The importance of clinical and labour market histories in psychiatric disability retirement: analysis of the comprehensive Finnish national-level RETIRE data.

OBJECTIVES: Despite the stable incidence of mental disorders in Finland and Europe, mental health-related occupational disability has been increasing. We unveiled the paths to permanent psychiatric disability, recovery, or death, by analysing sequences of labour market participation. METHODS: The RETIRE register database includes information regarding all persons (n = 42,170) awarded an ICD-10 psychiatric disability pension between 2010 and 2015 in Finland. We identified clusters of typical paths of pre-retirement labour market history. Controlling for major mental disorders, age, and sex, we evaluated factors associated with returning to work (RTW), or death, over a 5-year follow-up period. RESULTS: Only 10.5% of the disabled subjects returned to work within the follow-up. Half of them ended up with a permanent disability pension. Seven distinguishable paths to disability were identified. Subjects in the cluster characterized by steady employment were relatively often females, lost their work ability due to affective disorders, and had the highest rate of returning to work (16.3%). Mortality was highest (9%) among the cluster characterized by long-term unemployment. Distributions of major diagnostic groups, as well as age and sex, differed between clusters. After their adjustment in the analysis of RTW or death, the identified labour market history paths prior to losing work ability remained as important independent prognostic factors for both outcomes. CONCLUSIONS: The complex retirement process involves identifiable clinical and contextual associating factors. Labour market history patterns associate with varying prognoses after psychiatric retirement. Prolonged unemployment appears as a predictor of relatively poor prognoses, whereas employment indicates the opposite.

Discrepancies between self- and adult-perceptions of social competence in children with neuropsychiatric disorders.

BACKGROUND: The present study examines discrepancies between self- and adult-perceptions of social competence in children with attention deficit-hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and possible co-morbid disruptive behaviour disorders (DBD). METHOD: Self-reported questionnaires were collected from multiple informants at the baseline of a multi-systemic family intervention programme for children (aged 5-12) with ADHD, ASD and possible co-morbid DBD. In total, out of the 154 families eligible for the study, information was received concerning children from 124 families (children n = 121; mothers n = 117; fathers n = 86; teachers n = 97). In addition to this, a comparison community sample of 318 school-aged children (approximately 10 years old) was utilized to examine the perceptions of children's social competence across intervention and population groups in more detail. RESULTS: Children's self-perceptions in the prosocial dimension of social competence (i.e. cooperating skills, empathy) did not differ between the intervention and comparison groups. Interestingly, the children in the intervention sample expressed more impulsivity and disruptiveness - the antisocial dimension of social competence - when compared with the children in the comparison sample. Adult ratings demonstrated that mothers, fathers and teachers reported decreased prosocial behaviour and increased antisocial behaviour across overall dimensions and sub-dimensions when compared with adults' ratings of elementary school children. Informant discrepancies between self-ratings and adult ratings across intervention groups yielded significant effect sizes (eta-squared) across all domains of social competence ranging from .09 to .25. CONCLUSION: Children's positive self-ratings of social competence relative to adult ratings increased within intervention sample when compared with population sample. The intervention sample children appeared to acknowledge their social competence deficits, yet self-perceptions were inflated relative to adult ratings when focusing on peer relationship difficulties, particularly, aggression to peers.

Common variant at 16p11.2 conferring risk of psychosis.

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Both low birthweight and high birthweight are associated with cognitive impairment in persons with schizophrenia and their first-degree relatives.

BACKGROUND: Both low birthweight and high birthweight have been associated with an increased risk for schizophrenia and cognitive impairments in the general population. We assessed the association between birthweight and cognitive performance in persons with schizophrenia and their unaffected first-degree relatives. METHOD: We investigated a population-based family sample comprising persons with schizophrenia (n = 142) and their unaffected first-degree relatives (n = 277). Both patients and relatives were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV) and a comprehensive neuropsychological test battery was administered. Information on birthweight was obtained from obstetric records. We used generalized estimating equation (GEE) models to investigate the effect of birthweight, as a continuous variable, on cognitive functioning, adjusting for within-family correlation and relevant covariates. RESULTS: Both low birthweight and high birthweight were associated with lower performance in visuospatial reasoning, processing speed, set-shifting and verbal and visual working memory among persons with schizophrenia and their unaffected first-degree relatives compared to individuals with birthweight in the intermediate range. The group × birthweight interactions were non-significant. CONCLUSIONS: Both low birthweight and high birthweight are associated with deficits in cognition later in life. Schizophrenia does not seem to modify the relationship between birthweight and cognition in families with schizophrenia.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia.

