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Importance: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown., Objective: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features., Design, Setting, and Participants: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023., Exposures: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays., Main Outcomes and Measures: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models., Results: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015., Conclusions and Relevance: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

Introduction: Seasonality in depressive and bipolar disorders, are recognized in the ICD-10/11 and DSM-5 diagnostic systems. The existence of a seasonal pattern of hospital diagnosis of major depression, bipolar disorder and prescription of antidepressant medications has not been evaluated in the Danish population., Methods: We retrieved date and year for all first-time hospital contacts with depression or bipolar disorder between 1999 and 2019, registered in the Danish National Patient Registry. Depression was defined using the ICD-10 F32-F33 codes, and for bipolar disorder the F30 or F31 codes. Date and year of all first-time purchases of antidepressant medications with ATC codes (N06A) between 1999 and 2021 were retrieved from the Danish National Prescription Registry, containing information on all prescribed drugs dispensed at pharmacies since 1995. Data on sunlight hours from 2012 to 2021 were retrieved from the Danish Metrological Institute., Results: Incidences of hospital diagnoses as well as purchases of medication varied with month and season. The monthly variations were larger for antidepressant medication and smallest for bipolar disorder. The multiple linear regression analysis showed that number of first-time diagnoses of depression or bipolar disorder did not correlate with season. For antidepressant medication the number of first-time prescriptions was significantly lower in summer compared to the winter season., Conclusion: This study found a seasonal variation of first-time prescriptions of antidepressant medication. We did not find a seasonal variation in first-time hospital diagnoses. Further research looking into depression severity, polarity of bipolar illness episodes, lag-time for sunlight exposure, and specific parts of the yearly photoperiods should be conducted.

Objectives: Individuals with bipolar disorders (BD) have heterogenic pre-onset illness courses and responses to treatment. The pattern of illness preceding the diagnosis of BD may be a marker of future treatment response. Here, we examined associations between psychiatric morbidity preceding the diagnosis of BD and pharmacological treatment patterns in the 2 years following diagnosis., Methods: In this register-based study, we included all patients with a diagnosis of BD attending Danish Psychiatric Services between January 1, 2012 and December 31, 2016. We examined the association between a diagnosis of substance use disorder, psychosis (other than schizophrenia or schizoaffective disorder), unipolar depression, anxiety/OCD, PTSD, personality disorder, or ADHD preceding BD and pharmacological treatment patterns following the diagnosis of BD (lithium, valproate, lamotrigine, antidepressants, olanzapine, risperidone, and quetiapine) via multivariable Cox proportional hazards regression adjusted for age, sex, and year of BD diagnosis., Results: We included 9594 patients with a median age of 39 years, 58% of whom were female. Antidepressants, quetiapine, and lamotrigine were the most commonly used medications in BD and were all linked to prior depressive illness and female sex. Lithium was used among patients with less diagnostic heterogeneity preceding BD, while valproate was more likely to be used for patients with prior substance use disorder or ADHD., Conclusion: The pharmacological treatment of BD is linked to psychiatric morbidity preceding its diagnosis. Assuming that these associations reflect well-informed clinical decisions, this knowledge may inform future clinical trials by taking participants' prior morbidity into account in treatment allocation., (© 2024 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: This study aimed to explore the association between bipolar disorder and the risk of developing dementia, and whether the risk varies with age at the onset of bipolar disorder., Methods: In this study, 37,084 individuals with a first-time diagnosis of bipolar disorder diagnosed between 1969 and 2018 and a reference population (n = 189,662) matched on sex, birth year and time of bipolar diagnosis (index date) were followed in nationwide registries for incident dementia until October 2020. Associations were analysed using Cox proportional hazard regression with adjustment for sex, education level, alcohol or drug abuse, traumatic brain injury, ischemic heart disease, stroke and diabetes mellitus., Results: In total, 6.6 % of individuals with bipolar disorder and 4.0 % in the reference population developed dementia during the mean follow-up of 13.1 years. Compared to the reference population, individuals with bipolar disorder had a higher incidence of dementia during follow-up after adjusting for potential confounders (HR: 2.66, 95 % CI [2.53-2.79]). The strength of this association did not vary among individuals diagnosed with bipolar disorder before and after age 45., Limitations: The higher risk of dementia identified for individuals with bipolar disorder could be influenced by detection bias and, despite a large cohort, some of the age-stratified analyses were still affected by lack of statistical power., Conclusion: Individuals with bipolar disorder have a higher risk of developing dementia compared to a reference population without bipolar disorder, independent of the age at the onset of bipolar disorder., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Patients with schizophrenia or bipolar disorder are at increased risk of somatic illnesses and have more somatic complaints compared with the general population. Schizophrenia and bipolar disorder are highly heritable. Already during childhood, children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BD) are at increased risk of psychiatric disorders and cognitive and social impairments. Knowledge about physical conditions is sparse., Materials and Methods: Through blood tests ( n  = 293), interviews, and questionnaires, we assessed inflammatory markers, somatic complaints, medication - and health care use in 11-year-old children at FHR-SZ, FHR-BD, and population-based controls (PBC)., Results: Children at FHR-SZ had higher concentrations of leucocytes (mean 6.41, SD 0.73) compared with PBC (mean 5.78, SD 0.27, p  = 0.005) and of neutrophilocytes (FHR-SZ: mean 3.11, SD 1.32, PBC: mean 2.70, SD 0.96, p  = 0.024). Compared with PBC (26.6%), more children at FHR-SZ (40.5%, p  = 0.007) reported somatic complaints. So did caregivers and teachers to children at FHR-BD. Somatic complaints, higher concentrations of leucocytes, and neutrophilocytes were associated with lower levels of physical activity. Children at FHR-BD with psychiatric disorders reported more somatic complaints compared with those without., Conclusion: Children at FHR-SZ had higher concentrations of leucocytes and neutrophilocytes than PBC. Children at FHR-SZ or FHR-BP displayed more somatic complaints than controls. Our study highlights rarely explored disadvantage of being born to parents with schizophrenia or bipolar disorder. To enhance understanding of how physical conditions in childhood may interplay with later transition to mental disorders in children at FHR-SZ and FHR-BD, further research is needed.

Bipolar disorder (BD) is often accompanied by persistent cognitive impairment. However, screening for cognitive impairment in the clinic is challenged by a lack of consensus on screening procedures. This study assesses cognitive impairment prevalence and screening feasibility in alignment with the International Society for Bipolar Disorder Targeting Cognition Task Force recommendations. Between January 2022 and May 2023, 136 newly diagnosed BD outpatients were assessed with the Screen for Cognitive Impairment in Psychiatry after 15-20 months of specialised care at the Copenhagen Affective Disorder Clinic. Cognitive impairment patterns and associations with cognitive complaints, perceived stress, and functioning were examined. Most screened patients (73 %) achieved full or partial remission, with 51 % being cognitively normal, 38 % showing global impairments, and 11 % displaying selective impairments. Among remitted patients, 56 % were cognitively normal, while 31 % and 13 % exhibited global or selective impairments, respectively. Both objectively impaired patient groups reported more subjective cognitive difficulties than those who were cognitively normal. The globally impaired group also demonstrated poorer functioning, more depressive symptoms and lower quality of life than cognitively normal patients. Across all patients, lower cognitive performance correlated with more cognitive complaints, lower functioning, lower quality of life, and more depressive symptoms. Cognitive screenings were relatively easily implementable, involving only a 1.5 h session including mood ratings, feedback and cognitive strategy discussion. The study highlights the clinical relevance and feasibility of cognitive screenings in BD patients, emphasizing the need for tailored interventions given frequent cognitive impairment in clinically stable individuals., Competing Interests: Declaration of competing interest KWM reports having received consultancy fees from Lundbeck, Angelini, Gideon Richter and Janssen-Cilag in the past three years. LVK reports having received consultancy fees from Lundbeck and Teva in the past three years. JM, TR, JLB, ZKO, LH and report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias., Competing Interests: Declaration of competing interest Lars Vedel Kessing has the last three years been a consultant for Lundbeck and Teva. Christian Torp-Pedersen report grants for studies from Bayer and Novo Nordisk not related to current study. Michael Berk: Grant/Research Support: MRFF, NHMRC, Congressionally Directed Medical Research Programs (CDMRP) USA, AEDRTC Australian Eating Disorders Research and Translation Centre, Patient-Centered Outcomes Research Institute (PCORI), Baszucki Brain Research Fund, Danmarks Frie Forskningsfond. Psykiatrisk Center Kobenhavn, Stanley Medical Research Institute, Victorian Government Department of Jobs, Precincts and Regions, Wellcome Trust, Victorian Medical Research Acceleration Fund, Controversias Psiquiatria Barcelona, CRE, Victorian COVID-19 Research Fund, Consultancies: Lundbeck, Sandoz, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, RANZCP, Abbott India, ASCP, International Society of Bipolar Disorder, Precision Psychiatry, Penn State College of Medicine, Shanghai Mental Health Centre. (Last 3 years) – all unrelated to this work. Mark Bech Knudsen and Helene Charlotte Wiese Rytgaard report no financial disclosure and competing interests., (Copyright © 2024 Elsevier B.V. and ECNP. All rights reserved.)

