Twenty Years of Schizophrenia Research in the Northern Finland Birth Cohort 1966: A Systematic Review

Birth cohort designs are useful in studying adult disease trajectories and outcomes, such as schizophrenia. We review the schizophrenia research performed in the Northern Finland Birth Cohort 1966 (NFBC 1966), which includes 10,934 individuals living in Finland at 16 years of age who have been monitored since each mother's mid-pregnancy. By the age of 44, 150 (1.4%) had developed schizophrenia. There are 77 original papers on schizophrenia published from the NFBC 1966. The early studies have found various risk factors for schizophrenia, especially related to pregnancy and perinatal phase. Psychiatric and somatic outcomes were heterogeneous, but relatively poor. Mortality in schizophrenia is high, especially due to suicides. Several early predictors of outcomes have also been found. Individuals with schizophrenia have alterations in brain morphometry and neurocognition, and our latest studies have found that the use of high lifetime doses of antipsychotics associated with these changes. The schizophrenia research in the NFBC 1966 has been especially active for 20 years, the prospective study design and long follow-up enabling several clinically and epidemiologically important findings. When compared to other birth cohorts, the research in the NFBC 1966 has offered also unique findings on course and outcome of schizophrenia.

Related papers:

title: The antecedents of schizophrenia: a review of birth cohort studies.
abstract: Birth cohort (BC) studies demonstrate that individuals who develop schizophrenia differ from the general population on a range of developmental indices. The aims of this article were to summarize key findings from BC studies in order to identify areas of convergence and to outline areas requiring further research.



We define BC studies as studies based on general population BCs where data are collected prospectively from birth or childhood and which identify schizophrenia or related disorders as an outcome. To identify such studies, we searched various electronic databases using the search parameters (schizo* OR psych*) AND (birth cohort). We also checked the references of relevant articles and previous reviews.



We identified 11 BCs from 7 countries that have examined schizophrenia as an outcome in adulthood. There is relatively consistent evidence that, as a group, children who later develop schizophrenia have behavioral disturbances and psychopathology, intellectual and language deficits, and early motor delays. Evidence with respect to alterations in language, educational performance, and physical growth has also been identified in some studies. BC studies have also contributed evidence about a wide range of putative risk factors for schizophrenia.



BC studies have provided important, convergent insights into how the developmental trajectory of individuals who develop schizophrenia differs from their peers. The combination of new paradigms and larger cohorts, with the tools of modern epidemiology and biomedical science, is advancing our understanding of the developmental pathways to schizophrenia.

title: Non-participation in a field survey with respect to psychiatric disorders
abstract: Higher rates of psychiatric morbidity among non-participants may lead to biased estimates of prevalence and incidence in epidemiological studies of psychiatric disorders. We had a unique opportunity to explore psychiatric morbidity and non-participation in a large epidemiological survey including questionnaires and a clinical examination.  Members of the Northern Finland 1966 Birth Cohort were included in the study. In phase I, a postal questionnaire was mailed to all those with a known address in 1997 (N=11,540). In phase II, all subjects living in northern Finland or the Helsinki area (N=8463) were invited to a clinical examination. In phase III, clinical examination participants were given a questionnaire with psychological subscales to be filled in at home and returned by mail. The data on hospital-treated psychiatric disorders were obtained from the Finnish Hospital Discharge Register. Educational level was obtained from Statistics Finland.  The participation rates were 76%, 71% and 61% in phases I, II and III, respectively. Subjects with any psychiatric disorder participated less actively than those without any psychiatric disorder in all phases, in both genders and at all educational levels. Participation was not found to vary across specific disorders. Gender or education did not explain the association of psychiatric disorders with participation.  Owing to non-participation, the true prevalence of psychiatric disorders may be higher than the prevalence estimated from epidemiological field surveys.

title: Use of inverse probability weighting to adjust for non-participation in estimating brain volumes in schizophrenia patients
abstract: Low participation is a potential source of bias in population-based studies. This article presents use of inverse probability weighting (IPW) in adjusting for non-participation in estimation of brain volumes among subjects with schizophrenia. Altogether 101 schizophrenia subjects and 187 non-psychotic comparison subjects belonging to the Northern Finland 1966 Birth Cohort were invited to participate in a field study during 1999-2001. Volumes of grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) were compared between the 54 participating schizophrenia subjects and 100 comparison subjects. IPW by illness-related auxiliary variables did not affect the estimated GM and WM mean volumes, but increased the estimated CSF mean volume in schizophrenia subjects. When adjusted for intracranial volume and family history of psychosis, IPW led to smaller estimated GM and WM mean volumes. Especially IPW by a disability pension and a higher amount of hospitalisation due to psychosis had effect on estimated mean brain volumes. The IPW method can be used to improve estimates affected by non-participation by reflecting the true differences in the target population.

title: 1725 – Using Home Recruitment To Increase Representativeness Of Schizophrenia Research
abstract: The participation rates in epidemiologic studies have declined in recent decades. Missing data reduce sample size, statistical power, and scientific quality.  To study use of home interviews in recruiting individuals with a psychosis.  To evaluate effect of home-recruitment on non-response bias.  In the Northern Finland 1966 Birth Cohort, field surveys on psychosis were conducted in 1999-2001 and 2008-2010. In order to increase participation in the follow-up sample, cases were offered to be interviewed at home. We studied symptoms, illness severity, functioning, cognition, antipsychotics use, and grey matter (GM) volume between home-recruited and regular participants (RP), and non-participants (NP). Effect sizes (d) were calculated to compare the differences. ) out of the follow-up sample (n=54) were home-recruited, 27 did not participate. Home-recruited had more symptoms, lower functioning, cognition and GM volume, and they had used more antipsychotics compared to RP and NP in baseline. NP did not differ from RP. The same differences occurred when home-recruited were compared with RP in the follow-up study. Selected information from baseline study] Homerecruited participants Regular participants Nonparticipants ANOVA Mean (SD) Mean (SD) Mean (SD) P d1 d2 PANSS, negative 19 (11) 12 (6) 14 (10) 0.028 0.89 0.48 PANSS, disorganization 21 (9) 15 (7) 16 (9) 0.033 0.81 0.60 PANSS, excitement 13 (5) 10 (2) 12 (5) 0.025 0.91 0.38 SOFAS 40 (19) 57 (15) 54 (15) 0.002 -1.04 -0.85 CVLT, total recall 39 (14) 51 (13) 44 (16) 0.032 -0.89 -0.30 Dose years 44 (47) 15 (18) 12 (13) 0.002 0.92 1.00 Grey matter volume 593 (60) 642 (64) 623 (61) 0.039 -0.77 -0.49  Owing to the home-recruitment we were able to collect data that may be reasonably non-biased in terms of nonresponse bias, which will yield valid estimates in our future studies on change over time in brain and cognitive ability, prevalence and severity of psychotic illnesses, outcome, medication use, and other issues of interest.

title: A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort
abstract: As a prerequisite to the use of the Finnish National Hospital Discharge Register in psychiatric epidemiological research, we studied the diagnostic reliability of the register in terms of the psychiatric morbidity experienced by a national birth cohort. We investigated all entries to the register for a sample based upon the Northern Finland 1966 birth cohort at the age of 16 years (n=11017). Until the end of 1993 (age 27 years), a total of 563 subjects had a register diagnosis indicating a psychiatric illness, 37 of them being schizophrenia. When operational criteria (DSM-III-R) were applied to clinical information in the available original hospital records for cases of psychosis, personality disorder and substance abuse (n=249), 71 fulfilled criteria for schizophrenia, including all of the 37 cases in the register and an additional 34 (48% false-negatives), most frequently diagnosed in the register as schizophreniform or other psychosis. Despite the official use of DSM-III-R nomenclature, it appears that the clinical concept of schizophrenia in Finland, manifest within the register, remains very restrictive. The application of operational criteria is a necessary prerequisite for scientific research on schizophrenia.

title: Interaction between parental psychosis and risk factors during pregnancy and birth for schizophrenia — The Northern Finland 1966 Birth Cohort study
abstract: Our aim was to investigate the association between parental psychosis and potential risk factors for schizophrenia and their interaction. We evaluated whether the factors during pregnancy and birth have a different effect among subjects with and without a history of parental psychosis and whether parental psychosis may even explain their effects on the risk of schizophrenia. The sample comprised 10,526 individuals from the Northern Finland 1966 Birth Cohort. A total of 150 (1.4%) cohort members had schizophrenia by the age of 44 years, of them 18 (12.0%) had a parent with a history of psychosis. In non-psychotic cohort members, this figure was 495 (4.8%). In the parental psychosis group, significant early biological risk factors for schizophrenia included high birth weight (hazard ratio, HR 11.4; 95% confidence interval 3.3-39.7) and length (HR 4.1; 1.3-12.5), high birth weight in relation to gestational age (HR 3.2; 1.1-9.0), and high maternal age (HR 2.6.; 1.0-6.7). High birth weight and length and high maternal education had a significant interaction with parental psychosis. The presence of any biological risk factor increased the risk of schizophrenia significantly only among the parental psychosis group (HR 4.0; 1.5-10.5), whereas the presence of any psychosocial risk factor had no interaction with parental psychosis. Parental psychosis can act as an effect modifier on early risk factors for schizophrenia. Evaluation of the mechanisms behind the risk factors should, therefore, include consideration of the parental history of psychosis.

title: Schizophrenia in the offspring of antenatally depressed mothers in the northern Finland 1966 birth cohort: relationship to family history of psychosis.
abstract: Maternal depression is relatively common during pregnancy. The authors examined whether maternal antenatal depressed mood increased the risk of schizophrenia and other psychoses among offspring with and without a familial history of psychosis.



