Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Genetic contribution to microglial activation in schizophrenia.

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1ß) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

Factors contributing to readmission in patients with psychotic disorders, with a special reference to first follow-up visit in outpatient care.

BACKGROUND: Timely outpatient follow-up and readmission after discharge are common quality indicators in psychiatric care, but their association varies in previous research. We aimed to examine whether the impact of outpatient follow-up and other factors on readmission risk evolves over time in people with non-affective psychotic disorder (NAP). METHODS: The Finnish Quality of Care Register includes all people diagnosed with NAP since January 2010. Here, we followed patients with a hospital discharge between 2017 and 2021 until readmission, death, or up to 365 days. Time of the first outpatient follow-up appointment, length of stay (LOS), number of previous hospitalizations, psychosis diagnosis, substance use disorder (SUD), residential status, economic activity, gender, age, year, and region were included. Follow-up time was divided into five periods: week 1, weeks 2-4, weeks 5-13, weeks 14-25, and weeks 26-52, and each period was analyzed separately with Cox regression. RESULTS: Of the 29 858 discharged individuals, 54.1% had an outpatient follow-up within a week. A total of 10 623 (35.6%) individuals were readmitted. Short LOS increased the readmission risk in the first four weeks, whereas lack of outpatient follow-up raised the risk (adjusted HRs between 1.15 (95% CI 1.04-1.26) and 1.53 (1.37-1.71) in weeks 5-52. The number of previous hospitalizations remained a consistent risk factor throughout the follow-up, while SUD increased risk after 4 weeks and living without family after 13 weeks. CONCLUSIONS: Risk factors of readmission vary over time. These temporal patterns must be considered when developing outpatient treatment programs.

Life-Course Associations Between Smoking and Depressive Symptoms. A 30-Year Finnish Follow-up Study.

INTRODUCTION: Relatively little is known about whether the association between smoking and depressive symptoms changes with age and how the trajectories of smoking and depressive symptoms are intertwined during the life course. In this population-based study, these associations were examined from young adulthood to middle age. METHODS: Participants of a Finnish cohort study (N = 1955) were assessed at the ages of 22, 32, 42, and 52 using questionnaires covering daily smoking (yes/no) and the short 13-item Beck Depression Inventory. Longitudinal latent class and longitudinal latent profile analyses were used to identify life course trajectories of smoking and depressive symptoms. RESULTS: The proportions of daily smokers decreased, while levels of depressive symptoms increased among both females and males from age 22 to 52 years. Smoking was associated with higher levels of depressive symptoms from age 22 to 42 years, while not at 52. Associations among males prevailed when adjusting for education, marital status, and alcohol use. Four life course classes of daily smoking (nonsmokers, decreasing prevalence of smoking, persistent smokers, and increasing prevalence of smoking) and four trajectories of depressive symptoms (low, increasing/moderate, decreasing/moderate, and high) were identified. In males, persistent daily smokers (relative risk ratio (RRR) = 4.5, 95% confidence interval (CI): 2.2 to 9.2) and those in the class with increasing smoking prevalence (RRR = 3.2, 95% CI: 1.1 to 9.1) had an increased risk of belonging to the high depressive symptoms profile. In females these associations were nonsignificant. CONCLUSIONS: Compared to females, the relationship between smoking and depressive symptoms seems more robust among males during adulthood. Specifically, males smoking persistently from young adulthood to middle age have an increased risk of high depressive symptoms trajectory. IMPLICATIONS: This population-based cohort with 30 years of follow-up showed that the life course trajectories of daily smoking and depressive symptoms are associated. Persistent daily smokers and those starting late had an increased risk of belonging to the profile with constantly high levels of depressive symptoms during the life course. However, these associations were statistically significant only in males. Actions should be strengthened, especially in males, to prevent smoking initiation, to help smoking cessation, and to identify and treat depression in smokers with significant depressive symptoms.

Criminal behavior in alcohol-related dementia and Wernicke-Korsakoff syndrome: a Nationwide Register Study.

