Comorbidity within mental disorders: a comprehensive analysis based on 145 990 survey respondents from 27 countries.

AIMS: Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys. METHODS: The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women. RESULTS: Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2-110.8, interquartile range = 6.0-19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1-2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs. CONCLUSIONS: Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.

The cost of mental disorders: a systematic review.

AIMS: To identify and synthesise the literature on the cost of mental disorders. METHODS: Systematic literature searches were conducted in the databases PubMed, EMBASE, Web of Science, EconLit, NHS York Database and PsychInfo using key terms for cost and mental disorders. Searches were restricted to January 1980-May 2019. The inclusion criteria were: (1) cost-of-illness studies or cost-analyses; (2) diagnosis of at least one mental disorder; (3) study population based on the general population; (4) outcome in monetary units. The systematic review was preregistered on PROSPERO (ID: CRD42019127783). RESULTS: In total, 13 579 potential titles and abstracts were screened and 439 full-text articles were evaluated by two independent reviewers. Of these, 112 articles were included from the systematic searches and 31 additional articles from snowball searching, resulting in 143 included articles. Data were available from 48 countries and categorised according to nine mental disorder groups. The quality of the studies varied widely and there was a lack of studies from low- and middle-income countries and for certain types of mental disorders (e.g. intellectual disabilities and eating disorders). Our study showed that certain groups of mental disorders are more costly than others and that these rankings are relatively stable between countries. An interactive data visualisation site can be found here: https://nbepi.com/econ. CONCLUSIONS: This is the first study to provide a comprehensive overview of the cost of mental disorders worldwide.

Smokin' hot: adolescent smoking and the risk of psychosis.

OBJECTIVE: Daily smoking has been associated with a greater risk of psychosis. However, we are still lacking studies to adjust for baseline psychotic experiences and other substance use. We examined associations between daily smoking and psychosis risk in a 15-year follow-up while accounting for these covariates in a prospective sample (N = 6081) from the Northern Finland Birth Cohort 1986. METHODS: Self-report questionnaires on psychotic experiences (PROD-screen), tobacco smoking and other substance use were completed when the cohort members were 15-16 years old. Tobacco smoking was categorized into three groups (non-smokers, 1-9 cigarettes and ≥10 cigarettes/day). Psychosis diagnoses were obtained from national registers until the age of 30 years. RESULTS: Subjects in heaviest smoking category were at increased risk of subsequent psychosis (unadjusted HR = 3.15; 95% CI 1.94-5.13). When adjusted for baseline psychotic experiences the association persisted (HR = 2.87; 1.76-4.68) and remained significant even after adjustments for multiple known risk factors such as cannabis use, frequent alcohol use, other illicit substance use, parental substance abuse, and psychosis. Furthermore, number of smoked cigarettes increased psychosis risk in a dose-response manner (adjusted OR = 1.05; 1.01-1.08). CONCLUSION: Heavy tobacco smoking in adolescence was associated with a greater risk for psychosis even after adjustment for confounders.

Psychotic experiences and religiosity: data from the WHO World Mental Health Surveys.

OBJECTIVES: Religiosity is often associated with better health outcomes. The aim of the study was to examine associations between psychotic experiences (PEs) and religiosity in a large, cross-national sample. METHODS: A total of 25 542 adult respondents across 18 countries from the WHO World Mental Health Surveys were assessed for PEs, religious affiliation and indices of religiosity, DSM-IV mental disorders and general medical conditions. Logistic regression models were used to estimate the association between PEs and religiosity with various adjustments. RESULTS: Of 25 542 included respondents, 85.6% (SE = 0.3) (n = 21 860) respondents reported having a religious affiliation. Overall, there was no association between religious affiliation status and PEs. Within the subgroup having a religious affiliation, four of five indices of religiosity were significantly associated with increased odds of PEs (odds ratios ranged from 1.3 to 1.9). The findings persisted after adjustments for mental disorders and/or general medical conditions, as well as religious denomination type. There was a significant association between increased religiosity and reporting more types of PEs. CONCLUSIONS: Among individuals with religious affiliations, those who reported more religiosity on four of five indices had increased odds of PEs. Focussed and more qualitative research will be required to unravel the interrelationship between religiosity and PEs.

Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience.

The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.