In the Northern Finland 1966 birth cohort, mothers of 12,058 children were asked at mid-gestation at the antenatal clinic if they felt depressed. The offspring were followed for over 30 years, and subsequent schizophrenia and other psychoses were detected using the Finnish Hospital Discharge Register, which was also used for identifying psychosis in the parents. Familial risk for psychosis was considered as a genetic risk factor and mothers' depressed mood as an environmental or genetic risk factor.



The risk for schizophrenia was higher in the offspring with both maternal depressed mood during pregnancy and parental psychosis (OR=9.4, 95% CI=4.2-20.9 adjusted for sex and perinatal complications) than in those with a depressed mother but without parental psychosis (OR=1.0, 95% CI=0.6-1.8) or those without maternal depression and with a psychotic parent (OR=2.6, 95% CI=1.2-5.4). The reference group was birth cohort members without maternal antenatal depression and without parental psychosis.



Maternal depressed mood during pregnancy per se is unlikely to increase the risk for schizophrenia in the offspring but may affect subjects with a family history for psychosis. This finding could be an example of a gene-environment or possibly a gene-gene interaction in the development of schizophrenia. Mothers' antenatal depression may act as additive factor for subjects vulnerable to schizophrenia.

title: Advanced paternal age and parental history of schizophrenia
abstract: Advanced paternal age (APA) is a risk factor for nonaffective psychosis (NAP) in the offspring, although the mechanism(s) of this association are not clear. The aim of this study was to examine whether later childbearing can be explained by parental schizophrenia, and in doing so, further evaluate the "de novo mutation" hypothesis for the association between APA and NAP.



Using binary logistic regression, the association between APA and parental history of schizophrenia in the offspring, considering maternal and paternal history separately, was examined in 1) all persons with NAP born in Finland between 1950 and 1969 (Finnish NAP Cohort, n = 13,712), and 2) members of the Northern Finland 1966 Birth Cohort (NFBC 1966, n = 10,224), a general population birth cohort.



In the Finnish NAP Cohort, having a mother with schizophrenia was associated with APA (Odds Ratio [OR] for linear trend = 1.20, 95% confidence interval 1.12-1.29, p < 0.01). In the NFBC 1966 sample, having a mother with schizophrenia was associated with APA at the trend level (OR = 1.14, 0.99-1.31, p = 0.07). By contrast, there was no association between having a father with schizophrenia and APA.



In both a general population cohort and a birth cohort of subjects with nonaffective psychosis, APA was associated with maternal, but not paternal, schizophrenia. These findings suggest that increased genetic risk from the mother may explain the association between APA and nonaffective psychosis, and argue against the "de novo mutation" hypothesis.

title: A systematic meta-review grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia
abstract: Identifying the relative strength of evidence associated with non-genetic risk factors and putative antecedents of schizophrenia will guide research and may inform the design of early detection and intervention strategies.



To present and quality assess current evidence for non-genetic risk factors and putative antecedents derived from well-conducted systematic reviews that report pooled data.



Medline, Embase, CINAHL, Current Contents, and PsycINFO databases were searched systematically, and supplemented by hand searching. Review reporting quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, review methodology was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist, and evidence quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.



Twenty-four reviews met inclusion criteria. The risk factors with the highest quality evidence, reporting medium effect sizes, were advanced paternal age, obstetric complications, and cannabis use. The strongest evidence among the putative antecedents was identified for motor dysfunction and low IQ.



More research is required that applies sound methodological practices, taking into consideration specificity for schizophrenia and possible confounding factors, to robustly identify the non-genetic risk factors and putative antecedents of schizophrenia.

title: Meta-analysis of paternal age and schizophrenia risk in male versus female offspring.
abstract: Advanced paternal age (APA) is a reported risk factor for schizophrenia in the offspring. We performed a meta-analysis of this association, considering the effect of gender and study design.



We identified articles by searching Pub Med, PsychInfo, ISI, and EMBASE, and the reference lists of identified studies. Previously unpublished data from the Northern Finland 1966 Birth Cohort (NFBC 1966) study were also included.



There were 6 cohort studies and 6 case-control studies that met the inclusion criteria. In both study designs, there was a significant increase in risk of schizophrenia in the offspring of older fathers (≥30) compared to a reference paternal age of 25-29, with no gender differences. The relative risk (RR) in the oldest fathers (≥50) was 1.66 [95% confidence interval (95% CI): 1.46-1.89, P < 0.01]. A significant increase in risk was also found for younger fathers (<25) in males (RR = 1.08, 95% CI: 1.02-1.14, P = 0.01) but not females (RR = 1.04, 95% CI: 0.97-1.14, P = 0.28). The population attributable risk percentage (PAR%) was 10% for paternal age ≥30 and 5% for paternal age <25.



Both APA (≥30) and younger paternal age (<25) increase the risk of schizophrenia; younger paternal age may be associated with an increased risk in males but not females. This risk factor increases the risk of schizophrenia as much as any single candidate gene of risk. The mechanism of these associations is not known and may differ for older and younger fathers.

title: The persistence of developmental markers in childhood and adolescence and risk for schizophrenic psychoses in adult life. A 34-year follow-up of the Northern Finland 1966 birth cohort
abstract: Childhood precursors of schizophrenia include multiple abnormalities of development. Continuities between early and subsequent deviance are poorly characterised. We studied associations among premorbid developmental deviance using data at ages 1 year (learning to stand, walk, and speak, attainment of bladder and bowel control) and 16 years (success at school). Generalised linear modelling was used to examine differential linear associations and trends across adult psychiatric diagnoses. In babies who, as adults, suffered schizophrenia or any psychosis, those who learned to stand latest were also more likely to perform poorly at school in both motor and theoretical domains at age 16 when compared with earlier learners. The effect was independent of genetic and perinatal factors. We conclude that the early developmental deviation in the first year of life is associated with lower school performance at age 16. Developmental continuity among children who develop psychoses was stronger than among normal controls and those hospitalized for nonpsychotic psychiatric disorder. These findings are in line with the hypothesis that a neural diathesis is present during postnatal brain development before schizophrenia. This supports the longitudinal dimension and life span models of schizophrenia.

title: Early developmental differences between DSM-III-R schizophrenics treated with clozapine and typical neuroleptics.
abstract: Developmental deviance is known to be associated with schizophrenia. We tested the hypothesis that the most severe schizophrenia requiring treatment with clozapine would particularly show these effects. Therefore, associative factors from pregnancy, delivery, neonatal and socio-demographic characteristics were compared between the clozapine-treated schizophrenic cases (n = 17) and the remaining cases of schizophrenia treated with typical neuroleptics (n = 59) from an unselected, general population North Finland 1966 Birth Cohort, (n = 11,017). By the end of 1994, seventeen (22%) of a total 76 DSM-III-R schizophrenia patients, had received clozapine treatment. The mean length at birth was 52 cm in the clozapine group (in the non-clozapine group 50 cm) and correspondingly the mean one year weight 10.4 kg (9.8 kg), with the differences between the groups being statistically significant (P < 0.05). Other pregnancy, delivery, and socio-demographic characteristics were, however, similar in the clozapine-treated and the remaining cases with schizophrenia. There was no evidence that severe schizophrenia requiring treatment with clozapine was associated with impaired intrauterine or post-natal development. Indeed, during the first years of life the former group was larger in terms of weight and length than those treated with typical neuroleptics. These early developmental characteristics did not predict clinical severity of schizophrenia in adulthood.

title: Associations between brain morphology and outcome in schizophrenia in a general population sample
abstract: To analyse associations between brain morphology and longitudinal and cross-sectional measures of outcomes in schizophrenia in a general population sample.  The sample was the Northern Finland 1966 Birth Cohort. In 1999–2001, structural brain MRI and measures of clinical and functional outcomes were analysed for 54 individuals with schizophrenia around the age of 34. Sex, total grey matter, duration of illness and the use of antipsychotic medication were used as covariates.  After controlling for multiple covariates, increased density of the left limbic area was associated with less hospitalisations and increased total white matter volume with being in remission. Higher density of left frontal grey matter was associated with not being on a disability pension and higher density of the left frontal lobe and left limbic area were related to better functioning. Higher density of the left limbic area was associated with better longitudinal course of illness.  This study, based on unselected general population data, long follow-up and an extensive database, confirms findings of previous studies, that morphological abnormalities in several brain structures are associated with outcome. The difference in brain morphology in patients with good and poor outcomes may reflect separable aetiologies and developmental trajectories in schizophrenia.