BACKGROUND: Chronic heavy alcohol use may lead to permanent brain damage, cognitive impairment, and dementia. While the link between alcohol use and crime is strong, virtually no research exists on the criminal behavior of patients with the alcohol-related neurocognitive disorders of Wernicke-Korsakoff syndrome (WKS) and alcohol-related dementia (ARD). METHODS: The study population included all persons diagnosed with WKS (n = 1149) or ARD (n = 2432) in Finland in 1998-2015. Data on diagnoses, mortality, and crime were obtained from Finnish nationwide registers. Crime incidences were calculated 4 years before and after diagnosis. Crime types, incidences, and mortality were compared between disorders and with the general population. RESULTS: Altogether 35.6% of WKS patients and 23.6% of ARD patients had committed crimes in the 4 years preceding diagnosis, most commonly property and traffic crimes, followed by violent crimes. The incidence of criminal behavior decreased significantly after diagnosis; in WKS patients, the standardized criminality ratio (SCR), the ratio of observed to expected number of crimes (95% CI), was 3.91 (3.72-4.10) in 4 years before and 2.80 (2.61-3.00) in 4 years after diagnosis. Likewise, in ARD patients, the SCRs were 2.63 (2.51-2.75) before and 0.84 (0.75-0.92) after diagnosis. No significant difference emerged in mortality between persons with and without a criminal history. CONCLUSIONS: Persons with alcohol-related neurocognitive disorders frequently engage in criminal behavior prior to diagnosis, especially multiple offending. In the 4 years before and after diagnosis, crime rates declined in a linear fashion, with a marked reduction after diagnosis.

Geographical variation in treated psychotic and other mental disorders in Finland by region and urbanicity.

PURPOSE: In Finland, prevalence of schizophrenia is higher in the eastern and northern regions and co-occurs with the distribution of schizophrenia polygenic risk scores. Both genetic and environmental factors have been hypothesized to contribute to this variation. We aimed to examine the prevalence of psychotic and other mental disorders by region and degree of urbanicity, and the impacts of socio-economic adjustments on these associations. METHODS: Nationwide population registers from 2011 to 2017 and healthcare registers from 1975 to 2017. We used 19 administrative and three aggregate regions based on the distribution of schizophrenia polygenic risk scores, and a seven-level urban-rural classification. Prevalence ratios (PRs) were calculated by Poisson regression models and adjusted for gender, age, and calendar year (basic adjustments), and Finnish origin, residential history, urbanicity, household income, economic activity, and physical comorbidity (additional adjustments) on an individual level. Average marginal effects were used to visualize interaction effects between region and urbanicity. RESULTS: A total of 5,898,180 individuals were observed. All mental disorders were slightly more prevalent (PR 1.03 [95% CI, 1.02-1.03]), and psychotic disorders (1.11 [1.10-1.12]) and schizophrenia (1.19 [1.17-1.21]) considerably more prevalent in eastern and northern than in western coastal regions. After the additional adjustments, however, the PRs were 0.95 (0.95-0.96), 1.00 (0.99-1.01), and 1.03 (1.02-1.04), respectively. Urban residence was associated with increased prevalence of psychotic disorders across all regions (adjusted PR 1.21 [1.20-1.22]). CONCLUSION: After adjusting for socioeconomic and sociodemographic factors, the within-country distribution of mental disorders no longer followed the traditional east-west gradient. Urban-rural differences, on the other hand, persisted after the adjustments.

FreeSurfer 7 quality control: Key problem areas and importance of manual corrections.

We have studied the effects of manual quality control of brain Magnetic Resonance Imaging (MRI) images processed with Freesurfer. T1 images of first episode psychosis patients (N = 60) and healthy controls (N = 41) were inspected for gray matter boundary errors. The errors were fixed, and the effects of error correction on brain volume, thickness, and surface area were measured. It is commonplace to apply quality control to Freesurfer MRI recordings to ensure that the edges of gray and white matter are detected properly, as incorrect edge detection leads to changes in variables such as volume, cortical thickness, and cortical surface area. We find that while Freesurfer v7.1.1. does regularly make mistakes in identifying the edges of cortical gray matter, correcting these errors yields limited changes in the commonly measured variables listed above. We further find that the software makes fewer gray matter boundary errors when processing female brains. The results suggest that manually correcting gray matter boundary errors may not be worthwhile due to its small effect on the measurements, with potential exceptions for studies that focus on the areas that are more commonly affected by errors: the areas around the cerebellar tentorium, paracentral lobule, and the optic nerves, specifically the horizontal segment of the middle cerebral artery.

Continuity of antipsychotic medication use among migrant and Finnish-born populations with a psychotic disorder: a register-based study.