Introduction: People with severe mental illness (SMI) face a higher risk of premature mortality due to physical morbidity compared to the general population. Establishing regular contact with a general practitioner (GP) can mitigate this risk, yet barriers to healthcare access persist. Population initiatives to overcome these barriers require efficient identification of those persons in need., Objective: To develop a predictive model to identify persons with SMI not attending a GP regularly., Method: For individuals with psychotic disorder, bipolar disorder, or severe depression between 2011 and 2016 (n = 48,804), GP contacts from 2016 to 2018 were retrieved. Two logistic regression models using demographic and clinical data from Danish national registers predicted severe mental illness without GP contact. Model 1 retained significant main effect variables, while Model 2 included significant bivariate interactions. Goodness-of-fit and discriminating ability were evaluated using Hosmer-Lemeshow (HL) test and area under the receiver operating characteristic curve (AUC), respectively, via cross-validation., Results: The simple model retained 11 main effects, while the expanded model included 13 main effects and 10 bivariate interactions after backward elimination. HL tests were non-significant for both models (p = 0.50 for the simple model and p = 0.68 for the extended model). Their respective AUC values were 0.789 and 0.790., Conclusion: Leveraging Danish national register data, we developed two predictive models to identify SMI individuals without GP contact. The extended model had slightly better model performance than the simple model. Our study may help to identify persons with SMI not engaging with primary care which could enhance health and treatment outcomes in this group., (© 2024. The Author(s).)

Background and Hypothesis: Suicide is a leading cause of death in youth and is often preceded by suicidal ideation (SI) and non-suicidal self-injury (NSSI). Identifying early markers of risk for SI and NSSI could improve timely identification of at-risk individuals., Study Design: Children (mean age 11.9, SD 0.2) at familial high risk of schizophrenia (N = 171), or bipolar disorder (N = 104), and controls (N = 174) were assessed for psychotic experiences (PE), SI, NSSI, and Axis I mental disorders in face-to-face interviews in early and middle childhood (age 7 and 11)., Study Results: Having 2 types of early childhood PE predicted middle childhood SI after accounting for previous SI, NSSI, and mental disorders (OR 2.8, 95% CI 1.1-6.9; P = .03). Two PE predicted NSSI (OR 3.0, 95% CI 1.2-7.7; P = .02) in excess of previous SI, NSSI, mental disorders, and familial risk. Persistent and incident PE predicted SI (OR 3.2, 95% CI, 1.1-8.8; P = .03; OR 3.8, 95% CI, 1.3-11.5; P = .02) in the fully adjusted model. Nineteen percent of children with persistent PE reported middle childhood SI vs 3.8% of those who never reported PE. In children with early childhood mental disorders, those who reported 2 PE had 4.4-fold increased odds of later SI (95% CI, 1.2-16.7; P = .03) after adjustments. PE were nondifferentially associated with outcomes across familial risk groups., Conclusions: Early childhood PE index elevated risk for subsequent SI and NSSI beyond what can be attributed to presence of mental disorders. Mental health screenings and clinical assessments should include early childhood PE., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Despite the genetic overlap between bipolar disorder and schizophrenia, working memory impairments are mainly found in children of parents with schizophrenia. However, working memory impairments are characterized by substantial heterogeneity, and it is unknown how this heterogeneity develops over time. We used a data-driven approach to assess working memory heterogeneity and longitudinal stability in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP)., Methods: Based on the performances on four working memory tasks by 319 children (FHR-SZ, N = 202, FHR-BP, N = 118) measured at age 7 and 11, latent profile transition analysis was used to test for the presence of subgroups, and the stability of subgroup membership over time. Population-based controls (VIA 7, N = 200, VIA 11, N = 173) were included as a reference group. The working memory subgroups were compared based on caregiver- and teacher ratings of everyday working memory function, and dimensional psychopathology., Results: A model with three subgroups characterized by different levels of working memory function (an impaired subgroup, a mixed subgroup, and an above average subgroup) best fitted the data. The impaired subgroup had the highest ratings of everyday working memory impairments and psychopathology. Overall, 98 % (N = 314) stayed in the same subgroup from age 7 to 11., Conclusion: Persistent working memory impairments are present in a subset of children at FHR-SZ and FHR-BP throughout middle childhood. Attention should be given to these children, as working memory impairments influence daily life, and may serve as a vulnerability marker of transition to severe mental illness., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Knowledge about representativity of familial high-risk studies of schizophrenia and bipolar disorder is essential to generalize study conclusions. The Danish High Risk and Resilience Study (VIA 7), a population-based case-control familial high-risk study, creates a unique opportunity for combining assessment and register data to examine cohort representativity., Methods: Through national registers, we identified the population of 11,959 children of parents with schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and controls from which the 522 children participating in The VIA 7 Study (202 FHR-SZ, 120 FHR-BP and 200 controls) were selected. Socio-economic and health data were obtained to compare high-risk groups and controls, and participants versus non-participants. Selection bias impact on results was analyzed through inverse probability weights., Results: In the total sample of 11,959 children, FHR-SZ and FHR-BP children had more socio-economic and health disadvantages than controls (p < 0.001 for most). VIA 7 non-participants had a poorer function, e.g. more paternal somatic and mental illness (p = 0.02 and p = 0.04 for FHR-SZ), notifications of concern (FHR-BP and PBC p < 0.001), placements out of home (p = 0.03 for FHR-SZ), and lower level of education (p ≤ 0.01 for maternal FHR-SZ and FHR-BP, p = 0.001 for paternal FHR-BP). Inverse probability weighted analyses of results generated from the VIA Study showed minor changes in study findings after adjustment for the found selection bias., Conclusions: Familial high-risk families have multiple socio-economic and health disadvantages. In The VIA 7 Study, although comparable regarding mental illness severity after their child's birth, socioeconomic and health disadvantages are more profound amongst non-participants than amongst participants., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The jumping to conclusions (JTC) bias, ie, making decisions based on inadequate evidence, is associated with psychosis in adults and is believed to underlie the formation of delusions. Knowledge on the early manifestations of JTC and its associations with psychotic experiences (PE) in children and adolescents is lacking., Design: Preadolescent children (mean age 11.9 y, SD 0.2) at familial high risk of schizophrenia (FHR-SZ, n = 169) or bipolar disorder (FHR-BP, n = 101), and controls (n = 173) were assessed with the Beads Task to examine JTC. The number of beads drawn before making a decision, "draws to decision" (DTD) was used as a primary outcome. PE were ascertained in face-to-face interviews. General intelligence was measured with Reynolds Intellectual Screening Test., Results: Children at FHR-SZ took fewer DTD than controls (4.9 vs 5.9, Cohen's d = 0.31, P = .004). Differences were attenuated when adjusting for IQ (Cohen's d = 0.24, P = .02). Higher IQ was associated with a higher number of DTD (B = 0.073, P < .001). Current subclinical delusions compared with no PE were associated with fewer DTD in children at FHR-SZ (P = .04) and controls (P < .05). Associations between delusions and DTD were nullified when accounting for IQ., Conclusions: JTC marks familial risk of psychosis in preadolescence, not reducible to general intelligence. JTC is associated with subclinical delusions, but this may be an expression of intellectual impairment. Future studies should establish temporality between JTC and delusion formation and examine JTC as a target for early intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Childhood trauma increases the risk of developing mental illness as does being born to parents with schizophrenia or bipolar disorder. We aimed to compare prevalence of lifetime childhood trauma among 11-year-old children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) compared with population-based controls (PBCs)., Design: The study is a longitudinal, prospective cohort study of children at FHR-SZ, FHR-BP, and PBCs., Methods: A cohort of 512 children at FHR-SZ (N = 199), FHR-BP (N = 118), and PBCs (N = 195) were examined at baseline (mean age 7.8, SD 0.2) and 451 children at FHR-SZ (N = 172), FHR-BP (N = 104), and PBCs (N = 175) were examined at four-year follow-up (mean age 11.9, SD 0.2, retention rate 87.3%). Childhood trauma was measured with a semi-structured interview., Results: Children at FHR-BP had an elevated risk of exposure to any lifetime trauma (age 0-11 years) compared with PBCs (OR 2.082, 95%CI 1.223-3.545, p = .007) measured with binary logistic regression. One-way ANOVA revealed that both FHR-groups had a higher lifetime prevalence of exposure to a greater number of types of trauma compared with PBCs (FHR-SZ: observed mean: 1.53, 95%CI 1.29-1.77; FHR-BP: observed mean: 1.56, 95%CI 1.26-1.85; PBCs: observed mean: 0.99, 95%CI 0.82-1.17; p < .001). Binary logistic regression showed that the lifetime risk of exposure to interpersonal trauma (age 0-11 years) was elevated for both FHR-groups (FHR-SZ: OR 3.773, 95%CI 2.122-6.710, p < .001; FHR-BP: OR 3.602, 95%CI 1.913-6.783, p < .001)., Conclusions: Children at FHR-SZ and FHR-BP are at increased risk for being exposed to childhood trauma compared with PBCs. This study underscores the need for early detection, support, and prevention of childhood trauma in children at FHR-SZ and FHR-BP., (© 2022 The British Psychological Society.)