title: Socio-demographic and clinical predictors of occupational status in schizophrenic psychoses—follow-up within the Northern Finland 1966 Birth Cohort
abstract: We studied occupational status of persons with schizophrenic psychoses by age 34 in a longitudinal population-based cohort and predicted which demographic and illness-related factors could support the patients to maintain their occupational capacity. Subjects of the Northern Finland 1966 Birth Cohort with the diagnosis of DSM-III-R schizophrenic psychoses (n=113) by the year 1997 were followed until the end of year 2000. Various illness and socio-demographic factors at the time of onset of illness were used as predictors. At the end of the follow-up time 50 (44%) of patients were not pensioned and 22 (20%) were also working at least half of the time during year 2000. After adjusting for gender, being unemployed at onset, educational level and proportion of time spent in psychiatric hospitals, those who were married or cohabiting at the time of onset of illness were less often on pension than those who were single (OR 6.51; 95% CI 1.83-23.12). Thus, nearly half of the patients with schizophrenic psychoses were not pensioned after an average 10 years follow-up. Based on our findings, those who were single at time of their onset of illness probably need most support to retain their contacts to work life.

title: Association between age at onset and clinical features of schizophrenia: The Northern Finland 1966 birth cohort study
abstract: To study the association between age at onset and the clinical picture of schizophrenia in an unselected young birth cohort.  The study sample consists of 98 (64 males and 34 females) individuals with DSM-III-R schizophrenia collected from the Northern Finland 1966 birth cohort. Firstly, subjects were divided into very early- and young-onset subgroups by using the median age at onset (22 years in males and 20 in females), as a cut-off point. Secondly, we used age at onset as a continuous variable. Clinical features of schizophrenia were assessed using the Operational Criteria Checklist for Psychotic Illnesses (OCCPI).  Inappropriate affect, positive thought disorder and deterioration from premorbid level of function associate with very early-onset schizophrenia, while slowed activity and dysphoria relate to young-onset. These symptoms correlate significantly with the age at onset.  Differences in the clinical picture associating to the age at onset of schizophrenia are seen early.  These findings indicate that certain symptoms of schizophrenia are dependent on the age at onset, and schizophrenia occurring initially in early life has some typical features. Using the age at onset as a continuous variable is independent of arbitrary cut-off points and produces more explicable results.

title: Recovery from schizophrenic psychoses within the northern Finland 1966 Birth Cohort.
abstract: Because of widely disparate findings from follow-up studies, the likelihood of recovery from schizophrenia remains controversial. We report the extent of recovery from schizophrenia in a population-based cohort.



Subjects with psychotic disorders were recruited from the Northern Finland 1966 Birth Cohort. Of the 91 subjects who agreed to participate, 59 were diagnosed with schizophrenia and 12 were diagnosed with schizophrenia spectrum disorders (schizophreniform psychosis, schizoaffective or delusional disorder) by DSM-III-R criteria. Diagnoses were established by interviewing the subjects, checking the Finnish Hospital Discharge Register, and reviewing their medical records. To assess recovery, we used the Clinical Global Impressions; the Positive and Negative Syndrome Scale; the Social and Occupational Functioning Assessment Scale; and information about psychiatric hospitalizations, use of antipsychotic medication, and occupational status.



Only 1 subject (1.7%) with DSM-III-R schizophrenia and 3 subjects (25%) with schizophrenia spectrum disorders fully recovered; 1 schizophrenia subject (1.7%) and 2 schizophrenia spectrum subjects (16.7%) experienced partial recovery.



The data indicate that, at least until age 35, complete recovery from schizophrenia is rare, and the prognosis for the disorder is far more serious than suggested by some follow-up studies.

title: Patterns of psychiatric hospitalizations in schizophrenic psychoses within the Northern Finland 1966 Birth Cohort
abstract: We report patterns of hospitalization in schizophrenic psychoses by age 34 in a longitudinal population-based cohort. We test the predictive ability of various demographic and illness-related variables on patterns of hospitalization, with a special focus on the length of the first psychiatric hospitalization. All living subjects of the Northern Finland 1966 Birth Cohort with DSM-III-R schizophrenia (n=88) and other schizophrenia spectrum cases (n=27) by the year 1997 in the Finnish Hospital Discharge Register were followed for an average of 10.5 years. Measures of psychiatric hospitalization included time to re-hospitalization (as continuous and as re-hospitalization within 2 years) and the number of hospital episodes. Length of the first hospitalization, other illness-related and various socio-demographic predictors were used to predict hospitalization patterns. After adjusting for gender, age at first admission and number of hospital days a short (1–14 days) first hospitalization (reference >30 days; adjusted odds ratio 6.39; 95% CI 2.00–20.41) and familial risk of psychosis (OR 3.36; 1.09–10.39) predicted re-hospitalization within 2 years. A short first hospitalization also predicted frequent psychiatric admissions defined as the first three admissions within 3 years (OR 13.77; 3.92–48.36). A short first hospitalization was linked to increased risk of re-hospitalizations. Although short hospitalization is recommended by several guidelines, there may be a group of patients with schizophrenic psychoses in which too short a hospitalization may lead to inadequate treatment response.

title: A systematic review and meta-analysis of recovery in schizophrenia.
abstract: Our primary aims were (a) to identify the proportion of individuals with schizophrenia and related psychoses who met recovery criteria based on both clinical and social domains and (b) to examine if recovery was associated with factors such as gender, economic index of sites, and selected design features of the study. We also examined if the proportions who met our definition of recovery had changed over time.



A comprehensive search strategy was used to identify potential studies, and data were extracted for those that met inclusion criteria. The proportion who met our recovery criteria (improvements in both clinical and social domains and evidence that improvements in at least 1 of these 2 domains had persisted for at least 2 years) was extracted from each study. Meta-regression techniques were used to explore the association between the recovery proportions and the selected variables.



We identified 50 studies with data suitable for inclusion. The median proportion (25%-75% quantiles) who met our recovery criteria was 13.5% (8.1%-20.0%). Studies from sites in countries with poorer economic status had higher recovery proportions. However, there were no statistically significant differences when the estimates were stratified according to sex, midpoint of intake period, strictness of the diagnostic criteria, duration of follow-up, or other design features.



Based on the best available data, approximately, 1 in 7 individuals with schizophrenia met our criteria for recovery. Despite major changes in treatment options in recent decades, the proportion of recovered cases has not increased.

title: Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis
abstract: Duration of untreated psychosis (DUP) is one of the few potentially modifiable predictors of outcomes of schizophrenia. Long DUP as a predictor of poor short-term outcome has been addressed in previous meta-analyses, but the long-term effects of DUP remain unclear.  To analyse the associations between DUP and long-term outcomes of schizophrenia.  A systematic literature search was performed using seven electronic databases and manual searches. Random effects weighted meta-analysis with correlation coefficients was used to pool the results.  We identified 3493 unique publications, from which 33 samples met our predefined selection criteria. Long DUP correlated statistically significantly with poor general symptomatic outcome, more severe positive and negative symptoms, lesser likelihood of remission and poor social functioning and global outcome (correlations 0.13–0.18). Long DUP was not associated with employment, quality of life or hospital treatment.  The small but mostly consistent correlation between long DUP and poor outcome indicates that early intervention in psychosis may have at least subtle positive effects on the long-term course of illness.

title: The psychosis high-risk state: a comprehensive state-of-the-art review.
abstract: During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5.



To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain.



Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences.



Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field.



Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures.



