Systematic comparison of duration of untreated illness versus duration of untreated psychosis in relation to psychopathology and dysfunction in the Cavan-Monaghan first episode psychosis study (CAMFEPS).

This study systematically compared duration of untreated illness (DUI) with duration of untreated psychosis (DUP) in prediction of impairment at first-episode psychosis and investigated the extent to which these relationships are influenced by premorbid features. The Cavan-Monaghan First Episode Psychosis Study ascertained cases of first-episode psychosis in rural Ireland via all routes to care with limited variations in socioeconomic milieu. Cases were evaluated for DUI and DUP and assessed clinically for psychopathology, neuropsychology, neurology, insight and quality of life, together with premorbid features. Analyses then determined prediction of clinical assessments by DUI versus DUP. The study population consisted of 163 cases of first episode psychosis, among which 74 had a schizophrenia spectrum disorder. Shorter DUI but not DUP predicted less severe positive and general symptoms, while shorter DUP and particularly DUI predicted less severe negative symptoms; neither shorter DUP nor shorter DUI predicted less severe cognitive impairment or fewer neurological soft signs; shorter DUP and DUI predicted increased quality of life; shorter DUI but not DUP predicted greater insight. Only prediction of quality of life was weakened by consideration of premorbid features. Results were generally similar across the two diagnostic groupings. The present findings systematically delineate associations with DUI versus DUP across domains of impairment in first episode psychosis. They suggest that DUI may reflect a more insidious process than DUP and that reduction in DUI may be associated with more consistent and broader diminutions in impairment than for DUP.

Systematic epidemiological and clinical comparisons across all 12 DSM-IV psychotic diagnoses in the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS).

BACKGROUND: Research on psychotic illness is loosening emphasis on diagnostic stringency in favour of including a more dimensionally based conceptualization of psychopathology and pathobiology. However, to clarify these notions requires investigation of the full scope of psychotic diagnoses. METHODS: The Cavan-Monaghan First Episode Psychosis Study ascertained cases of first episode psychosis across all 12 DSM-IV psychotic diagnoses via all routes to care: public, private or forensic; home-based, outpatient or inpatient. There was no arbitrary upper age cut-off and minimal impact of factors associated with variations in social milieu, ethnicity or urbanicity. Cases were evaluated epidemiologically and assessed for psychopathology, neuropsychology, neurology, antecedent factors, insight and quality of life. RESULTS: Among 432 cases, the annual incidence of any DSM-IV psychotic diagnosis was 34.1/100 000 of population and encompassed functional psychotic diagnoses, substance-induced psychopathology and psychopathology due to general medical conditions, through to psychotic illness that defied contemporary diagnostic algorithms. These 12 DSM-IV diagnostic categories, including psychotic disorder not otherwise specified, showed clinical profiles that were consistently more similar than distinct. CONCLUSIONS: There are considerable similarities and overlaps across a broad range of diagnostic categories in the absence of robust discontinuities between them. Thus, psychotic illness may be of such continuity that it cannot be fully captured by operational diagnostic algorithms that, at least in part, assume discontinuities. This may reflect the impact of diverse factors each of which acts on one or more overlapping components of a common, dysfunctional neuronal network implicated in the pathobiology of psychotic illness.

Perspectives on paid work among men and women with schizophrenia: The results of a two study comparison in Ireland.

BACKGROUND: While research indicates that people with serious mental health conditions want to work, few studies have examined motivation and concerns associated with employment. OBJECTIVES: This study examined the work attitudes among two samples of Irish people with psychotic conditions, primarily schizophrenia. METHODS: Data gathered through two work related research projects was used. A self-report instrument, the work motivation scale (WMS), gathered data in two separate studies. It was possible to examine participants' motives and concerns due to the two factor structure, positive and negative, of this scale. Descriptive statistical analysis was conducted for each of the two samples individually. A sub-analysis by gender was also conducted. RESULTS: Across the two samples, analysis showed the consistent motivators were increased coping ability, improved self-identity, and enhanced self-worth. Men particularly wanted others to see them as good workers. On the other hand, women regarded a job as a means to forget about having a mental illness. A sizeable minority in both samples expressed apprehensions such as work being boring and an expectation from others that they should work rather than them being personally motivated to do so. CONCLUSIONS: While caution must be exercised in interpreting the results due to the small sample size, this study has extended our understanding in this under-researched but important topic.