Objective: Psychotic experiences are common in children and adolescents and are associated with concurrent and subsequent psychopathology. Most findings originate from general population studies, whereas little is known of the clinical outcomes of psychotic experiences in children and adolescents at familial high risk of psychosis. We examined the prevalence of psychotic experiences in middle childhood and whether early childhood psychotic experiences and developmental pathways of psychotic experiences predicted mental disorders in middle childhood in children at familial high risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and a population-based control group., Methods: In a longitudinal population-based cohort study children at FHR-SZ (N=170), FHR-BP (N=103), and the control group (N=174) were assessed for psychotic experiences and axis I disorders with face-to-face interviews in early and middle childhood (at 7 and 11 years of age)., Results: Psychotic experiences were more prevalent in children at FHR-SZ (31.8%, odds ratio 2.1, 95% CI 1.3-3.4) than in the control group (18.4%) in middle childhood. Early childhood psychotic experiences predicted mental disorders in middle childhood after adjusting for early childhood disorders and familial risk (odds ratio 2.0, 95% CI 1.2-3.1). Having three or more psychotic experiences increased odds the most (odds ratio 2.5, 95% CI 1.1-5.7). Persistent psychotic experiences were associated with increased odds of middle childhood disorders (odds ratio 4.1, 95% CI 2.1-8.4). Psychotic experiences were nondifferentially associated with mental disorders across the three familial risk groups., Conclusions: Early childhood psychotic experiences predict mental disorders in middle childhood. Psychotic experiences index vulnerability for psychopathology nondifferentially in children at familial high risk and the control group. Psychotic experiences should be included in mental health screenings including children at familial high risk.

Background: Children at familial high-risk of schizophrenia and bipolar disorder have an elevated prevalence of mental disorders but studies of children within a narrow age range are lacking and there are few conjoint studies of these two groups. Knowledge on their mental health is important for prevention and early intervention., Methods: The authors examined mental disorders and global functioning in children at familial high-risk of schizophrenia (FHR-SZ) and bipolar disorder (FHR-BP) compared with population-based controls. In a longitudinal cohort study, 450 children (FHR-SZ, n = 171; FHR-BP, n = 104; controls, n = 175), were assessed for Axis I disorders at baseline and four-year follow-up (mean age 11.9, SD 0.2) with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children and for global functioning with Children's Global Assessment Scale., Results: Cumulative incidence of Any Axis I disorder was elevated by age 11 in children at FHR-SZ (54.4%, OR 3.0, 95% CI 1.9-4.7, p < .001) and children at FHR-BP (52.9%, OR 2.8, 95% CI 1.7-4.7, p < .001) compared with controls (28.6%). Children at FHR-SZ and FHR-BP had higher rates of affective disorders (OR 4.4, 95% CI 1.4-13.5, p = .009; OR 5.1, 95% CI 1.6-16.4, p = .007), anxiety disorders (OR 2.1, 95% CI 1.1-4.0, p = .02; OR 3.0, 95% CI 1.5-6.1, p = .002), and stress and adjustment disorders (OR 3.3, 95% CI 1.4-7.5, p = .006; OR 5.3, 95% CI 2.2-12.4, p < .001). Disruptive behavior disorders (OR 2.8, 95% CI 1.0-7.3, p = .04) and ADHD (OR 2.9, 95% CI 1.6-5.3, p < .001) were elevated in children at FHR-SZ. Both FHR groups had lower global functioning than controls. Cumulative incidence of disorders increased equally across the three groups from early childhood to preadolescence and level of functioning did not change differentially., Conclusions: Children at FHR-SZ and FHR-BP have an elevated prevalence of mental disorders and poorer functioning than controls. Vulnerability in children at FHR manifests early and remains stable throughout childhood. Early attention toward their mental health and identification of those in need of intervention is warranted., (© 2021 Association for Child and Adolescent Mental Health.)

Throughout the COVID-19 pandemic, mental health of individuals with bipolar disorders (BD) is potentially more vulnerable, especially regarding COVID-19-related regulations and associated symptomatic changes. A multicentric online study was conducted in Austria, Germany, and Denmark during the COVID-19 pandemic. Overall, data from 494 participants were collected (203 individuals with BD, 291 healthy controls (HC)). Participants filled out questionnaires surveying emotional distress due to social distancing, fear of COVID-19, and the Brief Symptom Inventory-18 to assess symptom severity at four points of measurement between 2020 and 2021. General linear mixed models were calculated to determine the difference between the groups in these pandemic specific factors. Individuals with BD reported higher distress due to social distancing than HC, independently of measurement times. Fear of COVID-19 did not differ between groups; however, it was elevated in times of higher infection and mortality due to COVID-19. Individuals with BD reported higher psychiatric symptom severity than HC; however, symptom severity decreased throughout the measured time in the pandemic. Overall, individuals with BD experienced more distress due to the COVID-19 situation than HC. A supportive mental health system is thus recommended to ensure enhanced care, especially in times of strict COVID-19-related regulations.

Background: Studies of neurocognitive heterogeneity in young children at familial high-risk of bipolar disorder (FHR-BP) or schizophrenia (FHR-SZ) are important to investigate inter-individual neurocognitive differences. We aimed to identify neurocognitive subgroups, describe prevalence of FHR-BP or FHR-SZ children herein, and examine risk ratios (RR) compared with controls., Methods: In a population-based cohort of 514 7-year-old children (197 FHR-SZ, 118 FHR-BP, and 199 matched controls) we used hierarchical cluster analyses to identify subgroups across 14 neurocognitive indices., Results: Three neurocognitive subgroups were derived: A Mildly Impaired (30%), Typical (51%), and Above Average subgroup (19%). The Mildly Impaired subgroup significantly underperformed controls (Cohen d = 0.11-1.45; Ps < 0.001) except in set-shifting (P = .84). FHR-SZ children were significantly more prevalent in the Mildly Impaired subgroup; FHR-BP children were more so in the Above Average subgroup (X 2 (2, N = 315) = 9.64, P < .01). 79.7% FHR-BP and 64.6% FHR-SZ children demonstrated typical or above average neurocognitive functions. Neurocognitive heterogeneity related significantly to concurrent functioning, psychopathology severity, home environment adequacy, and polygenic scores for schizophrenia (Ps <. 01). Compared with controls, FHR-SZ and FHR-BP children had a 93% (RR, 1.93; 95% CI, 1.40-2.64) and 8% (RR, 1.08; 95% CI, 0.71-1.66) increased risk of Mildly Impaired subgroup membership., Limitations: Limitations include the cross-sectional design and smaller FHR-BP sample size., Conclusions: Identification of neurocognitive heterogeneity in preadolescent children at FHR-BP or FHR-SZ may ease stigma and enable pre-emptive interventions to enhance neurocognitive functioning and resilience to mental illness in the impaired sub-population., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Adolescence represents an important period in brain and mental development, which raises the question of whether measures of body size at entry into adult life influence the risk of developing mood disorders. We examined the association of BMI and height in a cohort of young men with risk of mood disorders throughout life. The study included 630,807 Danish men born 1939-1959 and 1983-1997 with measures of height and weight at conscription board examinations. Psychiatrist's diagnosis of mood disorders was obtained from national patient registries from 1969 to 2016. The associations of BMI and height with mood disorders were estimated by Cox proportional hazard regression analyses adjusting for education, cognitive ability, migration status drug and alcohol misuse. During a mean follow-up of 26.3 years, 2,608 (0.6%) and 19,690 (3.1%) men were diagnosed with bipolar disorder and depression, respectively. We found an inverse linear association of BMI with risk of bipolar disorder, whereas the association of BMI with depression was curve-linear with a decline in risk until BMI around 25 kg/m 2 , and an almost constant risk across the BMI range above 25 kg/m 2 . Height was not associated with bipolar disorder or depression. Comparison of brothers, assumed to share family factors of possible influence on the risk of mood disorders, showed similar results although with wider confidence intervals. BMI in the lower range at men's entry into adulthood is inversely associated with risk of bipolar disorder and depression throughout adult life, whereas height is not related., (© 2021. Springer Nature B.V.)