Gestational vitamin D deficiency and autism-related traits: the Generation R Study.

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l-1. Compared with the 25OHD sufficient group (25OHD>50 nmol l-1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, ß=0.06, P<0.001; cord blood n=1712, ß=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.

The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders.

The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

The role of genetic liability in the association of urbanicity at birth and during upbringing with schizophrenia in Denmark.

BACKGROUND: Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case-control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. METHODS: Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. RESULTS: Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], but not at birth (OR 1.09, 95% CI 0.95-1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18-2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97-1.78; overall p = 0.148). CONCLUSIONS: While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia.

The association between adolescent psychopathology and subsequent physical activity in young adulthood: a 21-year birth cohort study.

BACKGROUND: The beneficial effects of physical activity (PA) for both physical and mental wellbeing are well established. Given that adolescence presents a critical developmental period during which life-long patterns of PA become established, the exploration of the longitudinal impact of adolescent psychopathology on adult PA status is of interest. METHODS: We analysed prospective data from 3663 young adults who participated in the Mater-University of Queensland Study of Pregnancy. Psychopathology was measured using the Youth Self-Report (YSR) at age 14. Participants' engagement in three types of PA (vigorous exercise, moderate exercise and walking) at age 21 were dichotomised into either 'none' or 'any'. For our main analysis, we examined the association between the YSR score and subsequent PA engagement using logistic regression. We also conducted sensitivity analyses of longitudinal associations between the YSR internalising and externalising symptoms score at age 14 and PA engagement at age 21. RESULTS: We found no longitudinal association between the total YSR score at age 14 and PA engagement at age 21. In addition, there was no longitudinal association between the YSR internalising or externalising symptoms and PA engagement. CONCLUSION: Our findings suggest that there is no longitudinal association between adolescent psychopathology and PA in young adulthood.

The association between psychotic experiences and disability: results from the WHO World Mental Health Surveys.

OBJECTIVE: While psychotic experiences (PEs) are known to be associated with a range of mental and general medical disorders, little is known about the association between PEs and measures of disability. We aimed to investigate this question using the World Mental Health surveys. METHOD: Lifetime occurrences of six types of PEs were assessed along with 21 mental disorders and 14 general medical conditions. Disability was assessed with a modified version of the WHO Disability Assessment Schedule. Descriptive statistics and logistic regression models were used to investigate the association between PEs and high disability scores (top quartile) with various adjustments. RESULTS: Respondents with PEs were more likely to have top quartile scores on global disability than respondents without PEs (19.1% vs. 7.5%; χ2  = 190.1, P < 0.001) as well as greater likelihood of cognitive, social, and role impairment. Relationships persisted in each adjusted model. A significant dose-response relationship was also found for the PE type measures with most of these outcomes. CONCLUSIONS: Psychotic experiences are associated with disability measures with a dose-response relationship. These results are consistent with the view that PEs are associated with disability regardless of the presence of comorbid mental or general medical disorders.

The association between childhood adversities and subsequent first onset of psychotic experiences: a cross-national analysis of 23 998 respondents from 17 countries.

BACKGROUND: Although there is robust evidence linking childhood adversities (CAs) and an increased risk for psychotic experiences (PEs), little is known about whether these associations vary across the life-course and whether mental disorders that emerge prior to PEs explain these associations. METHOD: We assessed CAs, PEs and DSM-IV mental disorders in 23 998 adults in the WHO World Mental Health Surveys. Discrete-time survival analysis was used to investigate the associations between CAs and PEs, and the influence of mental disorders on these associations using multivariate logistic models. RESULTS: Exposure to CAs was common, and those who experienced any CAs had increased odds of later PEs [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.9-2.6]. CAs reflecting maladaptive family functioning (MFF), including abuse, neglect, and parent maladjustment, exhibited the strongest associations with PE onset in all life-course stages. Sexual abuse exhibited a strong association with PE onset during childhood (OR 8.5, 95% CI 3.6-20.2), whereas Other CA types were associated with PE onset in adolescence. Associations of other CAs with PEs disappeared in adolescence after adjustment for prior-onset mental disorders. The population attributable risk proportion (PARP) for PEs associated with all CAs was 31% (24% for MFF). CONCLUSIONS: Exposure to CAs is associated with PE onset throughout the life-course, although sexual abuse is most strongly associated with childhood-onset PEs. The presence of mental disorders prior to the onset of PEs does not fully explain these associations. The large PARPs suggest that preventing CAs could lead to a meaningful reduction in PEs in the population.

