Durk Wiersma

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

The effectiveness of supported employment for people with severe mental illness : a randomised controlled trial

BACKGROUND The value of the individual placement and support (IPS) programme in helping people with severe mental illness gain open employment is unknown in Europe. Our aim was to assess the effectiveness of IPS, and to examine whether its effect is modified by local labour markets and welfare systems. METHODS 312 patients with severe mental illness were randomly assigned in six European centres to receive IPS (n=156) or vocational services (n=156). Patients were followed up for 18 months. The primary outcome was the difference between the proportions of people entering competitive employment in the two groups. The heterogeneity of IPS effectiveness was explored with prospective meta-analyses to establish the effect of local welfare systems and labour markets. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, with the number NCT00461318. FINDINGS IPS was more effective than vocational services for every vocational outcome, with 85 (55%) patients assigned to IPS working for at least 1 day compared with 43 (28%) patients assigned to vocational services (difference 26.9%, 95% CI 16.4-37.4). Patients assigned to vocational services were significantly more likely to drop out of the service and to be readmitted to hospital than were those assigned to IPS (drop-out 70 [45%] vs 20 [13%]; difference -32.1% [95% CI -41.5 to -22.7]; readmission 42 [31%] vs 28 [20%]; difference -11.2% [-21.5 to -0.90]). Local unemployment rates accounted for a substantial amount of the heterogeneity in IPS effectiveness. INTERPRETATION Our demonstration of the effectiveness of IPS in widely differing labour market and welfare contexts confirms this service to be an effective approach for vocational rehabilitation in mental health that deserves investment and further investigation.

Reinstitutionalisation in mental health care: comparison of data on service provision from six European countries

Abstract Objective To establish whether reinstitutionalisation is occurring in mental health care and, if so, with what variations between western European countries. Design Comparison of data on changes in service provision. Setting Six European countries with different traditions of mental health care that have all experienced deinstitutionalisation since the 1970s—England, Germany, Italy, the Netherlands, Spain, and Sweden. Outcome measures Changes in the number of forensic hospital beds, involuntary hospital admissions, places in supported housing, general psychiatric hospital beds, and general prison population between 1990-1 and 2002-3. Results Forensic beds and places in supported housing have increased in all countries, whereas changes in involuntary hospital admissions have been inconsistent. The number of psychiatric hospital beds has been reduced in five countries, but only in two countries does this reduction outweigh the number of additional places in forensic institutions and supported housing. The general prison population has substantially increased in all countries. Conclusions Reinstitutionalisation is taking place in European countries with different traditions of health care, although with significant variation between the six countries studied. The precise reasons for the phenomenon remain unclear. General attitudes to risk containment in a society, as indicated by the size of the prison population, may be more important than changing morbidity and new methods of mental healthcare delivery.

Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy: Long-term Follow-up of a 2-Year Randomized Clinical Trial

IMPORTANCE Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before. OBJECTIVE To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial. DESIGN Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR. SETTING One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million-population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission. PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the original trial were located and consented to follow-up assessment. INTERVENTION After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician. MAIN OUTCOMES AND MEASURES Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters. RESULTS The DR patients experienced twice the recovery rate of the MT patients (40.4% vs 17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates. CONCLUSIONS AND RELEVANCE Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN16228411.

The Impact of Supported Employment and Working on Clinical and Social Functioning: Results of an International Study of Individual Placement and Support

BACKGROUND Concerns are frequently expressed that working might worsen the mental health of people with severe mental illness (SMI). Several studies of Individual Placement and Support (IPS), however, have found associations between working and better nonvocational outcomes. IPS has been found to double the return to work of people with SMI in 6 European countries. AIMS To explore separately associations between IPS, returning to work, and clinical and social outcomes. METHODS Patients (n = 312) in a randomized controlled trial of IPS in 6 European centers were followed up for 18 months. RESULTS There were no differences in clinical and social functioning between IPS and control patients at 18 months. Those who worked had better global functioning, fewer symptoms, and less social disability at final follow-up; greater job tenure was associated with better functioning. Working was associated with concurrently better clinical and social functioning, but this contrast was stronger in the control group, suggesting that IPS was better than the control service at helping more unwell patients into work. Working was associated with having been in remission and out of hospital for the previous 6 months. It was also associated with a slight decrease in depression and with being in remission over the subsequent 6 months. CONCLUSIONS Concerns among clinicians about possible detrimental effects of working and supported employment have been misplaced. Although some of the associations found may have been selection effects, there is sufficient evidence of work having beneficial effects on clinical and social functioning to merit further exploration.