Background Affective disorders (AD) have been associated with a higher prevalence of the gut Flavonifractor genus and a lower abundance of the gut Christensenellaceae family. Objective and methods By pooling two independent study samples of patients with AD (n = 176), their unaffected first-degree relatives (n = 70) and healthy controls (n = 101) we aimed to replicate and extend our prior findings of differential Flavonifractor prevalence and Christensenellaceae abundance when comparing patients with AD and healthy controls. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Results The pattern of higher prevalence of Flavonifractor and lower Centered Log-Ratio (CLR) abundance of Christensenellaceae was associated with AD. In generalized linear models the CLR abundance of Christensenellaceae was lower in patients with AD (p = 0.024), and in smokers (p = 1.9*10 -4 ), and inversely associated with increasing waist circumference (p = 0.031). The prevalence of Flavonifractor was higher in patients with AD (p = 0.033) and in smokers (p = 0.036). No impact of psychotropic medication was found. The CLR abundance of Christensenellaceae (p = 0.041), but not the prevalence of Flavonifractor (p = 0.20) could distinguish non-smoking patients with AD from non-smoking healthy controls, whereas no such associations were found in smokers. Unaffected relatives neither differed from patients with AD nor from healthy controls. Conclusion Compared with findings in healthy controls, AD was associated with a significantly lower CLR abundance of the health-linked Christensenellaceae and a significantly higher prevalence of Flavonifractor; findings that are associated with enhanced oxidative stress and systemic low-grade inflammation. If our observations are validated in future independent studies, they support the notion that parts of aberrant gut microbiota are shared by AD and states of dysmetabolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Psychiatric disorders have been associated with unfavourable outcome following respiratory infections. Whether this also applies to coronavirus disease 2019 (COVID-19) has been scarcely investigated., Methods: Using the Danish administrative databases, we identified all patients with a positive real-time reverse transcription-polymerase chain reaction test for COVID-19 in Denmark up to and including 2 January 2021. Multivariable cox regression was used to calculate 30-day absolute risk and average risk ratio (ARR) for the composite end point of death from any cause and severe COVID-19 associated with psychiatric disorders, defined using both hospital diagnoses and redemption of psychotropic drugs., Results: We included 144,321 patients with COVID-19. Compared with patients without psychiatric disorders, the standardized ARR of the composite outcome was significantly increased for patients with severe mental illness including schizophrenia spectrum disorders 2.43 (95% confidence interval [CI], 1.79-3.07), bipolar disorder 2.11 (95% CI, 1.25-2.97), unipolar depression 1.70 (95% CI, 1.38-2.02), and for patients who redeemed psychotropic drugs 1.70 (95% CI, 1.48-1.92). No association was found for patients with other psychiatric disorders 1.13 (95% CI, 0.86-1.38). Similar results were seen with the outcomes of death or severe COVID-19. Among the different psychiatric subgroups, patients with schizophrenia spectrum disorders had the highest 30-day absolute risk for the composite outcome 3.1% (95% CI, 2.3-3.9%), death 1.2% (95% CI, 0.4-2.0%) and severe COVID-19 2.7% (95% CI, 1.9-3.6%)., Conclusion: Schizophrenia spectrum disorders, bipolar disorder, unipolar depression and psychotropic drug redemption are associated with unfavourable outcomes in patients with COVID-19., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Individuals with bipolar disorder or schizophrenia have a higher risk of adverse outcomes from cardiovascular diseases. Oral anticoagulation therapy (OAT) for patients with atrial fibrillation (AF) is needed for stroke prevention, but whether patients with bipolar disorder or schizophrenia face disparities in receiving this therapy is unknown., Objective: To assess whether bipolar disorder or schizophrenia is associated with a lower rate of OAT initiation in patients with incident AF and lower prevalence of OAT in those with prevalent AF., Design, Setting, and Participants: A nationwide cohort study of Danish patients with AF was conducted from January 1, 2005, to December 31, 2016, and data were analyzed from January 1 to June 15, 2020. Data from national registries included information on all redeemed prescriptions and all hospital contacts of all patients with incident or prevalent AF (age, 18-100 years) and increased risk status, defined by a CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65-74 years, sex category) risk score greater than or equal to 2., Exposures: Hospital diagnosis of bipolar disorder or schizophrenia., Main Outcomes and Measures: Adjusted proportion differences for OAT initiation and OAT prevalence, comparing individuals with and without bipolar disorder or schizophrenia., Results: Patients included with incident AF (n = 147 810) had a mean (SD) age of 76.9 (10.1) years, 78 577 (53.2%) were women, 1208 (0.8%) had bipolar disorder, and 572 (0.4%) had schizophrenia. Accounting for age, sex, and calendar time, bipolar disorder and schizophrenia were associated with significantly lower frequency of OAT initiation within 90 days after incident AF (bipolar disorder: -12.7%; 95% CI, -15.3% to -10.0%; schizophrenia: -24.5%; 95% CI, -28.3% to -20.7%) and lower OAT prevalence in patients with prevalent AF (bipolar disorder: -11.6%; 95% CI, -13.9% to -9.3% schizophrenia: -21.6%; 95% CI, -24.8% to -18.4%). Adjusting for socioeconomic factors and other comorbid conditions attenuated these associations, particularly for patients with bipolar disorder. However, schizophrenia continued to be associated with a with a lower rate of OAT initiation (-15.5%, 95% CI, -19.3% to -11.7%) and a -12.8% (95% CI, -15.9% to -9.7%) lower OAT prevalence. These associations were also present after the introduction of non-vitamin K antagonists (adjusted proportion difference in 2013-2016: -12.4%; 95% CI, -18.7% to -6.1% for initiation and -10.1%; 95% CI, -13.8% to -6.4% for prevalence)., Conclusions and Relevance: In this study, patients with bipolar disorder or schizophrenia were less likely to receive OAT in the setting of AF. For patients with bipolar disorder, this deficit was largely associated with socioeconomic factors and comorbidities, especially toward the end of the study period. For patients with schizophrenia, disparities in this stroke prevention therapy persistently exceeded what could be explained by other patient characteristics.

We aimed to examine the prevalence of psychotic experiences (PEs) in children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and, in exploratory analyses, to examine the possible associations between PEs and mental disorders as well as level of functioning. A cohort of seven-year-old children with FHR-SZ (N = 199), FHR-BP (N = 118) and controls (N = 196) was recruited through Danish nationwide registers. Lifetime PEs were assessed through interviews using the psychosis section of the 'Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version' (K-SADS-PL). Lifetime DSM-IV diagnoses were ascertained through K-SADS-PL and the level of functioning of the children through 'Children's Global Assessment Scale'. Both children with FHR-SZ (OR = 2.9, 95% CI = 1.4-6.2, p = 0.005) and FHR-BP (OR = 2.9, 95% CI = 1.3-6.7, p = 0.011) had an increased risk of having experienced "severe" PEs compared with controls. In the overall cohort PEs were associated with any lifetime mental disorder, Attention-Deficit/Hyperactivity Disorder, anxiety disorders and a lower level of functioning. The findings of a higher proportion of high risk children reporting PEs could represent an early manifestation of later more severe psychopathology or simply an unspecific transitory symptom. Future follow-up studies of this cohort will explore the predictive value of the occurrence of PEs at age seven., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Benzodiazepines and Z-drugs are two of the most prescribed agents worldwide. However, because of their cognitive side effects, the question of their influence on the risk of dementia has been raised. The authors examined the association of benzodiazepines, Z-drugs, and other anxiolytics with incident dementia in patients with affective disorders., Methods: The authors conducted a cohort and nested case-control study of 235,465 patients over age 20 who were identified in the Danish National Patient Registry as having had a first-time hospital contact for an affective disorder between 1996 and 2015. From the Danish National Prescription Registry, information was obtained on all prescriptions for benzodiazepines, Z-drugs, and other anxiolytics, and patients were followed for incident dementia (defined by hospital discharge diagnosis or acetylcholinesterase inhibitor use). Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios and odds ratios with adjustment for sociodemographic and clinical variables., Results: A total of 75.9% (N=171,287) of patients had any use of benzodiazepines or Z-drugs, and during the median follow-up of 6.1 years (interquartile range, 2.7-11), 9,776 (4.2%) patients were diagnosed with dementia. Any use of benzodiazepines or Z-drugs showed no association with dementia after multiple adjustments in either the cohort analysis or a nested case-control design. In the cohort analysis, the number of prescriptions and the cumulated dose of benzodiazepines or Z-drugs at baseline were not associated with dementia. In the nested case-control study, where prescriptions were counted from 1995 until 2 years before the index date, there was a slightly higher odds ratio of dementia in patients with the lowest use of benzodiazepines or Z-drugs (odds ratio=1.08, 95% CI=1.01, 1.15) compared with no lifetime use. However, patients with the highest use had the lowest odds of developing dementia (odds ratio=0.83, 95% CI=0.77, 0.88)., Conclusions: This large cohort study did not reveal associations between use of benzodiazepines or Z-drugs and subsequent dementia, even when exposures were cumulated or divided into long- and short-acting drugs. Some results were compatible with a protective effect.