The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

title: Volumes of brain, grey and white matter and cerebrospinal fluid in schizophrenia in the Northern Finland 1966 Birth Cohort: An epidemiological approach to analysis
abstract: Magnetic resonance imaging (MRI) studies in schizophrenia have seldom involved a general population birth cohort or other epidemiological samples. We studied the Northern Finland 1966 Birth Cohort and identified all people with psychotic disorders. Along with an unaffected age-matched control sample (n = 100) from the cohort, 54 subjects with schizophrenia underwent MRI brain scan at age 33-35 years from which we defined volumes of whole brain, grey and white matter and intracranial cerebrospinal fluid (CSF). Whole brain, grey and white matter volumes were 2-3% smaller in the schizophrenia subjects, who showed a 7% increase in CSF volume. These volume changes were independent of the effects of gender, family history of psychosis, perinatal risks or age at onset of illness. Moreover, there was no evidence that the effects were due to particular subgroups of cases having very low or high values. Rather, there were linear trends in the associations between whole brain and grey matter volume measures and schizophrenia. Our study replicates the previous findings of brain volume differences in schizophrenia on a general population level.

title: Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort
abstract: Structural brain differences have been reported in many studies with schizophrenia, but few have involved a general population birth cohort. We investigated differences in volume, shape and laterality of hippocampus and amygdala in patients with schizophrenia, all psychoses and comparison subjects within a large general birth cohort sample, and explored effects of family history of psychosis, perinatal risk and age-at-onset of illness. All subjects with psychosis from the Northern Finland 1966 birth cohort were invited to a survey including MRI scan of the brain, conducted in 1999-2001. Comparison subjects not known to have psychosis were randomly selected from the same cohort. Volumes of hippocampus and amygdala were measured in 56 subjects with DSM-III-R schizophrenia, 26 patients with other psychoses and 104 comparison subjects. Small hippocampal volume reductions in schizophrenia (2%) and all psychoses (3%) were not significant when adjusted for total brain volume. The shape of hippocampus in schizophrenia did not differ significantly from comparison subjects. Right hippocampus and amygdala were significantly larger than the left in all groups. Mean amygdala volume in schizophrenia or all psychoses did not differ from comparison subjects. Patients with family history of psychosis had larger hippocampus than patients without. Neither perinatal risk nor age-at-onset of illness had any effect on hippocampal or amygdala volumes. Small hippocampal volume reduction in schizophrenia and all psychoses was not disproportionate to reduced whole brain volume in this population-based sample. Perinatal events that have been suggested as of etiological importance in structural pathology of psychosis had no effect.

title: Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia
abstract: Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33–35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

title: Longitudinal Changes in Total Brain Volume in Schizophrenia: Relation to Symptom Severity, Cognition and Antipsychotic Medication
abstract: Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999–2001 at the age of 33–35 years. A follow-up was conducted 9 years later during 2008–2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions.

title: Infant motor development and adult cognitive functions in schizophrenia
abstract: Childhood neuromotor dysfunction is a risk factor for schizophrenia, a disorder in which cognitive deficits are prominent. The relationship between early neurodevelopment and adult cognition in schizophrenia remains unclear.



We examined the associations between infant motor development and adult cognitive functions in schizophrenia (n = 61) and the general population (n = 104) in a sample drawn from the The Northern Finland 1966 Birth Cohort. Data on ages of learning to stand and walk with or without support were obtained at age 12 months by health visitor assessment. Neurocognitive measures at age 33-35 included executive function, verbal and visual episodic memory, and visuo-spatial working memory.



The schizophrenia group achieved neuromotor milestones later and performed significantly worse than the control group on all measures of cognition. In pooled analyses there were associations between infant motor development and adult cognition in the domains of executive function, verbal learning and visuospatial working memory, but not in visual object learning. The pattern of associations between development and cognition was similar in schizophrenia and the general population.



These findings are consistent with the hypothesis that in schizophrenia mild infant motor developmental delay and adult cognitive deficits (at least in some domains) are age dependent manifestations of the same underlying neural process. Thus, they may be better considered as part of a single longitudinal syndrome.

title: Linking the Developmental and Degenerative Theories of Schizophrenia: Association Between Infant Development and Adult Cognitive Decline
abstract: Neurodevelopmental and neurodegenerative theories may be viewed as incompatible accounts that compete to explain the pathogenesis of schizophrenia. However, it is possible that neurodevelopmental and neurodegenerative processes could both reflect common underlying causal mechanisms. We hypothesized that cognitive dysfunction would gradually deteriorate over time in schizophrenia and the degree of this deterioration in adulthood would be predicted by an infant measure of neurodevelopment. We aimed to examine the association between age of learning to stand in infancy and deterioration of cognitive function in adulthood. Participants were nonpsychotic control subjects (n = 76) and participants with schizophrenia (n = 36) drawn from the Northern Finland 1966 Birth Cohort study. The schizophrenia group showed greater deterioration in abstraction with memory than controls, but there were no differences between schizophrenia and controls in rate of change of other cognitive measures. Age of learning to stand in infancy significantly inversely predicted later deterioration of abstraction with memory in adult schizophrenia (later infant development linked to greater subsequent cognitive deterioration during adulthood), possibly suggesting a link between abnormal neurodevelopmental and neurodegenerative processes in schizophrenia.

title: Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia — An observational 9-year follow-up study
abstract: The association between the course of cognition and long-term antipsychotic medication in schizophrenia remains unclear. We analysed the association between cumulative lifetime antipsychotic medication dose and change of verbal learning and memory during a 9-year follow-up.



Forty schizophrenia subjects and 73 controls from the Northern Finland Birth Cohort 1966 were assessed by California Verbal Learning Test (CVLT) at the ages of 34 and 43 years. Data on the lifetime antipsychotic doses in chlorpromazine equivalents were collected. The association between antipsychotic dose-years and baseline performance and change in CVLT was analysed, controlling for baseline performance, gender, age of onset and severity of illness.



Higher antipsychotic dose-years by baseline were significantly associated with poorer baseline performance in several dimensions of verbal learning and memory, and with a larger decrease in short-delay free recall during the follow-up (p=0.031). Higher antipsychotic dose-years during the follow-up were associated with a larger decrease of immediate free recall of trials 1-5 during the follow-up (p=0.039). Compared to controls, decline was greater in some CVLT variables among those using high-doses, but not among those using low-doses.



This is the first report of an association between cumulative lifetime antipsychotic use and change in cognition in a long-term naturalistic follow-up. The use of high doses of antipsychotics may be associated with a decrease in verbal learning and memory in schizophrenia years after illness onset. The results do not support the view that antipsychotics in general prevent cognitive decline or promote cognitive recovery in schizophrenia.

title: 1913 – Longitudinal Change In Verbal Learning And Memory In Schizophrenia And Controls: a Nine-year Study In The Northern Finland Birth Cohort 1966
abstract: Patients with schizophrenia generally perform worse than control subjects on all cognitive domains, and particularly in memory functions. It is still unclear, how cognition changes during years of illness in schizophrenia.  Our aim was to analyze the change in verbal learning and memory functions in subjects with schizophrenia and healthy controls during a 9-year follow-up.  The sample was the general population based Northern Finland 1966 Birth Cohort. In 1999-2001 and in 2008-2010 field studies were performed, including repeated measures of clinical status and the California Verbal Learning Test (CVLT). CVLT was used for the estimation of the course of a possible change of verbal learning and memory during the follow-up. The sample included 41 individuals with schizophrenic psychoses and 74 non-psychotic controls.  Both cases and controls had statistically significant decline in measures of CVLT. However, the change in verbal learning and memory in the 9 -year follow-up was not statistically significantly different between cases and controls. Among cases, age of illness onset and sex had no statistically significant effect on change of verbal learning and memory.  According to our unselected, population based sample with long follow up, the impairments during the life span in verbal learning and memory in schizophrenia was not different compared to controls. These results imply that schizophrenia is not a progressing degenerative illness.

title: Meta-analysis of cognitive deficits in ultra-high risk to psychosis and first-episode psychosis: do the cognitive deficits progress over, or after, the onset of psychosis?
abstract: Cognitive dysfunction is a well-established feature of schizophrenia, and there is evidence suggesting that cognitive deficits are secondary to abnormal neurodevelopment leading to problems in acquiring such abilities. However, it is not clear whether there is also a decline in cognitive performance over, or after, the onset of psychosis. Our objective was to quantitatively examine the longitudinal changes in cognitive function in patients who presented with first-episode psychosis (FEP), ultra-high risk (UHR) for psychosis, and controls. Electronic databases were searched for the studies published between January 1987 and February 2013. All studies reporting longitudinal cognitive data in FEP and UHR subjects were retrieved. We conducted meta-analyses of 25 studies including 905 patients with FEP, 560 patients at UHR, and 405 healthy controls. The cognitive performances of FEP, UHR, and healthy controls all significantly improved over time. There was no publication bias, and distributions of effect sizes were very homogenous. In FEP, the degree of improvement in verbal working memory and executive functions was significantly associated with reduction in negative symptoms. There was no evidence of cognitive decline in patients with UHR and FEP. In contrast, the cognitive performances of both groups improved at follow-up. These findings suggest that cognitive deficits are already established before the prodromal phases of psychosis. These data support the neurodevelopmental model rather than neurodegenerative and related staging models of schizophrenia.

title: Is initiation of smoking associated with the prodromal phase of schizophrenia?
abstract: Although the association between smoking and schizophrenia is well known, little attention has been paid to the time between initiation of smoking and onset of schizophrenia. Our goal was to study this putative temporal relation among patients with schizophrenia.



We used data from the Northern Finland 1966 Birth Cohort (n = 11,017) linked with the National Finnish Hospital Discharge Register to study age at initiation of smoking and age at onset of schizophrenia, and we examined associations between family and environmental factors and the retrospectively determined regular smoking among patients with schizophrenia.