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Expanding the range of ZNF804A variants conferring risk of psychosis.

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Genetic origins of the association between verbal ability and alcohol dependence symptoms in young adulthood.

BACKGROUND: Cognitive deficits in alcohol dependence (AD) have been observed, poorer verbal ability being among the most consistent findings. Genetic factors influence both cognitive ability and AD, but whether these influences overlap is not known. METHOD: A subset of 602 monozygotic (MZ) and dizygotic (DZ) twins from FinnTwin16, a population-based study of Finnish twins, was used to study the associations of verbal ability with DSM-III-R diagnosis and symptoms of AD, the maximum number of drinks consumed in a 24-h period, and the Rutgers Alcohol Problem Index (RAPI) scores. These twins, most of them selected for within-pair discordance or concordance for their RAPI scores at age 18.5 years, were studied with neuropsychological tests and interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) in young adulthood (mean age 26.2 years, range 23-30 years). RESULTS: All alcohol problem measures were associated with lower scores on the Vocabulary subtest of the Wechsler Adult Intelligence Scale - Revised (WAIS-R), a measure of verbal ability. In bivariate genetic models, Vocabulary and the alcohol problem measures had moderate heritabilities (0.54-0.72), and their covariation could be explained by correlated genetic influences (genetic correlations -0.20 to -0.31). CONCLUSIONS: Poorer verbal ability and AD have partly overlapping biological etiology. The genetic and environmental influences on the development of cognitive abilities, alcohol problems and risk factors for AD should be studied further with prospective longitudinal designs.

The effect of psychiatric co-morbidity on cognitive functioning in a population-based sample of depressed young adults.

BACKGROUND: Psychiatric co-morbidity is often inadequately controlled for in studies on cognitive functioning in depression. Our recent study established no major deficits in cognition among young adults with a history of pure unipolar depression. The present study extends our previous work by examining the effects of psychiatric co-morbidity and other disorder characteristics on depression-related cognitive functioning. METHOD: Performance in verbal and visual short-term memory, verbal long-term memory and learning, attention, processing speed, and executive functioning was compared between a population-based sample aged 21-35 years with a lifetime history of unipolar depressive disorders (n=126) and a random sample of healthy controls derived from the same population (n=71). Cognitive functioning was also compared between the subgroups of pure (n=69) and co-morbid (n=57) depression. RESULTS: The subgroups of pure and co-morbid depression did not differ in any of the cognitive measures assessed. Only mildly compromised verbal learning was found among depressed young adults in total, but no other cognitive deficits occurred. Received treatment was associated with more impaired verbal memory and executive functioning, and younger age at first disorder onset with more impaired executive functioning. CONCLUSIONS: Psychiatric co-morbidity may not aggravate cognitive functioning among depressed young adults. Regardless of co-morbidity, treatment seeking is associated with cognitive deficits, suggesting that these deficits relate to more distress.

Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families.

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004-0.0000000004), memory (P=0.02-0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia.

Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.

Cognitive functioning in a population-based sample of young adults with a history of non-psychotic unipolar depressive disorders without psychiatric comorbidity.

BACKGROUND: There is evidence for cognitive dysfunction in unipolar depression among middle-aged and elderly patients, but cognitive functioning among depressed young adults has scarcely been systematically investigated. The aims of the present study were to examine cognitive functioning among depressed young adults identified from the general population and to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity and age at onset. METHODS: Performance in verbal and visual short-term memory, verbal long-term memory and learning, attention, processing speed, and executive functioning was compared between a population-based sample of 21-35-year-olds with a lifetime history of non-psychotic unipolar depressive disorders without psychiatric comorbidity (n=68) and healthy controls derived from the same population (n=70). RESULTS: Depressed young adults were not found to be impaired in any of the assessed cognitive functions, except for some suggestion of mildly compromised verbal learning. Nevertheless, younger age at depression onset was associated with more impaired executive functioning. LIMITATIONS: The results may slightly underestimate of the true association between depression and cognitive impairments in the young adult population due to possible dropout of participants. Additionally, the problem of multiple testing was not entirely corrected. CONCLUSION: The findings from this study indicate that a lifetime history of non-psychotic unipolar depressive disorders among young adults without psychiatric comorbidity may be associated only with minimal cognitive deficits, even when some residual depressive symptoms are prevalent. However, early-onset depression may represent a more severe form of the disorder, associated with more cognitive dysfunction.