Background: Odor identification deficits occur in individuals with schizophrenia and their unaffected first-degree relatives, while deficits are less pronounced in individuals with bipolar disorder. We hypothesized that children at familial high-risk for schizophrenia (FHR-SZ) show odor identification deficits compared to population-based controls and that children at familial high-risk for bipolar disorder (FHR-BP) perform intermediate., Methods: Odor identification was assessed at age 7 in 184 children with FHR-SZ, 106 children with FHR-BP, and 186 population-based controls with the Brief Smell Identification Test. Dimensional and predefined categorical outcomes were used in the analyses. Potential relationships with psychopathological, cognitive, and home environmental variables were conducted using hierarchical and logistic multiple regression analyses., Results: ANOVA revealed no between-group differences in odor identification. Using the recommended cut-off (below 5), we found a significantly greater proportion of boys at FHR-SZ than population-based boys with an abnormal odor identification (p = .013). However, a supplementary analysis using a Danish-based cut-off (below 4) did not support this. All children showed significant, positive associations of odor identification with female gender, social responsiveness, and verbal working memory. Lower social responsiveness predicted abnormal odor identification in boys at FHR-SZ, only using the recommended cut-off., Conclusions: Odor identification efficacy and risk status appear independent in this early developmental phase. Using the recommended threshold, abnormal odor identification is more frequent in young boys at FHR-SZ than in population-based boys and is linked to lower social responsiveness. The validity of these results is questioned by non-significant differences in the rates when using an exploratory Danish-based threshold., Competing Interests: Declaration of competing interest There are no conflicts of interest for any of the authors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The offspring of parents with severe mental illness (SMI) are at higher risk of mortality and of developing certain somatic diseases. However, across the full spectrum of somatic illness, there remains a gap in knowledge regarding morbidity., Methods: We conducted a register-based nationwide cohort study of all 2 000 694 individuals born in Denmark between 1982 and 2012. Maximum age of offspring at follow-up was 30 years. Information on parents' psychiatric diagnoses of schizophrenia, bipolar disorder, and unipolar depression was retrieved from the Psychiatric Central Register. We estimated incidence rate ratio (IRR), cumulative incidence percentage and mortality rate ratio of first hospital contact for a broad spectrum of somatic illnesses according to the International Statistical Classification of Diseases and Related Health Problems. Analyses were adjusted for important confounders., Results: Offspring of individuals with SMI had higher risk of somatic hospital contacts IRR: 1.17 (95% CI: 1.16-1.18) with maternal depression being associated with the highest IRR (1.22, 95% CI: 1.20-1.24). Offspring of parents with SMI had higher risk within most broad diagnostic categories with highest IRRs for unclassified somatic diagnoses, infections and endocrine diseases ranging from 1.27 (95% CI: 1.25-1.28) to 1.26 (95% CI: 1.23-1.29) (all P < .0001). Morbidity was particularly increased in children aged 0-7 years. The mortality rate ratio associated with parental SMI was 1.31 (95% CI: 1.21-1.41) with excess mortality mainly due to unnatural causes., Conclusion: Our findings indicate that offspring of parents with SMI experienced increased mortality and somatic morbidity warranting heightened vigilance and support for this population., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We aimed to investigate whether the polygenic risk score (PRS) for schizophrenia influences time in couple relationships for patients with severe mental illness and controls. We combined the nationwide Danish registers with genetic information from dried neonatal blood spots. We included 2,599 individuals with schizophrenia, 1,446 with bipolar disorder, 20,315 with depression, and 6,963 controls. PRS for schizophrenia, depression, and bipolar disorder were estimated using data from the Psychiatric Genetics Consortium and analyzed both as a scale-predictor and as highest versus other deciles. The main outcome was number of days in couple relationships. Patients with schizophrenia had markedly fewer days/year in couple relationships: 64 (95% CI; 61-69) than patients with depression: 119 (95% CI; 117-121), bipolar disorder: 103 (95% CI 97-110), and controls: 136 (95% CI 133-139). PRS for schizophrenia was associated with fewer days in couple relationships in patients with schizophrenia (scale-PRS: IRR = 0.95 (0.93-0.97)) or depression (highest decile: IRR = 0.93 (0.87-0.98)). PRS for bipolar disorder (as scale) was also associated with fewer days in couple relationships in patients with depression (IRR = 0.99 (0.99-1.00)) or bipolar disorder (IRR = 0.96 (0.94-0.99)) and controls (IRR = 0.99 (0.97-1.00), and IRR = 0.89 (0.81-0.98) for the highest decile). Due to the number of statistical tests, however, it cannot be concluded definitely that some of these may not be spurious findings. In conclusion, our findings implicate high genetic loading for schizophrenia as a predisposing factor to singleness in patients with schizophrenia or depression, and genetic loading for bipolar disorder a similar predisposing factor in patients with depression, bipolar disorder or controls., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The review summarises the available knowledge of psychiatric disorders in Greenland. The dominant problem is the increase in suicide rates especially among young men. The maximum was reached in the 1990s and remains among the world's highest. The incidence of schizophrenia is twice as high as in Denmark, and the course is significantly worse. There are also remarkable differences in the incidence of bipolar disorder and depression between Denmark and Greenland, and the reason is poorly understood.There is a great need for research in effective psychiatric preventive strategies.

Background: Mood disorders are known to be associated with poor socioeconomic outcomes, but no study has examined these associations across the entire worklife course. Our goal was to estimate the associations between bipolar disorder and depression in early adulthood and subsequent employment, income, and educational attainment., Methods: We conducted a nationwide prospective cohort study including all individuals (n = 2,390,127; 49% female) born in Denmark between 1955 and 1990. Hospital-based diagnoses of depression and bipolar disorder before age 25 were obtained from the Danish psychiatric register. Yearly employment, earnings, and education status from ages 25 to 61 were obtained from the Danish labor market and education registers. We estimated both absolute and relative proportions., Results: Population rates of hospital-diagnosed depression and bipolar between ages 15-25 were 1% and 0.12%, respectively. Compared to individuals without mood disorders, those with depression and particularly bipolar disorder had consistently poor socioeconomic outcomes across the entire work-life span. For example, at age 30, 62% of bipolar and 53% of depression cases were outside the workforce compared to 19% of the general population, and 52% of bipolar and 42% of depression cases had no higher education compared to 27% of the general population. Overall, individuals with bipolar disorder or depression earned around 36% and 51%, respectively, of the income earned by individuals without mood disorders. All associations were smaller for individuals not rehospitalized after age 25., Conclusions: Severe mood disorders with onset before age 25, particularly bipolar disorder, are associated with persistent poor socioeconomic outcomes across the entire work-life course., (© 2019 Wiley Periodicals, Inc.)