Disagreement between service-users and clinicians assessment of physical health during early psychosis.

AIMS: Physical illnesses account for the majority of excess deaths following psychosis; access to care and treatment is inequitable and schizophrenia has now been dubbed the life-shortening disease. We compared service-users and clinician's perspectives of their physical health assuming that one of the fundamental issues in prompting screening and treatment is the view that health is poor. METHODS: Data comprising sample characteristics, diagnosis, symptoms, insight, antecedents to psychosis and physical health perspectives were obtained prospectively as part of a larger epidemiological study of first-episode psychosis. We compared physical health perspectives between service-users and clinicians and examined clinical correlates. RESULTS: Contrary to our expectations, we found that service-users reported poorer physical health over time than clinicians did. CONCLUSION: Reconciling service-users and clinician's views of physical health may be an important step towards collaborative care and improving access to better quality healthcare for serious mental illness.

Functional outcome and service engagement in major depressive disorder with psychotic features: comparisons with schizophrenia, schizoaffective disorder and bipolar disorder in a 6-year follow-up of the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS).

OBJECTIVE: While long-term outcome following a first psychotic episode is well studied in schizophrenia (SZ), schizoaffective disorder (SA), and bipolar disorder (BD), major depressive disorder with psychotic features (MDDP) has received less investigation. This study compares MDDP with SZ, SA, and BD at 6-year follow-up. METHODS: At 6 years after a first psychotic episode, follow-up data on psychopathology, functioning, quality of life, and service engagement were obtained for 27 cases of MDDP in comparison to 60 SZ, 27 SA, and 35 BD. RESULTS: Positive psychotic symptoms were less prominent in MDDP and BD than in SZ and SA. Negative symptoms, impaired functioning, and reduction in objectively determined quality of life were less prominent in MDDP and BD, intermediate in SA and most prominent in SZ. However, subjectively determined quality of life was indistinguishable across diagnoses. Service engagement was highest for MDDP, intermediate for SA and BD, and lowest for SZ. CONCLUSIONS: At 6-year follow-up, these diagnoses are characterized by quantitative rather than qualitative differences in psychopathology, functionality, quality of life, and service engagement, with considerable overlap between them. These findings suggest that MDDP should join SZ, SA, and BD in a milieu of psychosis that transcends arbitrary boundaries.

Feasibility of a psychosis information intervention to improve mental health literacy for professional groups in contact with young people.

The aim of this study was to assess the feasibility of a psychosis information intervention for professionals in contact with young people in Ireland. A quasi-experimental pre- and post-intervention design was used. One thousand and thirty-two professionals received an information intervention designed to improve mental health literacy (MHL) and confidence in providing help to people with psychosis. Seven hundred and fifty-five participants completed the Psychosis Information and Confidence Questionnaire pre- and post-intervention. The information intervention significantly improved participants': (1) knowledge of psychosis; (2) ability to recognize signs and symptoms of psychosis; (3) awareness of how to access services; and (4) confidence in providing help to people experiencing psychosis. Findings provide promising support for the intervention's feasibility and acceptability. The intervention enhanced MHL regarding psychosis among professionals in contact with young people. Further research assessing if such improvements translate to the facilitation of appropriate help seeking, the enhanced early detection of psychosis and a reduction of the duration of untreated psychosis is required.

Predictors of change in social networks, support and satisfaction following a first episode psychosis: A cohort study.