Our main finding was that the initiation of regular smoking was closely related to the onset of schizophrenia. The mean difference in time between the initiation of regular smoking and the onset of schizophrenia among patients (n = 30) was 2.3 (standard deviation [SD] 6.6) years, which was statistically significantly lower than that for subjects with other psychoses (n = 18) (8.6 [SD 6.3] yr) (p < 0.001). Among patients with schizophrenia, the increased likelihood of smoking was associated only with paternal smoking in the family environment, but not with any other background factors (odds ratio 3.5, 95; confidence interval 1.9-11.3).



Smoking may be a sign of the prodromal phase of schizophrenia.

title: Poor premorbid school performance is associated with later cigarette smoking among schizophrenia patients
abstract: Schizophrenia patients who smoke have been postulated to have genetically mediated dysfunctional nicotinic neurotransmission. We hypothesized that this nicotinic dysfunction would manifest as poorer school performance in adolescence, before the onset of illness, in smoking compared with non-smoking schizophrenia patients. Over a 31-year follow-up period, 100 (65 men) cohort members of the Northern Finland 1966 Birth Cohort were hospitalized and diagnosed with DSM-III-R schizophrenia. The information on school performance was obtained at the end of compulsory schooling at age 16 years. The information on smoking habits was gathered from a questionnaire mailed to cohort members at the age of 31 years. Compared with non-smoking schizophrenia patients, schizophrenia patients who smoked in adulthood had lower overall mean grades, lower mean grades in combined mathematical subjects, and lower grades in music. Poor school performance might represent premorbid nicotinergic dysfunction associated with cognitive deficits in future smokers among schizophrenia patients compared with those who remained non-smokers.

title: A 4-fold risk of metabolic syndrome in patients with schizophrenia: the Northern Finland 1966 Birth Cohort study.
abstract: Schizophrenia is associated with a shortened life expectancy and increased somatic comorbidity with, e.g., cardiovascular disorders. One major risk factor for these disorders is the metabolic syndrome, which has been reported to have a higher frequency in schizophrenic patients. Our objective was to study the prevalence of metabolic syndrome in a population-based birth cohort.



The study sample consisted of 5613 members of the Northern Finland 1966 Birth Cohort who participated in the field study from 1997 to 1998. Subjects were divided into 4 diagnostic categories (DSM-III-R): (1) schizophrenia (N = 31), (2) other functional psychoses (N = 22), (3) nonpsychotic disorders (N = 105), and (4) no psychiatric hospital treatment (N = 5455, comparison group). Subjects were assessed for the presence of metabolic syndrome according to the criteria of the National Cholesterol Education Program.



The prevalence of metabolic syndrome was higher in subjects with schizophrenia compared with the comparison group (19% vs. 6%, p = .010). The prevalence of metabolic syndrome in subjects with other psychoses was 5%. After controlling for sex, the results of logistic regression analysis showed that the risk of metabolic syndrome in schizophrenia was 3.7 (95% CI = 1.5 to 9.0).



The high prevalence of metabolic syndrome in schizophrenia even at such a relatively young age underscores the need to select antipsychotic medications with no or little capability to induce metabolic side effects. Also, developing comprehensive efforts directed at controlling weight and diet and improving physical activity are needed.

title: Serum lipids in schizophrenia and other functional psychoses: a general population northern Finland 1966 birth cohort survey
abstract: To compare fasting serum lipid concentrations of subjects with schizophrenia with a comparison group.

title: Hyperlipidemia in persons using antipsychotic medication: a general population-based birth cohort study.
abstract: Shortly after phenothiazines were introduced, they were found to elevate serum triglyceride and total cholesterol levels. During the past decade, an increasing body of literature has also documented this effect in atypical antipsychotics. Previous studies of antipsychotic-associated hyperlipidemias are based on clinical samples, mostly from case series. We studied the prevalence of hyperlipidemia in subjects who did and did not take antipsychotic medication in a prospective, general population-based birth cohort.



The study sample consisted of 5654 members of the unselected Northern Finland 1966 Birth Cohort who participated in the 1997-1998 clinical examination at 31 years of age. Blood samples were taken after an overnight fast, and serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels were determined. Health habits and other possible correlates for hyperlipidemia were assessed using a questionnaire. The sample was analyzed in 4 categories according to use of antipsychotic medication: (1) atypical, (2) typical, (3) atypical and typical (for the 3 antipsychotic categories, total N = 45), and (4) no antipsychotic medication (N = 5609). Nonparametric tests and multiple logistic regression analysis were used to measure the effect of antipsychotics on serum lipids.



High lipid levels were found in persons treated with both atypical and typical medication (mean total cholesterol = 233 mg/dL, mean triglycerides = 163 mg/dL). Mean total cholesterol and triglycerides were also high in subjects who used only typical medication (215 mg/dL and 148 mg/dL, respectively). The prevalence of hypercholesterolemia, high LDL cholesterol, and hypertriglyceridemia was high in persons using antipsychotic medication (31.1%, 20.0%, and 22.2%, respectively) compared with persons not using such medication (12.2%, 10.2%, and 7.0%, respectively). After we adjusted for risk factors for hyperlipidemia (sex, diet, waist circumference, physical exercise, smoking, and alcohol consumption), the results of logistic regression analysis showed that in persons treated with antipsychotic medication the risk of hypercholesterolemia was 2.8 (95% CI = 1.4 to 5.6); of hypertriglyceridemia, 2.3 (95% CI = 1.0 to 5.4); and of high LDL cholesterol, 1.6 (95% CI = 0.7 to 3.5).



Lipid levels in subjects who used both atypical and typical medication and those who used only typical medication were high even in young age. As these persons are at special risk of hyperlipidemia, their lipid levels should be regularly monitored, and a cholesterol-lowering diet, as well as medication, should be considered. The results indicate an elevated risk of hyperlipidemia in persons using antipsychotic medication independent of the other risk factors assessed.

title: Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort.
abstract: We studied the comorbidity of psychiatric and physical disorders in a sample (n = 11,017) from the unselected, general population, Northern Finland 1966 Birth Cohort During the period 1982-1994, hospital-treated psychiatric patients were more likely than people without psychiatric diagnoses to have been treated for physical disease in hospital wards, 298 out of 387 (77%) vs 6687 out of 10,630 (62.9%) (OR = 2.0, 95% CI = 1.6-2.5). Injuries, poisonings and indefinite symptoms were a more common reason for hospital treatment in people with schizophrenia or other psychiatric disorder as compared with people without a psychiatric disorder. Men with psychiatric disorder had more than a 50-fold risk for poisoning by psychotropic drugs (OR = 52.6, 95% CI = 27.7-99.8), women with psychiatric disorder a 20-fold risk (OR = 19.0, 95% CI = 9.5-38.1) and schizophrenics more than a 30-fold (OR = 37.5, 95% CI = 19.1-73.8). Men with psychiatric disorders were more commonly hospitalised for a variety of gastrointestinal disorders and circulatory diseases (OR = 2.3, 95% CI = 1.2-4.4), as compared with men with no psychiatric disorder. Respiratory diseases (OR = 2.2, 95% CI = 1.2-4.2, vertebral column disorders (OR = 4.2, 95% CI = 1.8-9.9), gynaecological disorders (OR = 2.1, 95% CI = 1.2-3.6) and induced abortions (OR = 1.8, 95% CI = 1.2-2.7) were more prevalent in women with psychiatric disorder than in other women. Epilepsy was strongly associated with schizophrenia (OR = 11.1, 95% CI = 4.0-31.6). Nervous and sensory organ diseases in general (OR = 2.5, 95% CI = 1.1-5.8) and inflammatory diseases of the bowel (OR = 12.8, 95% CI = 3.8-42.7) were also overrepresented in schizophrenia when compared with people without a psychiatric disorder. Our results indicate that physicians must be alert for psychiatric disorder, and mental health professionals must be aware of the considerable morbidity in their patients.

title: Schizophrenia among patients treated for rheumatoid arthritis and appendicitis
abstract: The widely accepted negative association between schizophrenia and rheumatoid arthritis (RA) is based on the results of investigations which sought RA in large samples of schizophrenic patients. Using a discharge register, we examined the frequency of schizophrenia in a sample of 5626 RA patients. Appendicitis patients (n = 5330) were used as a comparison group. The cumulative incidence of hospital care with the diagnosis of schizophrenia during 8 years was higher in the RA group (0.64%) than in the appendicitis group (0.47%). Schizophrenia was significantly more common in the RA group than in the appendicitis group among the young. The age-adjusted prevalence of schizophrenia was 0.96% in the RA group and 0.51% in the appendicitis group. Because of this unexpected finding, we examined the incidence of RA and appendicitis among a birth cohort born in 1966. The frequencies of RA and appendicitis among schizophrenic cohort members (n = 76), cohort members with psychiatric diagnosis other than schizophrenia (n = 438), and members without psychiatric diagnosis (n = 10503) were similar. These findings do not support the negative association between schizophrenia and RA. Prolonged institutionalization per se may have been the protective factor against RA in the previous studies. The findings also raise the hypothesis that genes that predispose to schizophrenia provide protection from appendicitis, historically a common cause of mortality.