Persistent leisure-time physical activity in adulthood and use of antidepressants: A follow-up study among twins.

BACKGROUND: To study whether persistent leisure-time physical activity (PA) during adulthood predicts use of antidepressants later in life. METHODS: The Finnish Twin Cohort comprises same-sex twin pairs born before 1958, of whom 11 325 individuals answered PA questions in 1975, 1981 and 1990 at a mean age of 44 years (range 33-60). PA volume over 15-years was used as the predictor of subsequent use of antidepressants. Antidepressant use (measured as number of purchases) for 1995-2004 were collected from the Finnish Social Insurance Institution (KELA) prescription register. Conditional logistic regression was conducted to calculate odds ratios (OR) with 95% confidence intervals (CI) for the use of antidepressants in pairs discordant for PA (642, including 164 monozygotic (MZ) pairs). RESULTS: Altogether 229 persons had used at least one prescribed antidepressant during the study period. Active co-twins had a lower risk (unadjusted OR 0.80, 95%CI 0.67-0.95) for using any amount of antidepressants than their inactive co-twins; trends being similar for DZ (0.80, 0.67-0.97) and MZ pairs (0.78, 0.51-1.17). The lowest odds ratio (0.51, 0.26-0.98) was seen among MZ pairs after adjusting for BMI, smoking and binge drinking. The point estimates were similar but non-significant for long-term antidepressant use (4+purchases equivalent to 12 months use). LIMITATIONS: Self-reported physical activity and low number of discordant MZ pairs. DISCUSSION: Use of antidepressants was less common among physically active co-twins even when shared childhood experiences and genetic background were controlled for. Physical activity in midlife may therefore be important in preventing mild depression later in life.

Long-term use of benzodiazepines: Definitions, prevalence and usage patterns - a systematic review of register-based studies.

BACKGROUND: Numerous treatment guidelines recommend that long-term use of benzodiazepines (BZD) should be avoided primarily due to development of tolerance and a risk for BZD dependence. Despite this, long-term BZD use remains a controversial subject in clinical patient care with "for and against" debates. However, there is no explicit understanding of what is meant by long-term BZD use in real world. The aim of this study was to assess different definitions, usage patterns, prevalence and other characteristics of long-term BZD use based on published register-based studies. Synthesis of these characteristics is essential to derive a meaningful definition of long-term BZD. METHODS: Systematic review of register-based studies on long-term BZD use published in 1994-2014. RESULTS: Fourty-one studies met our predetermined inclusion criteria. The length of BZD use defined as "long-term" varied in these studies ranging from one month to several years. The most common definition was six months or longer during a year. The prevalence of long-term BZD use in the general population was estimated to be about 3%. The relative proportion of long-term BZD users (all definitions) in adult BZD users ranged from 6% to 76% (mean 24%; 95% CL 13-36%). The estimates were higher in studies only on the elderly (47%; 95% CL 31-64%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found. CONCLUSIONS: Long-term BZD use is common and a clinical reality. Uniform definitions for "long-term", which is in line with population-based evidence, is needed to have more comparable results between studies. Our systematic review suggests that duration of BZD treatment over six months, the most common definition for long-term BZD use in the included studies. As also recommended previously, it is a useful starting point for further analyses on disadvantages but also potential advantages associated with long-term BZD use.

Psychological defense styles in late adolescence and young adulthood: a follow-up study.

OBJECTIVE: The aims of this follow-up study were to examine in both sexes (1) the stability of defense styles from late adolescence to early adulthood and (2) the ability of adolescent defense styles to predict later psychiatric symptoms. METHOD: Defense styles were examined using the Defense Style Questionnaire. Five hundred sixteen high school students (337 females and 179 males) completed the questionnaire at 15 through 19 years of age, and again 5 years later. In the follow-up examination the General Health Questionnaire was used to assess psychiatric disturbance. RESULTS: Neurotic and immature defense style scores decreased significantly in both sexes, whereas mature defense style scores did not change significantly. Females had significantly higher neurotic defense style scores than males in both late adolescence and young adulthood. Psychiatric disturbance at follow-up was associated positively with baseline immature defense style scores in both sexes, and negatively with baseline mature defense style scores in females. CONCLUSIONS: Development of defenses was apparent as a decrease in neurotic and immature defense style scores. In both sexes, immaturity of defenses in late adolescence predicted psychiatric symptoms in young adulthood.