BACKGROUND: Diminished social networks are common in psychosis but few studies have measured these comprehensively and prospectively to determine how networks and support evolve during the early phase. There is little information regarding perceived support in the early phase of illness. The aim of this study was to describe social support, networks and perceived satisfaction, explore the clinical correlates of these outcomes and examine whether phases of untreated psychosis are linked with social network variables to determine potential opportunities for intervention. METHODS: During the study period, we assessed 222 people with first-episode psychosis at entry into treatment using valid and reliable measures of diagnosis, positive and negative symptoms, periods of untreated psychosis and prodrome and premorbid adjustment. For follow-up we contacted participants to conduct a second assessment (n=158). There were 97 people who participated which represented 61% of those eligible. Social network and support information obtained at both time points included the number of friends, self-reported satisfaction with support and social network size and clinician's evaluation of the degree of support received through networks. Mixed effects modelling determined the contribution of potential explanatory variables to social support measured. RESULTS: A number of clinical variables were linked with social networks, support and perceived support and satisfaction. The size of networks did not change over time but those with no friends and duration of untreated psychosis was significantly longer for those with no friends at entry into treatment (n=129, Median=24.5mths, IQR=7.25-69.25; Mann-Whitney U=11.78, p=0.008). Social support at baseline and at one year was predicted by homelessness (t=-2.98, p=0.001, CI -4.74 to -1.21), duration of untreated psychosis (t=-0.86, p=0.031, CI -1.65 to -0.08) and premorbid adjustment (t=-2.26, p=0.017, CI -4.11 to -0.42). Social support improved over time but the duration of untreated psychosis was not linked with the rate of improvement in this outcome. CONCLUSIONS: Improved social support could indicate greater reliance on social support or becoming more adept at mobilising resources to meet social needs. Particularly vulnerable groups with very long duration of untreated psychosis confirm the need for earlier intervention or targeted social network interventions to preserve social connectedness.

An exploratory study of the extent of social inclusion among people with psychosis and psychotic-related conditions.

BACKGROUND: Understanding social inclusion among at-risk populations will deepen our understanding of their specific needs. AIM: This study explored the level of social inclusion among people with psychotic-related conditions using a standardised interview. METHOD: The Social Inclusion Interview Schedule was used in two research projects. People with psychosis participated in both studies and had been recruited as part of an Irish programme of research on psychotic conditions. Descriptive statistics were used to quantify participants' level of social exclusion. RESULTS: Data from 71 participants were available, 38 in one cohort and 33 in the other. The smaller cohort had a shorter mean duration of illness. Participants' mean age was 40. The majority lived in the community and were satisfied with their living arrangements. In each cohort, the same two areas of community integration emerged as problematic - having something productive to do and being close to someone in the community. There was a higher level of perceived stigma among the cohort with the longer duration of illness. DISCUSSION/CONCLUSION: While evidence of social inclusion was found among participants, there were areas of concern particularly with regard to integration into work and social connectedness.

Subjective and objective quality of life at first presentation with psychosis.

AIM: Quality of life (QOL) in first-episode psychosis (FEP) is impaired when compared to non-clinical controls and several clinical factors including symptoms and untreated psychosis have been linked with poorer QOL. Measurement methods are varied, however, resulting in inconsistent findings and there is a need to simultaneously combine subjective and objective measures of QOL. METHODS: We examined both subjective (n = 128) and objective QOL (n = 178) in a catchment area cohort of individuals with FEP (n = 222) to determine correspondence between patient satisfaction and clinician-rated functional domains. We also examined the contribution of sociodemographic and clinical characteristics to both subjective and objective QOL. RESULTS: There were complex relationships between subjective and objective QOL domains in that patient's assessments of health status (psychological well-being, symptoms/outlook, physical health) were not correlated with clinicians but there were strong correlations between social functioning domains (occupation, social relations, financial status and activities of daily living) assessed by patients and clinicians. Longer duration of untreated psychosis, being treated as an inpatient, higher positive symptoms and poorer social functioning in client-rated QOL domains predicted poorer objective QOL. CONCLUSION: We found that both subjective and objective assessments of QOL displayed a degree of clinical utility demonstrated by relationships between clinical factors and both QOL perspectives. Moreover, the lack of association between patient characteristics and QOL shows some potential malleability of QOL outcomes through intervention as there were several clinical factors linked with both subjective and objective QOL.

Socioeconomic status at birth and risk for first episode psychosis in rural Ireland: Eliminating the features of urbanicity in the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS).