title: Juvenile mortality, mental disturbances and criminality: a prospective study of the Northern Finland 1966 birth cohort
abstract: Mortality, criminality and mental illness among young adults were studied in an unselected birth cohort of 12 058 children born live in Northern Finland during 1966. The cohort members were followed up to the age of 27 years. The total number of all deaths was 117, and 79.5% of these deaths were from unnatural causes. The mortality of males was more than threefold higher than that of females. There was a significantly higher mortality risk in men with schizophrenia (OR, 9.31; 95% CI, 3.14–25.53), other psychoses (OR, 10.28; 95% CI, 2.40–37.02), personality disorders (OR, 4.28; 95% CI, 1.04–14.67) and combined personality disorders and criminality (OR, 3.27,95% CI, 0.99–9.59). In the group of major mental disorders, 75% of deaths were suicides.

title: Suicidal behavior in patients with schizophrenia is related to COMT polymorphism
abstract: &NA; A common functional polymorphism that results in a three‐ to four‐fold difference in catechol‐O‐methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra‐ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other‐directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self‐ and other‐directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients.

title: Use of antipsychotic medication and suicidality—the Northern Finland Birth Cohort 1966
abstract: In addition to psychoses, antipsychotic drugs are nowadays also prescribed for other psychiatric disturbances, such as mood disorders. We wanted to find out whether there is any association between the use of antipsychotic drugs and suicidality in cases of psychotic and non‐psychotic disorders.

title: Specific major mental disorders and criminality: a 26-year prospective study of the 1966 northern Finland birth cohort.
abstract: The purpose of the study was to examine the quantitative risk of criminal behavior associated with specific mental disorders.



An unselected 1966 birth cohort (N = 12,058) in Northern Finland was prospectively studied until the end of 1992. The investigation started during the mothers' pregnancy, and the data on the subjects' family characteristics, mental and physical development, living habits, psychiatric morbidity, and criminal records were gathered at various times.



The prevalence of offenses was the highest among males with alcohol-induced psychoses and male schizophrenic subjects with coexisting alcohol abuse, and more than half of the schizophrenic offenders also had problems with alcohol. Eleven (7%) of the 165 subjects who committed violent crimes were diagnosed as psychotic. Male schizophrenic subjects had a moderately high risk for violent offenses, but the risk for other types of crimes was not elevated significantly. Odds ratios for criminal behavior were adjusted according to the socioeconomic status of the childhood family and were the same as or slightly lower than the crude odds ratios for all disorders except schizophrenia and mood disorders with psychotic features.



The results indicate that the risk of criminal behavior was significantly higher among subjects with psychotic disorders, even though the socioeconomic status of the childhood family was controlled. The higher risk for violent behavior was associated especially with alcohol-induced psychoses and with schizophrenia with coexisting substances abuse. The results suggest that schizophrenia without substance abuse may also be associated with a higher risk of offenses, but this finding is tentative and requires further investigation.

title: Schizophrenia, Alcohol Abuse, and Violent Behavior: A 26-Year Followup Study of an Unselected Birth Cohort
abstract: It has been suggested that schizophrenia and alcoholism are associated with violent behavior. But so far there are no published studies from unselected cohorts quantifying the actual risk associated with schizophrenia both with and without comorbid alcoholism. In this study, an unselected birth cohort (n = 11,017) was prospectively followed to the age of 26, and data on psychiatric disorders and crimes were collected from national registers. The odds ratios for violent offenses and recidivism were calculated for each diagnostic group. Men who abused alcohol and were diagnosed with schizophrenia were 25.2 (95% confidence interval (CI) 6.1-97.5) times more likely to commit violent crimes than mentally healthy men. The risk for nonalcoholic patients with schizophrenia was 3.6 (95% CI 0.9-12.3) and for other psychoses, 7.7 (95% CI 2.2-23.9). None of the patients with schizophrenia who did not abuse alcohol were recidivists (> 2 offenses), but the risk for committing more crimes among alcoholic subjects with schizophrenia was 9.5-fold (95% CI 2.7-30.0). This study suggests that to prevent the crimes being committed by people with schizophrenia, it is important that clinicians watch for comorbid alcohol abuse.

title: Characteristics of Subjects With Schizophrenia Spectrum Disorder With and Without Antipsychotic Medication – a 10-Year Follow-Up of the Northern Finland 1966 Birth Cohort Study
abstract: To estimate the prevalence of non-medicated subjects having schizophrenia spectrum disorder and to study how they differ from medicated subjects in terms of sociodemographic and illness-related variables. We also aim to find the predictors for successful antipsychotic withdrawal.  Data of 70 subjects with schizophrenic psychoses (mean duration of illness 10.4 years) from the Northern Finland 1966 Birth Cohort were gathered by interview at the age of 34 and from hospital records. The stability of remission was assessed by comparing hospitalization rates between non-medicated and medicated subjects over an 8.7-year additional follow-up period.  Twenty-four (34%) subjects were currently not receiving medication. They were more often males, less often on a disability pension, more often in remission, and had better clinical outcomes. Relapses during the follow-up were equally frequent between non-medicated and medicated subjects (47% vs. 56%). Not having been hospitalised during previous 5 years before the interview predicted long-term successful antipsychotic withdrawal without relapse.  Despite a lack of precise predictors, there might be subgroup of schizophrenia spectrum subjects who do not need permanent antipsychotic medication, and a fewer previous psychiatric treatments may indicate such a subgroup.

title: Biological Insights From 108 Schizophrenia-Associated Genetic Loci
abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

title: Identifying Schizophrenia and Other Psychoses With Psychological Scales in the General Population
abstract: We study the predictive power and associations of several psychopathology and temperament scales with respect to schizophrenia and other psychotic disorders. Measures of psychopathology (Physical and Social Anhedonia Scales, Perceptual Aberration Scale, Hypomanic Personality Scale, Bipolar II Scale, and Schizoidia Scale) and the Temperament and Character Inventory were included in the 31-year follow-up of the prospective Northern Finland 1966 birth cohort (N = 4926). The Perceptual Aberration Scale was the best scale for concurrent validity in psychoses, and also the best psychopathology scale in terms of discriminant validity. Participants scoring high in hypomanic personality were at the highest risk for developing psychosis during the 11-year follow-up. Harm avoidance was a dominant temperament dimension in individuals with psychosis compared with participants without psychiatric diagnoses. These scales are useful as vulnerability markers in studying psychoses.

title: Predicting Depression with Psychopathology and Temperament Traits: The Northern Finland 1966 Birth Cohort
abstract: We studied the concurrent, predictive, and discriminate validity of psychopathology scales (e.g., schizotypal and depressive) and temperament traits for hospitalisations due to major depression. Temperament, perceptual aberration, physical and social anhedonia, Depression Subscale of Symptom Checklist (SCL-D), Hypomanic Personality Scale, Schizoidia Scale, and Bipolar II Scale were completed as part of the 31-year follow-up survey of the prospective Northern Finland 1966 Birth Cohort (n = 4941; 2214 males). Several of the scales were related to depression. Concurrent depression was especially related to higher perceptual aberration (effect size when compared to controls, d = 1.29), subsequent depression to high scores in SCL-D (d = 0.48). Physical anhedonia was lower in subjects with subsequent depression than those with other psychiatric disorders (d = −0.33, nonsignificant). Participants with concurrent (d = 0.70) and subsequent (d = 0.54) depression had high harm avoidance compared to controls, while differences compared to other psychiatric patients were small. Subjects with depression differed from healthy controls in most of the scales. Many of the scales were useful predictors for future hospital treatments, but were not diagnosis-specific. High harm avoidance is a potential indicator for subsequent depression.

title: Early-life origins of schizotypal traits in adulthood
abstract: Although schizotypal traits, such as anhedonia and aberrant perceptions, may increase the risk for schizophrenia-spectrum disorders, little is known about early-life characteristics that predict more pronounced schizotypal traits.  To examine whether birth size or several other early-life factors that have been previously linked with schizophrenia predict schizotypal traits in adulthood.  Participants of the Northern Finland 1966 Birth Cohort Study (n = 4976) completed a questionnaire on positive and negative schizotypal traits at the age of 31 years.  Lower placental weight, lower birth weight and smaller head circumference at 12 months predicted elevated positive schizotypal traits in women after adjusting for several confounders (P<0.02). Moreover, higher gestational age, lower childhood family socioeconomic status, undesirability of pregnancy, winter/autumn birth, higher birth order and maternal smoking during pregnancy predicted some augmented schizotypal traits in women, some in men and some in both genders.  The results point to similarities in the aetiology of schitzotypal traits and schizophrenia-spectrum disorders.

title: Association of variants in DISC1 with psychosis-related traits in a large population cohort.
abstract: There is an abundance of data from human genetic studies and animal models that implies a role for the disrupted in schizophrenia 1 gene (DISC1) in the etiology of schizophrenia and other major mental illnesses.