Correlates of initiation to cannabis use: a 5-year follow-up of 15-19-year-old adolescents.

Initiation to cannabis is often the first step in the use of illicit drugs. We studied the correlates of initiation in a 5-year follow-up study. A total of 21.4% of the subjects reported using cannabis at some time. Of the 139 users, 89.2% had tried cannabis not more than once or a few times. This initiation to cannabis was related to male gender, absence of mother, frequent lack of interest and early age at first sexual intercourse in logistic regression analysis. These factors seem to be useful in predicting initiation to cannabis.

White matter hyperintensities and cognitive performance in adult patients with bipolar I, bipolar II, and major depressive disorders.

PURPOSE: We evaluate for the first time the associations of brain white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) with neuropsychological variables among middle-aged bipolar I (BPI), II (BPII) and major depressive disorder (MDD) patients and controls using a path model. METHODS: Thirteen BPI, 15 BPII, 16 MDD patients, and 21 controls underwent brain MRI and a neuropsychological examination. Two experienced neuroradiologists evaluated WMHs on the MRI scans. We constructed structural equation models to test the strength of the associations between deep WMH (DWMH) grade, neuropsychological performance and diagnostic group. RESULTS: Belonging in the BPI group as opposed to the control group predicted higher DWMH grade (coefficient estimate 1.13, P=0.012). The DWMH grade independently predicted worse performance on the Visual Span Forward test (coefficient estimate -0.48, P=0.002). Group effects of BPI and MDD were significant in predicting poorer performance on the Digit Symbol test (coefficient estimate -5.57, P=0.016 and coefficient estimate -5.66, P=0.034, respectively). LIMITATIONS: Because of the small number of study subjects in groups, the negative results must be considered with caution. CONCLUSIONS: Only BPI patients had an increased risk for DWMHs. DWMHs were independently associated with deficits in visual attention.

Activities of daily living, social functioning and their determinants in persons with psychotic disorder.

OBJECTIVE: The determinants of everyday functioning in persons with psychotic disorder have not been widely studied in community dwelling samples. Our aim was to investigate limitations in everyday functioning among subjects with psychotic disorders in a population-based study. METHOD: Everyday functioning was assessed in a nationally representative sample of 7112 persons aged 30+ using interviewer observations and self-reports, while verbal fluency and memory were also measured. Diagnostic assessment of DSM-IV psychotic disorders was based on SCID interview and case-note data. Lifetime-ever diagnoses of psychotic disorder were classified into schizophrenia (n=61), other non-affective psychotic disorders (ONAP) (n=79) and affective psychoses (n=45). RESULT: Non-affective psychotic disorder was significantly associated with limitations in everyday functioning, as well as with deficits in verbal fluency and memory. Negative symptoms, depression, age, gender, verbal memory deficits, and reduced visual acuity were predictors of limitations in everyday functioning even after controlling for sociodemographic factors and chronic medical conditions, and difficulties in social functioning were also related to expressive speech problems. CONCLUSION: Persons with schizophrenia and ONAP have significantly more problems in everyday functioning than the general population. One significant predictor of problems was reduced visual acuity, which at least in some situations could be easily corrected.

Cognitive functioning in a population-based sample of young adults with anxiety disorders.

OBJECTIVE: Cognitive functioning in anxiety disorders has received little investigation, particularly among young adults and in non-clinical samples. The present study examined cognitive functioning in a population-based sample of young adults with anxiety disorders in comparison to healthy peers. METHODS: A population-based sample of 21-35-year-olds with a lifetime history of anxiety disorders (n=75) and a random sample of healthy controls (n=71) derived from the same population were compared in terms of performance in neuropsychological tests measuring verbal and visual short-term memory, verbal long-term memory, attention, psychomotor processing speed, and executive functioning. RESULTS: In general, young adults with anxiety disorders did not have major cognitive impairments when compared to healthy peers. When participants with anxiety disorder in remission were excluded, persons with current anxiety disorder scored lower in visual working memory tests. Current psychotropic medication use and low current psychosocial functioning associated with deficits in executive functioning, psychomotor processing speed, and visual short-term memory. CONCLUSION: Lifetime history of anxiety disorders is not associated with cognitive impairment among young adults in the general population. However, among persons with anxiety disorders, current psychotropic medication use and low psychosocial functioning, indicating more severe symptoms, may associate with cognitive impairments.