BACKGROUND: There is a paucity of research on the relationship between social environment at birth and risk for psychosis in rural settings. This study examined the relationship between individual- and neighbourhood-level socioeconomic indicators proximal to the time of birth and risk for a first psychotic episode in a rural context using a prospective dataset of unusual epidemiological completeness. METHODS: A matched case-control design was used. 186 cases were identified from the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS) and 679 age- and sex-matched controls from the same rural setting were identified and analysed for relationships with individual and neighbourhood-level socioeconomic indicators at the level of Electoral Divisions. RESULTS: While neither the distribution nor the ordinal scale of parental social class differed between cases and controls, logistic regression revealed both parental social class III and increasing level of rurality to be associated (p≤0.05) with reduced risk for affective psychosis. There was a prominent relationship (p<0.001) between lower parental social class and older age at first presentation [mean age at first presentation for all psychoses: social class I, 22.8; social class VI, 44.3]. CONCLUSIONS: These findings indicate modest effects of individual- and neighbourhood-level socioeconomic indicators and risk for psychosis by place at birth within a rural environment. Thus, these factors are not confined to large urban settings and apply across the urban-rural continuum. The substantive finding in relation to age at first presentation may indicate that a gradient of socioeconomic position is influential on delay in presentation to mental health services.

The relationship between mental health literacy regarding schizophrenia and psychiatric stigma in the Republic of Ireland.

BACKGROUND: There is an unclear relationship between mental health literacy (MHL) and psychiatric stigma. MHL is associated with both positive and negative attitudes to mental illness. To our knowledge, no published peer reviewed study has examined this relationship in the Republic of Ireland. AIMS: This study was conducted to assess MHL regarding schizophrenia and the degree of psychiatric stigma displayed by the general public in the Republic of Ireland. METHOD: A face-to-face in-home omnibus survey was conducted with a representative sample of residents of the Republic of Ireland. Participants (N = 1001) were presented with a vignette depicting schizophrenia and were asked questions to determine their ability to recognise the condition and to ascertain their attitudes towards schizophrenia and mental illness. RESULTS: Among the participants, 34.1% correctly identified schizophrenia. Higher age, higher socioeconomic status, and an urban geographic location predicted identification. Those who did not correctly identify schizophrenia were significantly more optimistic about recovery and perceived people with schizophrenia as less dangerous. However, only the relationship with perceived dangerousness was considered robust. CONCLUSIONS: Participants with higher MHL displayed more negative attitudes to mental illness. Findings have implications internationally for MHL and anti-stigma campaigns.

Environmental factors and the age at onset in first episode psychosis.

OBJECTIVE: Factors that influence the age at onset in psychotic disorders could provide valuable insights into precipitating or causative factors of the disorder. Despite being established risk factors, it is not yet known whether migration status, place of birth, social class at birth and season of birth influence the age at onset of psychotic disorders. This study aimed to determine whether these environmental factors, in addition to cannabis abuse and obstetric complications, influence the age at onset. Additionally, we investigated whether environmental factors could have a cumulative effect on the age at onset. METHOD: Data was obtained from two first episode of psychosis (FEP) cohort studies. Diagnosis was established using the Structured Clinical Interview for DSM IV diagnoses. RESULTS: The age at onset was determined for 555 individuals with a FEP and the median age at onset was 27.3years. Individuals with a history of cannabis abuse had an earlier age at onset by nearly six years. There was a trend for a history of obstetric complications to be associated with a younger age at onset by 2.7years and this was significant in the subgroup with a family history of psychosis. Social class at birth, migration status, place of birth and season of birth were not associated with the age at onset. Exposure to a higher number of environmental factors was associated with an earlier age at onset. CONCLUSIONS: Cannabis and obstetric complications are associated with an earlier age at onset and there appears to be a cumulative effect of exposure to multiple environmental factors.

Negative symptom domain prevalence across diagnostic boundaries: The relevance of diagnostic shifts.

Negative symptoms are included in diagnostic manuals as part of criteria for schizophrenia spectrum psychoses only, however some studies have found their presence in other diagnoses. This study sought to clarify negative symptom domain prevalence across diagnostic categories, while investigating whether negative symptoms predicted diagnostic shift over time. Scale for the Assessment of Negative Symptoms (SANS) data were collected at first presentation in 197 individuals presenting with first episode psychosis and again at one year follow-up assessment. Negative symptoms were highest among individuals with schizophrenia and among those whose diagnosis shifted from non-schizophrenia spectrum at baseline to schizophrenia spectrum at follow-up. In a non-schizophrenia spectrum group negative symptoms at baseline were not a significant predictor of diagnostic shift to schizophrenia spectrum diagnoses. The study suggests negative symptoms can present among individuals with non-schizophrenia spectrum diagnoses, although this is most relevant for individuals following diagnostic shift from non-schizophrenia spectrum to schizophrenia spectrum diagnoses. The findings support introduction of a negative symptom dimension when describing a range of psychotic illnesses, and indicate that further research investigating the evolution of negative symptoms in non-schizophrenia diagnoses is needed.

