatients living in five European countries

RATIONALE The expanded version of the Brief Psychiatric Rating Scale (BPRS-E) has improved the instruments coverage and interrater reliability, but there is little knowledge on its subsyndromes. OBJECTIVES To assess: (1) whether there are common underlying BPRS-E subscales in patients living in different countries and (2) if this is the case, whether these subscales behave the same in all populations and, if not, what are the differences over these populations. METHODS Data are part of the EPSILON study, a collaborative project carried out in Denmark, England, Holland, Italy and Spain. A random representative sample of 404 adult patients with a ICD-10 diagnosis of schizophrenia who have been in contact with mental health services of a defined catchment area in each site were assessed. Simultaneous component analysis (SCA) was used to find component weights that optimally explain the variance of the variables in different populations simultaneously. RESULTS Symptom severity differed significantly among the five EPSILON sites in 12 out of 24 BPRS-E items, but a common component solution could be found. It explained 48.8% of the variance and gave four well-interpretable components: manic excitement/disorganization, depression/anxiety, negative and positive symptoms. Each components internal consistency and intercomponent correlation matrix differed significantly among sites. The four components mean score differed significantly among sites for negative symptoms and depression/anxiety. CONCLUSIONS In spite of the heterogeneity of symptoms severity in the various countries, the way symptoms cluster in schizophrenia is rather stable cross-culturally. Data demonstrate that to explore schizophrenia a third component, including mania/disorganization items, is necessary beside the positive-negative symptom dimensions. The subscales derived from these analyses can be readily used in clinical trials and epidemiological studies.

Predictors of changes in caregiving burden in people with schizophrenia: a 3-year follow-up study in a community mental health service

Objective:  The aims of this study were to measure changes over 3‐years in caregiving burden and emotional distress in relatives of people with schizophrenia and to identify factors predicting the levels of caregiving burden.

Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients

There is evidence suggesting that Dysbindin (DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was associated with schizophrenia and its symptoms in a representative group of schizophrenic patients from a Community‐Based Mental Health Service (CMHS) in Verona, Italy. A prevalence cohort of schizophrenic patients (n = 141) was assessed at baseline and then 3 and 6 years later. Eighty patients and 106 healthy controls were genotyped for polymorphisms in dysbindin. We tested if diagnosis, clinical symptoms as measured by the Brief Psychiatric Rating Scale (BPRS), and functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin high‐risk haplotypes had a more unfavorable longitudinal clinical outcome. A trend towards statistical association (P = 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538‐P1583 (P = 0.048), P1320‐P1757 (P = 0.034), and rs2619538‐P1583‐P1578 (P = 0.040) haplotypes occurred more often in cases compared to controls before correction for multiple testing. The rs2619538‐P1583 haplotype was more likely to be transmitted to subjects with more severe and persistent psychopathology. These preliminary results are compatible with the view that DTNBP1 is a susceptibility factor for schizophrenia, and is associated with worse psychopathology.

Applications and usefulness of routine measurement of patients satisfaction with community-based mental health care

Objective:  This study was conducted within the framework of the South‐Verona Outcome Project (SVOP) in a sample of patients, with the full spectrum of psychiatric diagnoses, who are attending the South‐Verona Community‐based Mental Health Service (CMHS). It aims to exemplify some applications of routine measurements of service satisfaction and specifically: i) identify strengths and weaknesses, in the patients’ perspectives, of a ‘real world’ service; ii) monitor whether this specific service provides satisfactory care over 3 years and iii) identify if there are any patients’ characteristics that might be associated with service dissatisfaction.