BACKGROUND: Higher incidence of psychotic disorders and underuse of mental health services have been reported among many migrant populations. This study examines the initiation and continuity of antipsychotic treatment among migrants and non-migrants with a non-affective psychosis during a new treatment episode. METHODS: This study is based on a nationwide sample of migrants and Finnish-born controls. Participants who were diagnosed with a psychotic disorder in 2011-2014 were identified from the Care Register for Health Care (n = 1693). Information on purchases of antipsychotic drugs in 2011-2015 was collected from the National Prescription Register. The duration of antipsychotic treatment since diagnosis was estimated using the PRE2DUP model. Cox regression analysis was used to study factors that are associated with discontinuing the use of medication. RESULTS: There were fewer initiators of antipsychotic treatment after being diagnosed with psychosis among migrants (68.1%) than among Finnish-born patients (73.6%). After controlling for sociodemographic background and factors related to the type of disorder and treatment, migrants were more likely to discontinue medication (adjusted hazard ratio 1.28, 95% confidence interval 1.08-1.52). The risk of discontinuation was highest among migrants from North Africa and the Middle East and Sub-Saharan Africa and among recent migrants. Non-use of antipsychotic treatment before being diagnosed with psychosis, involuntary hospitalization and diagnosis other than schizophrenia were associated with earlier discontinuation both among migrants and non-migrants. CONCLUSIONS: Migrants with a psychotic disorder are less likely to continue antipsychotic treatment than non-migrants. The needs of migrant patients have to be addressed to improve adherence.

Functional Characterization of Six SLCO1B1 (OATP1B1) Variants Observed in Finnish Individuals with a Psychotic Disorder.

Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2',7'-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.

Criminal Behaviour After Diagnosis of a Neurocognitive Disorder: A Nationwide Finnish Register Study.

OBJECTIVE: To explore criminal behavior of individuals with Alzheimer's disease (AD), frontotemporal dementia (FTD), or Lewy body dementias (LBD) after the diagnosis. DESIGN: Nationwide register study. SETTING: Information on diagnoses and criminality was received from Finnish registers. Crime types and incidences were compared between disorders and the general population. PARTICIPANTS: All Finnish individuals diagnosed with AD, LBD, or FTD (n = 92 189) during 1998-2015. MEASUREMENTS: Types of crimes and incidences, the standardized criminality ratio (SCR, number of actual crimes per number of expected crimes), numbers of observed cases, and person-years at risk counted in 5-year age groups and for both sexes and yearly. RESULTS: Among men, at least one crime was committed by 2.8% of AD, 7.2% of FTD, and 4.8% of LBD patients. Among women, the corresponding figures were 0.4%, 2.0%, and 2.1%. The most frequent type of crime was traffic offence, followed by property crime. After age adjustment, the relative number of crimes between groups did not differ, except that men with FTD and LBD committed more crimes than those with AD. The SCR (95% CI) among men were 0.40 (0.38-0.42) in AD, 0.45 (0.33-0.60) in FTD, and 0.52 (0.48-0.56) in LBD. Among women, these were 0.34 (0.30-0.38), 0.68 (0.39-1.09), and 0.59 (0.51-0.68). CONCLUSIONS: The diagnosis of a neurocognitive disorder does not increase criminal behavior, but rather reduces it by up to 50%. Differences in crime activity are present between different neurocognitive disorders and between the sexes.

Use of benzodiazepine and related drugs in migrants and Finnish-born persons: a nationwide register-based study.

AIMS: Benzodiazepines and related drugs (BZDR) are often used longer than generally recommended. The aim is to study patterns of use among migrant and Finnish-born users of BZDR, and to identify factors that are associated with long-term use and BZDR polytherapy. METHODS: This register-based study includes a nationwide sample of migrants (n=8729) and their Finnish-born controls (n=11 388) who had purchased BZDR in 2011-2014, but not in 2009-2010. Information on drug purchases was obtained from the National Prescription Register and the duration of drug use was estimated using PRE2DUP method. The main outcomes were long-term use of BZDR, polytherapy and time until discontinuation of BZDR use. Sociodemographic variables and information on preceding psychiatric diagnoses were included as covariates. Logistic and Cox regression analyses were the statistical methods used. RESULTS: Only migrants from Sub-Saharan Africa were more likely to discontinue the medication once initiated than Finnish-born users. Migrants were significantly less likely to be long-term users (adjusted odds ratio 0.79, 95% CI 0.70-0.89) or polytherapy users (aOR 0.90, 95% CI 0.84-0.97) of BZDR compared with Finnish-born participants. CONCLUSIONS: Migrants had less long-term and concomitant use of several BZDR than Finnish-born participants. The pattern of use is more optimal among migrants, but it may also reflect poorer access to mental health treatment.

Temporal changes in the associations between diagnosed psychiatric disorders and dropping out of school early.