Prodromal symptoms and remission following first episode psychosis.

INTRODUCTION: Describing the trajectory of prodromal symptoms has obvious appeal in supporting advances towards sub-clinical intervention. Identifying clinical phenomena associated with unfavourable illness outcomes could have greater significance in explaining some heterogeneity within and between psychotic disorders and advancing understanding of pre-psychotic typologies. Few studies have assessed the continuity, if any, between prodromal phases and illness outcome one year after treatment. METHODS: We assessed 375 people with first-episode psychosis (FEP) and 215 (57.4%) were seen approximately one year later. We performed factor analysis on prodromal symptom items obtained by interview with families and participants and identified a five-factor solution. We determined whether these factors predicted non-remission from psychosis in the presence of other factors that may predict outcome including premorbid adjustment, duration of prodrome and untreated psychosis (DUP), baseline symptoms and DSM-IV diagnoses. We used random forest classification to predict the most important variables and logistic regression to identify specific predictors. RESULTS: We identified five prodromal symptom factors comprising Negative Symptoms, General Psychopathology, Reality Distortion, Strange Ideas and Irritability. Prodromal symptoms did not predict a greater risk of non-remission with the exception of Irritability and this factor was also associated with earlier age at onset, being male and a diagnosis of substance-induced psychosis. Being male, DUP and baseline positive symptoms predicted non-remission at one year. CONCLUSION: Prodromal symptoms were not linked with outcome after a year of treatment which could be explained by greater heterogeneity in illness psychopathology which may be more pronounced in broad FEP diagnoses at different stages. It could also be explained by prodromal symptoms exerting greater influence earlier in the course illness.

Social class at birth and risk of psychosis.

BACKGROUND: Individuals with psychotic disorders are represented more in the lower social classes, yet there is conflicting evidence to whether these individuals drift into the lower social classes or whether lower social class is a risk factor for developing psychosis. The aim of this study was to examine whether the social class at birth is a risk factor for developing psychosis. METHODS: We included individuals with a first episode of psychosis (FEP) whose social class at birth was determined from birth records. We employed a case-control study design and also compared the distribution of the social classes at birth of the cases to that of the general population. RESULTS: A total of 380 individuals with an FEP and 760 controls were included in the case-control study. The odds ratio for developing an FEP associated with social class (low vs high) was .62 (95% confidence interval (CI): .46-.85, p < .001), indicating that individuals from a lower social class at birth have a reduced risk of psychosis. Individuals born between 1961 and 1980 with an FEP were more likely to be from a higher social class at birth compared to the general population (60.8% vs 36.7%, χ(2) = 60.85, df = 1, p < .001). However, this association was not observed for those born between 1981 and 1990. CONCLUSION: A higher social class at birth is associated with a greater risk for developing a psychotic disorder; however, this effect may show temporal variation.

Work life after psychosis: A detailed examination.

BACKGROUND: Conducting research on the work outcomes of first episode psychosis (FEP) samples may extend our understanding of the factors associated with the work outcome of people with schizophrenia and other psychotic illnesses. OBJECTIVE: To conduct a detailed study of the work outcome of an FEP sample. METHODS: Members of a FEP cohort, who had completed a 12-year clinical outcome assessment, were invited to participate in an adjunctive work outcome study. Engagement in paid and non-paid work was first established and the relationship with potentially influential baseline characteristics investigated. Subsequently the influence of work outcome to participants' level of quality of life, mental health, recovery, and social inclusion were examined. RESULTS: Among the 38 participants the mean percentage of time spent in work was 62% of which 50% was in paid work and 12% was in non-paid work. Being employed at inception was the only independent predictor of the duration of the follow-up period spent in work. Relationships between work outcome and all measures of wellbeing were found. CONCLUSION: The paid and non-paid work attained by people affected by a psychotic illness played an important role in the extent of their wellbeing, recovery, and social inclusion.