Predictors of employment for people with severe mental illness : results of an international six-centre randomised controlled trial

BACKGROUND An international six-centre randomised controlled trial comparing individual placement and support (IPS) with usual vocational rehabilitation for people with serious mental illness found IPS to be more effective for all vocational outcomes. AIMS To determine which patients with severe mental illness do well in vocational services and which process and service factors are associated with better outcomes. METHOD Patient characteristics and early process variables were tested as predictors of employment outcomes. Service characteristics were explored as predictors of the effectiveness of IPS. RESULTS Patients with previous work history, fewer met social needs and better relationships with their vocational workers were more likely to obtain employment and work for longer. Remission and swifter service uptake were associated with working more. Having an IPS service closer to the original IPS model was the only service characteristic associated with greater effectiveness. CONCLUSIONS The IPS service was found to be more effective for all vocational outcomes. In addition, maintaining high IPS fidelity and targeting relational skills would be a valuable focus for all vocational interventions, leading to improved employment outcomes. Motivation to find work may be decreased by satisfaction with current life circumstances.

Social disability in schizophrenia: its development and prediction over 15 years in incidence cohorts in six European centres

Background. This paper focuses on the long-term course of social disability in schizophrenia assessed at first onset, and after 1, 2 and 15 years in incidence cohorts in six European centres in Bulgaria, Germany, Ireland, The Netherlands, the Czech Republic and the United Kingdom. The study population comprises 349 patients comprising 75% of the original cohorts. Methods. Social disability was assessed in a standardized way with the WHO Disability Assessment Schedule. Results. Social disability in schizophrenia appears to be a persistent phenomenon. Its severity decreased overall in the period of follow-up, but this was not so in a small group traced to hospital or sheltered accommodation. Only 17% of subjects had no disability and 24% still suffered from severe disability. The great majority lived with their family, a partner, or alone. A deteriorating course was more frequent than late improvement. Gender, age, onset, duration of untreated psychosis or type of remission during the first 2 years did not predict the long-term outcome of disability. Severity of disability at the first three assessments of the illness contributed significantly to the explanation of its variance at 15 years. Conclusion. Disability generally ameliorates, but less than expected or hoped. It needs continuing attention and care in this era of de-institutionalization.

The five-factor model of the Positive and Negative Syndrome Scale I: confirmatory factor analysis fails to confirm 25 published five-factor solutions

OBJECTIVE The aim of this study was to test the goodness-of-fit of all previously published five-factor models of the Positive and Negative Syndrome Scale (PANSS). METHODS We used confirmatory factor analysis (CFA) with a large data set (N = 5769). RESULTS The different subsamples were tested for heterogeneity and were found to be homogeneous. This indicates that despite variability in age, sex, duration of illness, admission status, etc., in the different subsamples, the structure of symptoms is the same for all patients with schizophrenia. Although previous research has shown that a five-factor model fits the data better than models with three or four factors, no satisfactory fit for any of the 25 published five-factor models was found with CFA. CONCLUSIONS Variability in age, sex, admission status and duration of illness has no substantial effect on the structure of symptoms in schizophrenia. The lack of fit can be caused by ill-defined items that aim to measure several properties in a single rating. Another explanation is that well-defined symptoms can have two or more causes. Then a double or triple loading item should not be discarded, but included because the complexity of symptoms in schizophrenia is represented by these multiple loadings. Such a complex model not only needs confirmation by CFA, but also has to be proven stable. A 10-fold cross-validation is suggested to develop a complex and stable model.

The Groningen Social Disabilities Schedule: Development, Relationship with I.C.I.D.H., and Psychometric Properties.

Most of the existing instruments for the assessment of social dysfunctioning of psychiatric patients are merely lists of precoded items, leaving little or no room for posing supplementary questions. In this article a new, semi-structured questionnaire--the Groningen Social Disabilities Schedule (GSDS)--is described, in which this shortcoming is met. The development of the GSDS is based on social role theory and on the existence of a hierarchy in social disabilities, demonstrated in an earlier World Health Organization study. Compatibility was sought with the International Classification of Impairments, Disabilities and Handicaps (ICIDH), a trial-classification of the World Health Organization, to be used in research on the consequences of illness. It is concluded that the inter-rater reliability of the GSDS is good. To a large extent the hierarchy proved to hold true for this instrument. Some implications for future research and for the ICIDH are discussed.

CLINICAL RECOVERY IN FIRST EPISODE PSYCHOSIS

Introduction: Generally agreed outcome criteria in psychosis are required to evaluate the effectiveness of new treatment strategies. The aim of this study is to explore clinical recovery in first-episode patients, defined by meeting criteria for both symptomatic and functional remission. Method: In a sample of first-episode patients (N = 125), symptomatic and functional remission during the last 9 months of a 2-year follow-up period were examined, as well as recovery and its predictors. Results: Half the patients (52.0%) showed symptomatic remission and a quarter (26.4%) functional remission, while one-fifth (19.2%) met both criteria sets and were considered recovered. Recovery was significantly associated with short duration of untreated psychosis and better baseline functioning. Conclusion: Most functionally remitted patients were also symptomatically remitted, while a minority of symptomatically remitted patients were also functionally remitted. Treatment delay may affect chance of recovery.