Objective: Drug repurposing is an increasingly promising idea in many fields of medicine. We systematically used Danish nation-wide population-based registers to investigate whether continued use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, high-dose aspirin, statins, allopurinol, and angiotensin agents decrease the rate of incident mania/bipolar disorder., Methods: A nation-wide population-based longitudinal study using Poisson regression analyses including all persons in Denmark who purchased the exposure medication of interest and a random sample of 30% of the Danish population. The follow-up period comprised a 10 years period from 2005 to 2015. Two different outcome measures were included, (1) a diagnosis of mania/bipolar disorder at a psychiatric hospital contact as inpatient or outpatient and (2) a combined measure of a diagnosis of mania/bipolar disorder or initiation of lithium use., Results: A total of 1,605,365 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015, median age 57 years [quartiles: 43;69], and female proportion of 53.1%. Continued use of low-dose aspirin, statins, and angiotensin agents were associated with decreased rates of incident mania/bipolar disorder on both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident bipolar disorder. There were no statistically significant associations for allopurinol., Conclusions: The study supports the potential of agents acting on inflammation and the stress response system in bipolar disorder and illustrates that population-based registers can be used to systematically identify drugs with repurposing potentials., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The primary aim of this study was to examine whether the mortality of patients with bipolar disorder has increased over the past two decades as compared with the background population., Methods: All patients registered with a bipolar disorder diagnosis in the Danish Psychiatric Research Registry from 1965 until the end of 2014, living in Denmark, alive and below the age of 65 years in the study period from 1995 to 2014 were included. Included patients reaching the age of 65 years during the study period were censored at that time point. Overall standardized mortality ratios (SMRs) were calculated for each calendar year over the study period, and trends in SMR over the study period were examined using linear regression. In addition, the SMRs were stratified according to age groups., Results: Patients with bipolar disorder had an overall elevated mortality rate relative to the general population with an SMR of 2.8, 95% confidence interval (CI): 2.8-2.9. The highest SMR was found among the youngest (15-29 years: 8.2, 95% CI: 6.7-10.1; 30-34 years: 7.7, 95% CI: 6.4-9.3; 35-39 years: 6.2, 95% CI: 5.4-7.2; 40-44 years: 4.6, 95% CI: 4.1-5.1; 45-49 years: 3.5, 95% CI: 3.3-3.8; 50-54 years: 3.2, 95% CI: 3.0-3.4; 55-59 years: 2.7, 95% CI: 2.6-2.8; and 60-64 years: 2.2, 95% CI: 2.1-2.3). An increase in SMR of 0.03 per year in patients diagnosed with bipolar disorder (P < 0.01) was found., Conclusions: The mortality gap between patients with bipolar disorder and the general Danish population has widened over the past two decades, which is a cause for concern, although reasons for the increasing mortality gap are unknown., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Substance use disorder is highly prevalent in people with psychiatric disorders, and known to impede the psychiatric treatment. Some studies show increased rates of service use, while others show a decrease. These conflicting results are further hampered by a lack of large-scale studies. The aim of this study was to investigate the association between substance use disorder and psychiatric service use in psychiatric patients., Methods: The study was a prospective registry-based cohort study including patients with severe mental illness. The primary outcome was the number of hospitalisations, bed days and the number of psychiatric emergency department contacts. The association was calculated with incidence rate ratio with 95% confidence intervals., Results: The study included all psychiatric patients born since 1955. In total, 21 558 patients with schizophrenia (47.54% with substance use disorder), 80 778 patients with depression (28.78% with substance use disorder), 10 560 patients with bipolar affective disorder (40.08% with substance use disorder) and 69 252 patients with a personality disorder (39.18% with substance use disorder) were included. Patients with comorbid substance use disorder had significantly increased rates of hospitalisations, bed days and psychiatric emergency department contacts (p < 0.001) for the majority of the included substances, compared with patients without such disorders., Conclusion: Substance use disorder was associated with an increased number of hospitalisations, bed days and increased number of psychiatric emergency department contacts for the majority of the included substances.

Background: Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.AimsTo test the prospective relationship of ADHD and anxiety with onset of bipolar disorder., Method: We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models., Results: Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12-2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98-27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47-27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83-87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66-41.40) compared with those with no prior ADHD or anxiety., Conclusions: Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.Declaration of interestNone.

Background: Schizophrenia (SZ) and bipolar disorder (BP) are causes of severe disability worldwide and parents' severe mental illness (SMI) is associated with childhood adversity, and socio-emotional and cognitive problems in children. Yet, how parental BP and SZ affect educational attainment in offspring is still unclear., Method: We included all children (N = 684.248) born and living in Denmark between 1986 and 1996 and their parents. Our follow-up lasted from 1986 until children's graduation in 2014. The main outcome variable was their school grades following their primary education. School outcomes were divided into four categories: not graduated, low-grade point average (GPA), medium GPA and high GPA. We then performed a multiple logistic regression with medium GPA as the reference category, with the children of parents without SZ or BP as the reference group., Results: Children of parents with SZ faced higher odds than their peers of not graduating primary education (OR 2.6), along with low GPA (odds ratios (OR) 1.6) and lower odds for a high GPA (OR 0.7). Moreover, it was the children of mothers rather than fathers with BP who had higher odds of not graduating primary education (OR 1.6). Lastly, child placement was associated with lower grades and lower graduation rates, and outcomes for children of parents with SMI were favorable compared with other children placed in care., Conclusion: For children, parental SZ is associated with lower grades and lower chances for graduating primary education. In contrast, the children of parents with BP were indistinguishable from the reference group regarding school grades. This signifies that specificity of parental severe mental illness is important in relation to educational achievement of children.

Objective: Postpartum psychiatric disorders are common and morbid complications of pregnancy. The authors sought to evaluate how family history of psychiatric disorders is associated with postpartum psychiatric disorders in proband mothers with and without a prior psychiatric history by assessing degree of relationship, type of disorder, and sex of family members., Method: The authors linked Danish birth and psychiatric treatment registers to evaluate familial risk of postpartum psychiatric episodes in a national population-based cohort. Probands were first-time mothers who were born in Denmark in 1970 or later and who gave birth after age 15 and before Dec. 31, 2012 (N=362,462). The primary exposure was a diagnosed psychiatric disorder in a relative. Cox regression models were used to estimate the hazard ratio of postpartum psychiatric disorders in proband mothers., Results: The relative risk of psychiatric disorders in the postpartum period was elevated when first-degree family members had a psychiatric disorder (hazard ratio=1.45, 95% CI=1.28-1.65) and highest when proband mothers had a first-degree family member with bipolar disorder (hazard ratio=2.86, 95% CI=1.88-4.35). Associations were stronger among proband mothers with no previous psychiatric history. There were no notable differences by sex of the family member., Conclusions: Family history of psychiatric disorders, especially bipolar disorder, is an important risk factor for postpartum psychiatric disorders. To assist in identification of women at risk for postpartum psychiatric disorders, questions related to female and male first-degree relatives with bipolar disorder are of the highest importance and should be added to routine clinical screening guidelines to improve prediction of risk.

Importance: Children at familial high risk of schizophrenia spectrum disorders (FHR-SZ) or bipolar disorder (FHR-BP) exhibit neurocognitive impairments. Large studies of neurocognition in young children at familial high risk at the same age are important to differentiate the pathophysiology and developmental trajectory of these 2 groups., Objective: To characterize neurocognitive functions in 7-year-old children with FHR-SZ or FHR-BP and a control population., Design, Setting, and Participants: This multisite population-based cohort study collected data from January 1, 2013, to January 31, 2016, in the first wave of the Danish High Risk and Resilience Study VIA 7 at 2 university hospital research sites in Copenhagen and Aarhus using Danish registries. Participants (n = 514) included 197 children with FHR-SZ, 118 with FHR-BP, and 199 controls matched with the FHR-SZ group for age, sex, and municipality. Assessors were blinded to risk status., Exposures: Parents with schizophrenia, bipolar disorder, or neither diagnosis., Main Outcomes and Measures: Neurocognitive functions were measured across 23 tests. Four neurocognitive domains were derived by principal component analysis, including processing speed and working memory, verbal functions, executive and visuospatial functions, and declarative memory and attention., Results: A total of 514 children aged 7 years were included in the analysis (46.3% girls), consisting of 197 children with FHR-SZ (46.2% girls), 118 with FHR-BP (46.6% girls), and 199 controls (46.2% girls). Children with FHR-SZ were significantly impaired compared with controls on processing speed and working memory (Cohen d = 0.50; P < .001), executive and visuospatial functions (Cohen d = 0.28; P = .03), and declarative memory and attention (Cohen d = 0.29; P = .02). Compared with children with FHR-BP, children with FHR-SZ performed significantly poorer in processing speed and working memory (Cohen d = 0.40; P = .002), executive and visuospatial functions (Cohen d = 0.35; P = .008), and declarative memory and attention (Cohen d = 0.31; P = .03). Children with FHR-BP and controls did not differ., Conclusions and Relevance: Children with FHR-SZ had widespread neurocognitive impairments, supporting the hypothesis of neurocognitive functions as endophenotypes of schizophrenia. The absence of neurocognitive deficits in children with FHR-BP suggests distinct neurodevelopmental manifestations in these familial high-risk groups at this age. Early detection of children with FHR-SZ and cognitive impairments is warranted to investigate associations of neurocognition with transition to psychosis, add to the knowledge of their developmental pathophysiology, and inform early intervention programs.