Improving social functioning and reducing social isolation and loneliness among people with enduring mental illness: Report of a randomised controlled trial of supported socialisation.

BACKGROUND: This randomised controlled trial examined if for people with enduring mental illness, being supported to socialise leads to improved social functioning, increased self-esteem and extended social networks; a reduction in social isolation, social, emotional and family loneliness and a reduction in illness symptoms, namely depression. METHODS: A prospective randomised controlled trial was undertaken from November 2007 to September 2011. Service users with a diagnosis of enduring mental illness (>18 years) were invited to participate. Participants were randomly allocated to intervention or control group conditions in a 1:1 ratio. Intervention group participants were matched with a volunteer partner, asked to engage in social/leisure activities for 2 hours weekly over a 9-month period, and received a €20 stipend monthly. Control group participants received a €20 monthly stipend and were asked to engage in a weekly social/leisure activity. Social functioning, the primary outcome, was measured using the Social Functioning Scale (SFS) at three time points (baseline, midpoint and endpoint). FINDINGS: In all, 107 people completed this study. There were no significant differences between control and intervention groups at the commencement of the intervention on demographic characteristics or the main outcome measures of interest. Overall social functioning positively changed throughout the three time points from a mean of 99·7 (standard deviation (SD) = 15.1) at baseline, to a mean of 106.0 (SD = 27.0) at the endpoint for the control group, and from a mean of 100·4 (SD = 15.0) at Time 1 for the intervention group, to a mean of 104.1 (SD = 23.4) at the endpoint for the intervention group. CONCLUSIONS: The intervention showed no statistical differences between the control and intervention groups on primary or secondary outcome measures. The stipend and the stipend plus volunteer partner led to an increase in recreational social functioning; a decrease in levels of social loneliness, in depression and in the proportion living within a vulnerable social network.

Social class mobility in first episode psychosis and the association with depression, hopelessness and suicidality.

BACKGROUND: Psychotic disorders are associated with a significant impairment in occupational functioning that can begin in the prodromal phase of the disorder. As a result, individuals with a psychotic disorder may not maintain their social class at birth. The aim of this study was to examine the distribution of the social classes of individuals presenting with a first episode of psychosis (FEP) compared to the general population and to their family of origin. We evaluated whether social drift was associated with depression, hopelessness and suicidality at first presentation. METHODS: All individuals with a FEP presenting to a community mental health service between 1995 and 1999 and to an early intervention service between 2005 and 2011were included. Diagnosis was established using the Structured Clinical Interview for DSM IV diagnoses and clinical evaluations included the Calgary Depression Scale for Schizophrenia, Beck Hopelessness Scale and the Suicidal Intent Scale. RESULTS: 330 individuals were included in the study and by the time of presentation, individuals with a FEP were more likely to be represented in the lower social classes compared to the general population. 43% experienced a social drift and this was associated with a diagnosis of a non-affective disorder, co-morbid cannabis abuse and a longer DUP. Individuals who did not experience a social drift had a higher risk of hopelessness. CONCLUSIONS: Social drift is common in psychotic disorders; however, individuals who either maintain their social class or experience upward social class mobility are more susceptible to hopelessness.

Daily weather variables and affective disorder admissions to psychiatric hospitals.

Numerous studies have reported that admission rates in patients with affective disorders are subject to seasonal variation. Notwithstanding, there has been limited evaluation of the degree to which changeable daily meteorological patterns influence affective disorder admission rates. A handful of small studies have alluded to a potential link between psychiatric admission rates and meteorological variables such as environmental temperature (heat waves in particular), wind direction and sunshine. We used the Kruskal-Wallis test, ARIMA and time-series regression analyses to examine whether daily meteorological variables--namely wind speed and direction, barometric pressure, rainfall, hours of sunshine, sunlight radiation and temperature--influence admission rates for mania and depression across 12 regions in Ireland over a 31-year period. Although we found some very weak but interesting trends for barometric pressure in relation to mania admissions, daily meteorological patterns did not appear to affect hospital admissions overall for mania or depression. Our results do not support the small number of papers to date that suggest a link between daily meteorological variables and affective disorder admissions. Further study is needed.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.