To study the effect of previously identified risk alleles of DISC1 on quantitative intermediate phenotypes for psychosis in an unselected population.



We examined 41 single-nucleotide polymorphisms within DISC1 and performed tests of association with 4 quantitative phenotypes.



Academic research.



Individuals from an unselected birth cohort in Finland. Originally, everyone born in the catchment area in 1966 (N = 12 058) was included in the study. Of these, 4651 (38.6%) attended the 31-year follow-up and could be included in the study.



Scores on 4 psychometric instruments selected to function as proxies for positive and negative aspects of psychotic disorders, including the Perceptual Aberration Scale, Revised Social Anhedonia Scale, Revised Physical Anhedonia Scale, and Schizoidia Scale by Golden and Meehl.



Carriers of the minor allele of marker rs821577 had significantly higher scores on social anhedonia (P < .001). The minor allele of marker rs821633 was strongly associated with lower scores on social anhedonia when analyzed dependent on the absence of the minor alleles of markers rs1538979 and rs821577 (P < .001).



Variants in DISC1 affect the level of social anhedonia, a cardinal symptom of schizophrenia in the general population. DISC1 might be more central to human psychological functioning than previously thought, as it seems to affect the degree to which people enjoy social interactions.

title: Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.
abstract: Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.

title: Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1.
abstract: In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.

title: Phenotype mining in CNV carriers from a population cohort.
abstract: Phenotype mining is a novel approach for elucidating the genetic basis of complex phenotypic variation. It involves a search of rich phenotype databases for measures correlated with genetic variation, as identified in genome-wide genotyping or sequencing studies. An initial implementation of phenotype mining in a prospective unselected population cohort, the Northern Finland 1966 Birth Cohort (NFBC1966), identifies neurodevelopment-related traits-intellectual deficits, poor school performance and hearing abnormalities-which are more frequent among individuals with large (>500 kb) deletions than among other cohort members. Observation of extensive shared single nucleotide polymorphism haplotypes around deletions suggests an opportunity to expand phenotype mining from cohort samples to the populations from which they derive.

title: Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders
abstract: Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3β in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.

title: Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.
abstract: Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain.



To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change.



Predictors of brain volume changes were assessed prospectively based on multiple informants.



Data from the Iowa Longitudinal Study.



Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years).



Brain volumes.



During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted.



Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.

title: Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies
abstract: Context Antipsychotic treatment is the first-line treatment option for schizophrenia. Individual studies suggested they can significantly affect brain structure and account for progressive brain changes observed during the illness.  To quantitatively examine the effect of antipsychotics as compared to illness related factors on progressive brain changes in schizophrenia.  Electronic databases were searched until April 2012. All magnetic resonance imaging studies reporting progressive brain changes in schizophrenia subjects and antipsychotic exposure were retrieved. Study selection 30 longitudinal MRI studies with antipsychotic administration in schizophrenia patients met the inclusion criteria.  Brain volumes before and after antipsychotic exposure, duration of illness, severity of psychotic symptoms as well as demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors.  The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity.  Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment.

title: A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring
abstract: Several studies have implicated early infections, including maternal infection with herpes simplex virus 2 (HSV-2), as an environmental risk factor for schizophrenia.



A 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.



Elevated 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).



The 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.

title: Prenatal determinants of schizophrenia: what we have learned thus far?
abstract: The Prenatal Determinants of Schizophrenia (PDS) study was designed to examine early antecedents to schizophrenia. Based in the Child Health and Development Study cohort assembled in 1959-1967, over 12,000 cohort members were followed in the PDS study for psychiatric disorders. Using the extensive data and biological samples prospectively collected beginning during pregnancy, PDS investigators have examined the influence of prenatal exposures on risk of schizophrenia in adulthood. Here we describe a few key findings from the PDS with respect to prenatal infection, nutrition, and toxic exposures.  NIMH 1R01MH 63264-01A1 (A.S.B.), NIMH 1R01MH-60249 (A.S.B.), 1R01MH-60249-03S2 (A.S.B.), 1K02MH65422-01 (A.S.B.), aNARSAD Independent Investigator Award (A.S.B.).

title: Population-based cohort studies on premorbid cognitive function in schizophrenia.
abstract: Many previous studies have found associations between poor cognitive function and schizophrenia. However, the majority of these studies used retrospective data, leading to the possibility of selection and recall biases. Retrospective studies are also unable to distinguish whether cognitive deficits exist prior to the onset of schizophrenia, suggesting that they are important in etiology, or following onset, suggesting that they are secondary to the disorder or its treatment. The current review used a systematic search strategy to identify and summarize the results of all studies that have used population-based cohorts to examine associations between prospectively collected data on premorbid cognitive functioning in childhood or adolescence and subsequent risk for schizophrenia. Three broad categories of study have addressed these questions: birth cohort designs with cognitive testing during childhood, army conscript designs with cognitive performance measured at conscription, and studies using school grades. Birth cohort and conscript studies are consistent in reporting strong associations between poor performance on cognitive batteries and increased risk of schizophrenia. Studies on school performance have been less consistent, although the largest such study showed strong associations across all school subjects. In conclusion, children and adolescents with poor cognitive abilities in childhood are at increased risk of schizophrenia. This suggests that poor cognitive function is either directly causal or associated with causal factors that are involved in etiology.

title: Association of maternal genital and reproductive infections with verbal memory and motor deficits in adult schizophrenia
abstract: Maternal exposure to genital and reproductive infections has been associated with schizophrenia in previous studies. Impairments in several neuropsychological functions, including verbal memory, working memory, executive function, and fine-motor coordination occur prominently in patients with schizophrenia. The etiologies of these deficits, however, remain largely unknown. We aimed to assess whether prospectively documented maternal exposure to genital/reproductive (G/R) infections was related to these neuropsychological deficits in offspring with schizophrenia and other schizophrenia spectrum disorders. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Cases were assessed for verbal memory, working memory, executive function, and fine-motor coordination. Compared to unexposed cases, patients exposed to maternal genital/reproductive infection performed more poorly on verbal memory, fine-motor coordination, and working memory. Stratification by race revealed associations between maternal G/R infection and verbal memory and fine-motor coordination for case offspring of African-American mothers, but not for case offspring of White mothers. Significant infection-by-race interactions were also observed. Although independent replications are warranted, maternal G/R infections were associated with verbal memory and motor function deficits in African-American patients with schizophrenia.

title: Birth weight and neurocognition in schizophrenia spectrum disorders.
abstract: Low birth weight is associated with both schizophrenia and neurocognitive impairment. Yet, to our knowledge, no previous study has examined the relationship between lower birth weight and neurocognitive deficits in schizophrenia spectrum disorders (SSD). In this preliminary study, we investigated the relationship using a broad neuropsychological battery in cases with SSD and matched control subjects. The sample consisted of all subjects in the Developmental Insult and Brain Anomaly in Schizophrenia study, a nested case-control investigation developed from a large birth cohort, which followed subjects longitudinally. Case ascertainment was based on computerized record linkages between the birth cohort members and the Kaiser Permanente Medical Care Plan, and all diagnoses were confirmed by consensus diagnosis following the Diagnostic Interview for Genetic Studies. Lower birth weight was associated with impairment in executive function, working memory, generalized intellectual function, and neuromotor function in cases with SSD but not in control subjects. No deficits were observed in verbal memory for either group. These results support the hypothesis that lower birth weight plays a role in neuropsychological disruptions in SSD and that the antecedents of lower birth weight may have a greater impact on these disruptions in SSD than in controls. These data may facilitate a better understanding of the etiopathogenesis of the cognitive underpinnings of SSD.

title: Neuropsychological decline in schizophrenia from the premorbid to the postonset period: evidence from a population-representative longitudinal study.
abstract: Despite the widespread belief that neuropsychological decline is a cardinal feature of the progression from the premorbid stage to the chronic form of schizophrenia, few longitudinal studies have examined change in neuropsychological functioning from before to after illness onset. The authors examined whether neuropsychological decline is unique to schizophrenia, whether it is generalized or confined to particular mental functions, and whether individuals with schizophrenia also have cognitive problems in everyday life.



Participants were members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed prospectively to age 38, with 95% retention. Assessment of IQ and specific neuropsychological functions was conducted at ages 7, 9, 11, and 13, and again at age 38. Informants also reported on any cognitive problems at age 38.