Psychiatric problems are risk markers for poor educational attainment. The number of adolescents receiving treatment has increased. We investigated whether the association between psychiatric problems in early adolescence and dropping out of school had changed. We used the register-based 1987 and 1997 Finnish Birth Cohort studies, which include all live births in Finland. Hospital districts with incomplete records were excluded, leaving 25,421 participants born in 1987 and 32,025 born in 1997. The main outcome was not having applied for secondary education by the year the cohort members turned 18. Our main predictors were psychiatric and neurodevelopmental disorders diagnosed by specialized services during 1998-2003 and 2008-2013, when the cohort members were 10-16 years old. We found that 511 (2.0) of subjects born in 1987 and 499 (1.6%) born in 1997 dropped out of school. Having any diagnosis at 10-16 of age was associated with dropping out of school early in both cohorts: 3.9% in 1987 and 4.8% in 1997. The highest proportions were in the subgroup with autism spectrum disorders (ASD), 19.4% in 1987 and 16.2% in 1997. Dropping out early increased among adolescents diagnosed with any psychiatric or neurodevelopmental disorder, from 3.9 to 4.8%, with the clearest increase for learning disabilities, from 3.4 to 9.0%. Dropping out decreased for those with depression, from 4.5 to 2.1%. Adolescents with psychiatric and especially neurodevelopmental disorders, need effective interventions to prevent them dropping out of school early. Increased detection of psychopathology did not result in decreased dropout rates.

Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia.

Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)-derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron-astrocyte co-cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder.

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Suicides from 2016 to 2020 in Finland and the effect of the COVID-19 pandemic.

The COVID-19 pandemic has had negative mental health outcomes in populations, but the suicide numbers in Finland have remained unchanged compared with expected levels based on the pre-pandemic period. We included all deaths from suicide verified by the official cause-of-death investigations, including forensic autopsy with analysis of forensic toxicology samples, between 1 January 2016 and 31 December 2020 in Finland. There was a decline in suicide incidence from 2016 to 2020 in men, and a declining tendency in suicide rates for every consecutive month during the COVID-19 pandemic period. The COVID-19 governmental policy responses do not seem to have led to an increase in suicide numbers.

Psychiatric disorders diagnosed in adolescence and subsequent long-term exclusion from education, employment or training: longitudinal national birth cohort study.

BACKGROUND: Long-term 'not in education, employment or training' (NEET) status is an important indicator of youth marginalisation. AIMS: To carry out a comprehensive overview of the associations between different psychiatric illnesses and long-term NEET status. METHOD: We used the register-based 1987 Finnish Birth Cohort study, which includes all live births in Finland during that year. The analyses comprised 55 273 individuals after exclusions for intellectual disability, death or emigration. We predicted that psychiatric disorders, diagnosed by specialist services between 1998 and 2007 when the cohort were 10-20 years of age, would be associated with subsequent long-term NEET (defined as NEET for at least 5 years between 2008 and 2015, when they were 20-28 years of age). RESULTS: In total, 1438 individuals (2.6%) were long-term NEET during follow-up and the associations between long-term NEET and the 11 diagnostic categories we studied were statistically significant (P < 0.001). In multivariate models we included sociodemographic characteristics and upper secondary education as covariates, and the highest effect sizes, measured by odds ratios (OR) with 95% confidence intervals (CI), were found for psychosis (OR = 12.0, 95% CI 9.5-15.2) and autism spectrum disorder (OR = 17.3, 95% CI 11.5-26.0). If individuals had not successfully completed this education, 70.6% of those with autism spectrum disorder and 48.4% of those with psychosis were later long-term NEET. CONCLUSIONS: Adolescents who receive treatment for psychiatric disorders, particularly autism spectrum disorder or psychosis, need support to access education and employment. This could help to prevent marginalisation in early adulthood.

Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population.

We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06-1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07-1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

Incidence and mortality of alcohol-related dementia and Wernicke-Korsakoff syndrome: A nationwide register study.