Background: Offspring of parents with severe mental illness (SMI: schizophrenia, bipolar disorder or major depressive disorder) have an increased risk of developing mental disorder themselves. In childhood they may have neurodevelopmental delays, cognitive deficits and social adversities. We aimed to investigate if these individuals are more at risk of being diagnosed with a mental disorder during childhood/adolescence in a national sample., Methods: By linking Danish registers we established a cohort consisting of all persons born to parents with SMI with those born to parents without SMI serving as a reference group. Incidence rate ratios (IRRs) for offspring diagnosed with a mental disorder by parental mental disorder were calculated., Results: Offspring of parents with SMI showed increased IRR for all diagnoses of child and adolescent mental disorders compared to the reference group. Offspring of mothers with schizophrenia had IRR of 2.60 (CI: 2.50-2.70, N=2550) of having any diagnoses, for children of fathers with schizophrenia IRR was 2.06 (CI: 1.97-2.16, N=1901) and for offspring of two parents with schizophrenia IRR was 4.57 (CI: 3.94-5.31, N=175). For individuals with a mother with bipolar disorder the IRR was 2.29 (CI: 2.09-2.50, N=502), with a father 1.77 (CI: 1.74-1.87, N=320), whereas the IRR was 2.96 (CI: 2.63-3.34, N=264) if both parents had unipolar depression., Discussion: Offspring of parents with a SMI have a higher risk of being diagnosed with any child and adolescent mental disorder. The IRRs for all diagnoses during childhood were increased by a factor 2-4. Having two ill parents increased the IRR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Conversion from unipolar depression (UD) to bipolar disorder (BD) is a clinically important event that should lead to treatment modifications. Unfortunately, recognition of this transition is often delayed. Therefore, the objective of this study was to identify predictors of diagnostic conversion from UD to BD., Method: Historical prospective cohort study based on 91 587 individuals diagnosed with UD in Danish hospital psychiatry between 1995 and 2016. The association between a series of potential predictors and the conversion from UD to BD during follow-up (702 710 person-years) was estimated by means of Cox regression with death as competing risk., Results: During follow-up, 3910 individuals with UD developed BD. The cumulative incidence of conversion was slightly higher in females (8.7%, 95% CI: 8.2-9.3) compared to males (7.7%, 95% CI: 7.0-8.4). The strongest predictor of conversion from UD to BD was parental history of BD (adjusted hazard ratio (aHR) = 2.60, 95% CI: 2.20-3.07)). Other predictors included psychotic depression at the index UD episode (aHR = 1.73, 95% CI: 1.48-2.02), a prior/concomitant non-affective psychosis (aHR = 1.73, 95% CI: 1.51-1.99), and in-patient treatment at the index episode (aHR = 1.76, 95% CI: 1.63-1.91)., Conclusion: Diagnostic conversion from UD to BD is predicted by severe depression requiring in-patient treatment, psychotic symptomatology, and parental history of BD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The authors investigated the rates of conversion to schizophrenia and bipolar disorder after a substance-induced psychosis, as well as risk factors for conversion., Method: All patient information was extracted from the Danish Civil Registration System and the Psychiatric Central Research Register. The study population included all persons who received a diagnosis of substance-induced psychosis between 1994 and 2014 (N=6,788); patients were followed until first occurrence of schizophrenia or bipolar disorder or until death, emigration, or August 2014. The Kaplan-Meier method was used to obtain cumulative probabilities for the conversion from a substance-induced psychosis to schizophrenia or bipolar disorder. Cox proportional hazards regression models were used to calculate hazard ratios for all covariates., Results: Overall, 32.2% (95% CI=29.7-34.9) of patients with a substance-induced psychosis converted to either bipolar or schizophrenia-spectrum disorders. The highest conversion rate was found for cannabis-induced psychosis, with 47.4% (95% CI=42.7-52.3) converting to either schizophrenia or bipolar disorder. Young age was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar disorder occurred within 4.4 years., Conclusions: Substance-induced psychosis is strongly associated with the development of severe mental illness, and a long follow-up period is needed to identify the majority of cases.

Background: Hospitalizations for ambulatory care-sensitive conditions (ACSCs) and early rehospitalizations increase health care costs., Objectives: To determine if individuals with serious mental illnesses (SMIs) (eg, schizophrenia or bipolar disorder) are at increased risk for hospitalizations for ACSCs, and rehospitalization for the same or another ACSC, within 30 days., Research Design: Population-based cohort study., Participants: A total of 5.9 million Danish persons aged 18 years and older between January 1, 1999 and December 31, 2013., Measures: The Danish Psychiatric Central Register provided information on SMI diagnoses and the Danish National Patient Register on hospitalizations for ACSCs and 30-day rehospitalizations., Results: SMI was associated with increased risk for having any ACSC-related hospitalization after adjusting for demographics, socioeconomic factors, comorbidities, and prior primary care utilization [incidence rate ratio (IRR): 1.41; 95% confidence interval (95% CI), 1.37-1.45]. Among individual ACSCs, SMI was associated with increased risk for hospitalizations for angina (IRR: 1.14, 95% CI, 1.04-1.25), chronic obstructive pulmonary disease/asthma exacerbation (IRR: 1.87; 95% CI, 1.74-2.00), congestive heart failure exacerbation (IRR: 1.25; 95% CI, 1.16-1.35), and diabetes (IRR: 1.43; 95% CI, 1.31-1.57), appendiceal perforation (IRR: 1.49; 95% CI, 1.30-1.71), pneumonia (IRR: 1.72; 95% CI, 1.66-1.79), and urinary tract infection (IRR: 1.70; 95% CI, 1.62-1.78). SMI was also associated with increased risk for rehospitalization within 30 days for the same (IRR: 1.28; 95% CI, 1.18-1.40) or for another ACSC (IRR: 1.62; 95% CI, 1.49-1.76)., Conclusion: Persons with SMI are at increased risk for hospitalizations for ACSCs, and after discharge, are at increased risk for rehospitalizations for ACSCs within 30 days.

Objectives: A recent alarming finding suggested an increased risk of renal tumors among long-term lithium users. The objectives of the present study were to estimate rates of renal and upper urinary tract tumors (RUT), malignant and benign, among individuals exposed to successive prescriptions for lithium, anticonvulsants, and other psychotropic agents used for bipolar disorder, and among unexposed individuals., Methods: This was a nationwide, population-based longitudinal study including time-specific data from all individuals exposed to lithium (n = 24,272) or anticonvulsants (n = 386,255), all individuals with a diagnosis of bipolar disorder (n = 9,651), and a randomly selected sample of 1,500,000 from the Danish population. The study period was from 1995 to 2012, inclusive. Outcomes were hazard rate ratios (HR) for RUT in three groups: (i) combined malignant and benign, (ii) malignant, and (iii) benign. Analyses were adjusted for the number of prescriptions for lithium/anticonvulsants, antipsychotic agents, antidepressants, and use of all other types of medication; age; gender; employment status; calendar year; and a diagnosis of bipolar disorder., Results: Continued treatment with lithium was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.67-1.18, p (trend) = 0.70; adjusted HR malignant: 0.61-1.34, p (trend) = 0.90; adjusted HR benign: 0.74-1.18, p (trend) = 0.70]. Similarly, continued treatment with anticonvulsants was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.97-1.18, p (trend) = 0.10; adjusted HR malignant: 0.82-1.15, p (trend) = 0.80; adjusted HR benign: 0.94-1.36, p (trend) = 0.20]. The associations were confirmed among the 9,651 patients with a diagnosis of bipolar disorder., Conclusions: Treatment with lithium is not associated with increased rates of RUT., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics., Method: We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1-15 years among a cohort of 985 058 individuals born in Denmark 1971-1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed., Results: Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective., Conclusions: Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity.