Individuals with schizophrenia exhibited declines in IQ and in a range of mental functions, particularly those tapping processing speed, learning, executive function, and motor function. There was little evidence of decline in verbal abilities or delayed memory, however, and the developmental progression of deficits in schizophrenia differed across mental functions. Processing speed deficits increased gradually from childhood to beyond the early teen years, whereas verbal deficits emerged early but remained static thereafter. Neuropsychological decline was specific to schizophrenia, as no evidence of decline was apparent among individuals with persistent depression, children with mild cognitive impairment, individuals matched on childhood risk factors for schizophrenia, and psychiatrically healthy individuals. Informants also noticed more cognitive problems in individuals with schizophrenia.



There is substantial neuropsychological decline in schizophrenia from the premorbid to the postonset period, but the extent and developmental progression of decline varies across mental functions. Findings suggest that different pathophysiological mechanisms may underlie deficits in different mental functions.

title: Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls.
abstract: Cortical gray matter volume reductions and cerebrospinal fluid (CSF) volume increases are robust correlates of schizophrenia, but their sources have not been established conclusively.



Structured diagnostic interviews and magnetic resonance imaging scans of the brain were obtained on 75 psychotic probands (63 with schizophrenia and 12 with schizoaffective disorder), ascertained so as to be representative of all such probands in a Helsinki, Finland, birth cohort; 60 of their nonpsychotic full siblings; and 56 demographically similar control subjects without a personal or family history of treated psychiatric morbidity.



Patients with schizophrenia and their siblings exhibited significant reductions in cortical gray matter volume and significant increases in sulcal CSF volume compared with controls. The patients, but not their siblings, also exhibited significant reductions in white matter volume and significant increases in ventricular CSF volume. Regional effects were most robust when component volumes were expressed as percentages of overall regional volumes; in this case, for patient and sibling groups, gray matter volume reductions and sulcal CSF volume increases were significantly more pronounced in the frontal and temporal lobes than in the remainder of the brain. None of the group differences varied significantly by sex or hemisphere.



Structural alterations of the cerebral cortex, particularly in the frontal and temporal lobes, are present in patients with schizophrenia and in some of their siblings without schizophrenia; such changes are thus likely to reflect genetic (or shared environmental) effects. Ventricular enlargement is unique to the clinical phenotype and is thus likely to be affected primarily by nonshared causative factors.

title: Cardiovascular morbidity, mortality and pharmacotherapy in patients with schizophrenia
abstract: Patients with schizophrenia have excess cardiovascular morbidity and mortality. Previous studies suggest that this may be partly due to inadequate somatic treatment and care, such as non-optimal use of lipid-lowering and antihypertensive pharmacotherapy, but longitudinal studies on such aetiological pathways are scarce.  We investigated the use of lipid-lowering and antihypertensive pharmacotherapy, and the risk of hospitalization for and death from coronary heart disease and stroke among patients with schizophrenia in a birth cohort of 12 939 subjects (Helsinki Birth Cohort Study). This cohort was followed for over 30 adult years by using national databases on cardio- and cerebrovascular hospitalizations and mortality and on reimbursement entitlements and use of drugs for treatment of hypertension, dyslipidaemia, coronary heart disease and diabetes.  Individuals with schizophrenia had a higher risk of hospitalization for coronary heart disease [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.03–2.57], and mortality from this disease was markedly higher (HR 2.92, 95% CI 1.70–5.00), particularly among women (p=0.001 for women, p=0.008 for men). Women with schizophrenia had also marginally increased stroke mortality (p=0.06). However, patients with schizophrenia used less lipid-lowering (odds ratio 0.47, 95% CI 0.27–0.80) and antihypertensive drug treatment (HR 0.37, 95% CI 0.22–0.61).  In this longitudinal study, coronary heart disease morbidity was increased and coronary heart disease mortality markedly increased in patients, especially in women with schizophrenia. These patients nevertheless received less antihypertensive and lipid-lowering treatment.

title: Mental disorders and violence in a total birth cohort: results from the Dunedin Study.
abstract: We report on mental disorders and violence for a birth cohort of young adults, regardless of their contact with the health or justice systems.



We studied 961 young adults who constituted 94% of a total-city birth cohort in New Zealand, April 1, 1972, through March 31, 1973. Past-year prevalence of mental disorders was measured using standardized DSM-III-R interviews. Past-year violence was measured using self-reports of criminal offending and a search of official conviction records. We also tested whether substance use before the violent offense, adolescent excessive perceptions of threat, and a juvenile history of conduct disorder accounted for the link between mental disorders and violence.



Individuals meeting diagnostic criteria for alcohol dependence, marijuana dependence, and schizophrenia-spectrum disorder were 1.9 (95% confidence interval [CI], 1.0-3.5), 3.8 (95% CI, 2.2-6.8), and 2.5 (95% CI, 1.1-5.7) times, respectively, more likely than control subjects to be violent. Persons with at least 1 of these 3 disorders constituted one fifth of the sample, but they accounted for half of the sample's violent crimes (10% of violence risk was uniquely attributable to schizophrenia-spectrum disorder). Among alcohol-dependent individuals, violence was best explained by substance use before the offense; among marijuana-dependent individuals, by a juvenile history of conduct disorder; and among individuals with schizophrenia-spectrum disorder, by excessive perceptions of threat and a history of conduct disorder.



In the age group committing most violent incidents, individuals with mental disorders account for a considerable amount of violence in the community. Different mental disorders are linked to violence via different core explanations, suggesting multiple-targeted prevention strategies.

title: Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia: A Danish national birth cohort-based study
abstract: Epidemiological studies indicate that having any family member with schizophrenia increases the risk of schizophrenia in the probands. However, genome-wide association studies (GWAS) have accounted for little of this variation. The aim of this study was to use a population-based sample to explore the influence of single-nucleotide polymorphisms (SNPs) on the excess schizophrenia risk in offspring of parents with a psychotic, bipolar affective or other psychiatric disorder.



A nested case-control study with 739 cases with schizophrenia and 800 controls. Their parents and siblings. Information from national health registers and GWAS data from the national neonatal biobank.



Offspring schizophrenia risk was elevated in those whose mother, father or siblings had been diagnosed with schizophrenia or related psychosis, bipolar affective disorder or any other psychiatric disorder. The rate ratio was 9.31 (3.85; 22.44) in offspring whose 1st degree relative was diagnosed with schizophrenia. This rate ranged between 8.31 and 11.34 when adjusted for each SNP individually and shrank to 8.23 (3.13; 21.64) when adjusted for 25% of the SNP-variation in candidate genes. The percentage of the excess risk associated with a family history of schizophrenia mediated through genome-wide SNP-variation ranged between -6.1%(-17.0%;2.6%) and 4.1%(-3.9%;15.2%). Analogous results were seen for each parent and for histories of bipolar affective and other psychiatric diagnoses.



The excess risk of schizophrenia in offspring of parents who have a psychotic, bipolar affective or other psychiatric disorder is not currently explained by the SNP variation included in this study in accordance with findings from published genetic studies.

title: Psychopathology during childhood and adolescence predicts delusional-like experiences in adults: a 21-year birth cohort study.
abstract: Community surveys have shown that many otherwise well individuals report delusional-like experiences. The authors examined psychopathology during childhood and adolescence as a predictor of delusional-like experiences in young adulthood.



The authors analyzed prospective data from the Mater-University of Queensland Study of Pregnancy, a birth cohort of 3,617 young adults born between 1981 and 1983. Psychopathology was measured at ages 5 and 14 using the Child Behavior Checklist (CBCL) and at age 14 using the Youth Self-Report (YSR). Delusional-like experiences were measured at age 21 using the Peters Delusional Inventory. The association between childhood and adolescent symptoms and later delusional-like experiences was examined using logistic regression.



High CBCL scores at ages 5 and 14 predicted high levels of delusional-like experiences at age 21 (odds ratios for the highest versus the other quartiles combined were 1.25 and 1.85, respectively). Those with YSR scores in the highest quartile at age 14 were nearly four times as likely to have high levels of delusional-like experiences at age 21 (odds ratio=3.71). Adolescent-onset psychopathology and continuous psychopathology through both childhood and adolescence strongly predicted delusional-like experiences at age 21. Hallucinations at age 14 were significantly associated with delusional-like experiences at age 21. The general pattern of associations persisted when adjusted for previous drug use or the presence of nonaffective psychoses at age 21.



Psychopathology during childhood and adolescence predicts adult delusional-like experiences. Understanding the biological and psychosocial factors that influence this developmental trajectory may provide clues to the pathogenesis of psychotic-like experiences.

title: Young people at risk for psychosis: case finding and sample characteristics of the Oulu Brain and Mind Study
abstract: Set within the general population‐based Northern Finland Birth Cohort 1986, the Oulu Brain and Mind Study aims to explore the causes and pathogenesis of psychotic illness by following young people at risk for psychosis due to having a first‐degree relative with psychotic illness or due to having experienced psychotic‐like symptoms themselves. We report the study methods and explore the relationship between these definitions of high risk for psychosis and operational criteria for a prodromal psychosis syndrome based on interview.