BACKGROUND: Epidemiological data on alcohol-related cognitive disorders are scarce. Up-to-date population-based incidence and mortality rates for Wernicke-Korsakoff syndrome (WKS) and alcohol-related dementia (ARD) are necessary to understand the burden of these diseases. METHODS: We collected diagnostic data from the Finnish Hospital Discharge Register and mortality data from Statistics Finland for all persons aged ≥40 years who had received a diagnosis of WKS (n = 1149) or ARD (n = 2432) between 1998 and 2015 in Finland. We calculated the incidences and mortality in relation to the age-, sex- and calendar year-matched general population. Causes of death were ascertained from death certificates. RESULTS: For WKS, the incidence per 100,000 person-years (95% confidence interval (CI)) was 3.7 (3.4-3.9) in men and 1.2 (1.1-1.3) in women. For ARD, the incidence was 8.2 (7.9-8.6) in men and 2.1 (1.9-2.3) in women. The incidence of WKS peaked in people aged 50-59 years and the incidence of ARD in people aged 70-79 years. The standardized mortality ratio (95% CI) was 5.67 (5.25-6.13) in WKS patients and 5.41 (5.14-5.70) in ARD patients. Most of the excess mortality resulted from alcohol-related causes. CONCLUSIONS: To our knowledge, this is the first study describing population-based incidence and mortality rates, sex-segregated data and causes of death in patients with WKS or ARD. Our results establish a point of reference for the incidence of WKS and ARD and show the high mortality and poor prognosis of these disorders.

Healthcare workers' heterogeneous mental-health responses to prolonging COVID-19 pandemic: a full year of monthly follow up in Finland.

BACKGROUND: The COVID-19 pandemic strained healthcare workers but the individual challenges varied in relation to actual work and changes in work. We investigated changes in healthcare workers' mental health under prolonging COVID-19 pandemic conditions, and heterogeneity in the mental-health trajectories. METHODS: A monthly survey over a full year was conducted for employees of the HUS Helsinki University Hospital (n = 4804) between 4th June 2020 to 28th May 2021. Pandemic-related potentially traumatic events (PTEs), work characteristics (e.g., contact to COVID-19 patients), local COVID-19 incidence, and demographic covariates were used to predict Mental Health Index-5 (MHI-5) and Insomnia Severity Index (ISI) in generalized multilevel and latent-class mixed model regressions. RESULTS: Local COVID-19 log-incidence (odds ratio, OR = 1.21, with 95% CI = 1.10-1.60), directly caring for COVID-19 patients (OR = 1.33, CI = 1.10-1.60) and PTEs (OR = 4.57, CI = 3.85-5.43) were all independently associated with psychological distress, when (additionally) adjusting for age, sex, profession, and calendar time. Effects of COVID-19 incidence on mental health were dissociable from calendar time (i.e., evolved in time) whereas those on sleep were not. Latent mental-health trajectories were characterized by a large class of "stable mental health" (62% of employees) and minority classes for "early shock, improving" (14%) and "early resilience, deteriorating" mental health (24%). The minority classes, especially "early shock, improving", were more likely to live alone and be exposed to PTEs than the others. CONCLUSIONS: Healthcare workers faced changing and heterogeneous mental-health challenges as the COVID-19 pandemic prolonged. Adversity and mental ill-being may have accumulated in some employees, and factors like living arrangements may have played a role. Knowledge on employees' demographic and socioeconomic background, as well as further research on the factors affecting employees' resilience, may help in maintaining healthy and efficient workforce in the face of a prolonging pandemic.

Cognitive functioning and cannabis use in first-episode psychosis.

AIM: Cannabis use is common in people with psychotic disorders. However, the effect of cannabis on cognition in psychosis remains unclear. Our study investigates relationships between the history of cannabis use and cognitive performance in patients with first-episode psychosis (FEP) during a one-year follow-up. METHODS: The present study included FEP (N = 91) and control (N = 61) groups. Cannabis use was evaluated with a self-report questionnaire, clinical assessment, and medical records during a lifetime and 12 months prior to the treatment onset (recent). Symptoms of psychosis and anxiety were evaluated on the brief psychiatric rating scale. Negative symptoms were assessed using the scale for the assessment of negative symptoms. Cognitive tests were used to evaluate neurocognition (summarized in the g factor) and social cognition. Crude regression analyses for the g factor included variables of cannabis use as independent variables. Full regression models were controlled for gender, education, and clinical symptoms. RESULTS: In the FEP group, men used cannabis more frequently than women. In the crude regression model for FEP patients, never having used cannabis was associated with a better neurocognitive profile at 12 months. In the full model, more severe anxiety symptoms were associated with better neurocognition at two months, and less severe negative symptoms were associated with better neurocognition at 12 months. Cannabis use was not associated with social cognition. No associations between cognitive performance and cannabis use emerged in the controls. CONCLUSION: Negative and affective symptom severity in FEP was associated with cognitive performance to a greater degree than a lifetime history of cannabis use.