Objective: To study how often severe psychiatric disorders adversely affect a person's ability to be a parent, indicated by the child being placed in out-of-home care., Method: This study was conducted in 2013 as a prospective, register-based cohort study covering all first-born singletons in the entire Danish population born after 1982 (N = 782,092) and their parents. Rates of out-of-home placement of children with parents diagnosed with schizophrenia, bipolar disorder, or unipolar depression, according to the criteria of the International Statistical Classification of Diseases and Related Health Problems, 8th revision (ICD-8) and ICD, 10th revision (ICD-10), were analyzed. The rates were compared with those of children with parents from the general population., Results: A parental diagnosis of schizophrenia was the most prominent risk factor for children placed outside the home, with an accumulated risk for being placed in care at some point during childhood-40% for children with mothers with schizophrenia and 20% for children with fathers with schizophrenia. Children of mothers (incidence rate ratio [IRR] = 23.75; 95% CI, 20.94-26.93) and fathers (IRR = 7.85; 95% CI, 6.67-9.25) with a diagnosis of schizophrenia had the overall highest IRRs of placement in care. Having a mother with bipolar disorder was the second most prominent risk factor (IRR = 5.76; 95% CI, 4.50-7.36), followed by a maternal diagnosis of unipolar depression (IRR = 4.28; 95% CI, 3.73-4.90). Risks were especially high during the child's first year of life, indicating a critical period, especially for children with mothers with schizophrenia (IRR = 80.19; 95% CI, 68.09-94.43). Risks varied greatly with parents' socioeconomic factors in all diagnostic groups., Conclusions: Parental schizophrenia is a strong risk factor for placement of children in out-of-home care., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Introduction: Childhood adversity is gaining increasing attention as a plausible etiological factor in the development of psychotic disorders. Childhood residential mobility is a potential risk factor that has received little attention in this context., Methods: We used registry data to estimate associations of residential mobility with narrow and broad schizophrenia and bipolar disorder across the course of childhood among 1.1 million individuals born in Denmark 1971-1991 and followed from age 15 through 2010. We assessed effect modification by sex, family history of mental disorder, the presence of siblings close in age, and distance moved., Results: In individual-year models adjusted for family history, urbanicity at birth, and parental age, mobility at all ages except the year of birth was associated with heightened risk of narrow and broad schizophrenia, and risk increased with age at moving and with the number of moves. Further adjustment for mobility at all ages 0-15 revealed associations mainly during the latter half of childhood, which were strongest during adolescence. Associations between mobility and bipolar disorder were fewer and weaker compared to schizophrenia. There was modest evidence of interaction with family history of psychiatric diagnosis, but little evidence for interaction by sex, the presence of closely-aged siblings, or distance moved. Schizophrenia associations did not appear attributable to increased mobility among adolescents with earlier onset., Conclusions: Mobility may increase risk for psychotic disorders, particularly schizophrenia. Children may be especially vulnerable during adolescence. Future research should investigate the importance of school changes and the potential for interaction with genetic risk., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The aim of the study was to explore the profile of acute and long-term psychiatric side effects associated with mefloquine., Methods: Subjects (n = 73) reported to a Danish national register during five consecutive years for mefloquine associated side effects were included. Acute psychiatric side effects were retrospectively assessed using the SCL-90-R and questions based on Present State Examination (PSE). Subjects reporting suspected psychotic states were contacted for a personal PSE interview. Electronic records of psychiatric hospitalizations and diagnoses were cross-checked. Long-term effects were evaluated with SF-36. SCL-90-R and SF-36 data were compared to age- and gender matched controls., Results: In the SCL-90-R, clinically significant scores for anxiety, phobic anxiety and depression were found in 55%, 51%, and 44% of the mefloquine group. Substantial acute phase psychotic symptoms were found in 15% and were time-limited. Illusions/hallucinations were more frequently observed among women. Cases of hypomania/mania in the acute phase were 5.5%. Significant long-term mental health effects were demonstrated for the SF-36 subscales mental health (MH), role emotional (RE), and vitality (VT) in the mefloquine group compared to matched controls., Conclusion: The most frequent acute psychiatric problems were anxiety, depression, and psychotic symptoms. Data indicated that subjects experiencing acute mefloquine adverse side effects may develop long-term mental health problems with a decreased sense of global quality of life with lack of energy, nervousness, and depression., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular (CV) co-morbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area are sparse., Method: We used Danish population registers to calculate incidence rate ratios (IRRs) for CV drug use, and mortality rate ratios comparing subjects with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization., Results: IRRs for CV prescriptions were significantly decreased in patients with schizophrenia or bipolar disorder compared with the general population. Among persons without previous myocardial infarction (MI) or cerebrovascular disease, persons with schizophrenia or bipolar disorder had an up to 6- and 15-fold increased mortality from all causes or unnatural causes, respectively, compared with the general population, being most pronounced among those without CV treatment (16-fold increase). Among those with previous MI or cerebrovascular disease, excess all-cause and unnatural death was lower (up to 3-fold and 7-fold increased, respectively), but was similar in CV-treated and -untreated persons., Conclusions: The present study shows an apparent under-prescription of most CV drugs among patients with schizophrenia or bipolar disorder compared with the general population in Denmark. The excess of mortality by unnatural deaths in the untreated group suggests that the association between CV treatment and mortality may be confounded by severity of illness. However, our results also suggest that treatment of CV risk factors is neglected in these patients.

Objective: Studies investigating the relationship between head injury and subsequent psychiatric disorders often suffer from methodological weaknesses and show conflicting results. The authors investigated the incidence of severe psychiatric disorders following hospital contact for head injury., Method: The authors used linkable Danish nationwide population-based registers to investigate the incidence of schizophrenia spectrum disorders, unipolar depression, bipolar disorder, and organic mental disorders in 113,906 persons who had suffered head injuries. Data were analyzed by survival analysis and adjusted for gender, age, calendar year, presence of a psychiatric family history, epilepsy, infections, autoimmune diseases, and fractures not involving the skull or spine., Results: Head injury was associated with a higher risk of schizophrenia (incidence rate ratio [IRR]=1.65, 95% CI=1.55-1.75), depression (IRR=1.59 95% CI=1.53-1.65), bipolar disorder (IRR=1.28, 95% CI=1.10-1.48), and organic mental disorders (IRR=4.39, 95% CI=3.86-4.99). This effect was larger than that of fractures not involving the skull or spine for schizophrenia, depression, and organic mental disorders, which suggests that the results were not merely due to accident proneness. Head injury between ages 11 and 15 years was the strongest predictor for subsequent development of schizophrenia, depression, and bipolar disorder. The added risk of mental illness following head injury did not differ between individuals with and without a psychiatric family history., Conclusions: This is the largest study to date investigating head injury and subsequent mental illness. The authors demonstrated an increase in risk for all psychiatric outcomes after head injury. The effect did not seem to be solely due to accident proneness, and the added risk was not more pronounced in persons with a psychiatric family history.

Objectives: Patients with unipolar psychotic depression (PD) are at high risk of developing bipolar disorder (BD). This conversion has important implications for the choice of treatment. This study, therefore, aimed to identify risk factors associated with diagnostic conversion from PD to BD., Methods: We conducted a population-based, historical prospective cohort study by merging data from Danish registers. Patients assigned an ICD-10 diagnosis of PD between 1 January 1995 and 31 December 2007 were identified in the Danish Central Psychiatric Research Register and were followed until the development of BD, death, loss to follow-up, or 31 December 2007. Potential risk factors for conversion to BD, also defined through various Danish registers, were tested in multiple logistic regression analyses with risk expressed as adjusted odds ratios (AOR)., Results: We identified 8,588 patients with PD, of whom 609 (7.1%) developed BD during follow-up. The following characteristics were significantly associated with diagnostic conversion from PD to BD: early onset of PD [AOR = 0.99 (per year of increasing age), p = 0.044], recurrent depression [AOR = 1.02 (per episode), p = 0.036], living alone (AOR = 1.29, p = 0.007), receiving a disability pension (AOR = 1.55, p < 0.001), and the highest educational level being a technical education (AOR = 1.55, p < 0.001), short-cycle higher education (AOR = 2.65, p < 0.001), or medium-cycle higher education (AOR = 1.75, p < 0.001)., Conclusions: Diagnostic conversion to BD was prevalent among patients with PD. The following characteristics were significantly associated with this conversion: early onset of PD, recurrent depression, living alone, receiving a disability pension, and the highest educational level being a technical education, short-cycle higher education, or medium-cycle higher education., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To determine incidence and age of onset of the ICD-10 category of 'acute and transient psychotic disorders' (ATPDs) characterised by subtypes with polymorphic, schizophrenic and predominantly delusional symptoms, pointing out differences from schizophrenia (SZ) and bipolar affective disorder (BD)., Methods: We identified all subjects aged 15-64 years who were listed for the first time in the Danish Psychiatric Register with a diagnosis of ATPDs (n = 3,350), SZ (n = 4,576) and BD (n = 3,200) in 1995-2008. Incidence rates and rate ratios (IRR; 95 % confidence interval) by gender and age were calculated., Results: The incidence of ATPDs was 6.7 per 100,000 person-years, similarly high for both genders (IRR 1.0; 0.9-1.1). Among the ATPD subtypes, polymorphic psychotic disorder was more common in females (IRR 1.4; 1.2-1.6) as opposed to those featuring schizophrenic symptoms, which tended to occur in younger males (IRR 1.4; 1.2-1.7). No significant gender difference was found for acute predominantly delusional disorder (IRR 1.0; 0.9-1.2), which had a later onset than any ATPD subtypes. SZ had an incidence twice as high in males (IRR 2.0; 1.9-2.2), and an earlier age of onset than ATPDs. A different pattern was observed for BD in terms of a slightly greater incidence in females (IRR 1.1; 1.0-1.1), and a later age of onset than both ATPDs and SZ., Conclusion: These findings are likely to reflect the heterogeneity of the clinical features encompassed by ATPDs, and contribute to building a case for their revision in ICD-11.