Mental disorders among college students in the World Health Organization World Mental Health Surveys.

BACKGROUND: Although mental disorders are significant predictors of educational attainment throughout the entire educational career, most research on mental disorders among students has focused on the primary and secondary school years. METHOD: The World Health Organization World Mental Health Surveys were used to examine the associations of mental disorders with college entry and attrition by comparing college students (n = 1572) and non-students in the same age range (18-22 years; n = 4178), including non-students who recently left college without graduating (n = 702) based on surveys in 21 countries (four low/lower-middle income, five upper-middle-income, one lower-middle or upper-middle at the times of two different surveys, and 11 high income). Lifetime and 12-month prevalence and age-of-onset of DSM-IV anxiety, mood, behavioral and substance disorders were assessed with the Composite International Diagnostic Interview (CIDI). RESULTS: One-fifth (20.3%) of college students had 12-month DSM-IV/CIDI disorders; 83.1% of these cases had pre-matriculation onsets. Disorders with pre-matriculation onsets were more important than those with post-matriculation onsets in predicting subsequent college attrition, with substance disorders and, among women, major depression the most important such disorders. Only 16.4% of students with 12-month disorders received any 12-month healthcare treatment for their mental disorders. CONCLUSIONS: Mental disorders are common among college students, have onsets that mostly occur prior to college entry, in the case of pre-matriculation disorders are associated with college attrition, and are typically untreated. Detection and effective treatment of these disorders early in the college career might reduce attrition and improve educational and psychosocial functioning.

Correlates of physical activity in people living with psychotic illness.

OBJECTIVE: In the light of the high prevalence of physical comorbidities in people with psychotic illness, there is a need to explore modifiable risk factors that may contribute to this disease burden. The benefits of physical activity to both physical and mental health have been well established. We aimed to examine the prevalence and correlates of physical activity in a national sample of adults living with psychotic illness. METHODS: Physical activity was assessed in 1801 people using the International Physical Activity Questionnaire. Participants were dichotomised into low and moderate-high physical activity groups and associations between physical activity and a range of sociodemographic, clinical and physical comorbidity variables were examined using logistic regression. RESULTS: More than half the participants were categorised in the moderate-high physical activity group with nearly half of the sample engaged in physical activity every day. There were significant associations between low physical activity and older age, unemployment, educational non-participation, antipsychotic medication use, social dysfunction, self-reported loneliness and obesity. However, there was no significant association between physical activity and sex, psychosis type, illness duration, physical comorbidity or negative symptoms. CONCLUSION: The findings from this study may inform future interventions designed to increase physical activity in people with psychotic illness.

Vitamin D status during fetal life and childhood kidney outcomes.

BACKGROUND/OBJECTIVES: Maternal vitamin D deficiency during pregnancy may influence offspring kidney health. We aimed to examine the associations of 25-hydroxyvitamin D (25(OH)D) blood levels during fetal life with kidney outcomes at school age. SUBJECTS/METHODS: This study was embedded in a population-based prospective cohort study among 4212 mother-child pairs. We measured maternal second trimester (18-25 weeks) and fetal cord blood (at birth) 25(OH)D levels. At a median age of 6.0 years, we measured children's combined kidney volume, glomerular filtration rate (eGFR) from creatinine and cystatin C serum levels, and microalbuminuria from albumin and creatinine urine levels. RESULTS: Of all mothers, 21.9% had severely deficient levels (25(OH)D <25.0 nmol/l), 25.7% had deficient levels (25.0-49.9 nmol/l), 25% had sufficient levels (50.0-74.9 nmol/l) and 27.4% had optimal levels (⩾75.0 nmol/l). Maternal 25(OH)D levels were not consistently associated with childhood combined kidney volume. Higher maternal 25(OH)D levels were associated with lower childhood eGFR (difference -0.94 ml/min per 1.73 m(2) (95% confidence interval, -1.73; -0.15) per 1 standard deviation (s.d.) increase in 25(OH)D). Maternal 25(OH)D levels were not associated with microalbuminuria. Cord blood 25(OH)D levels were not associated with childhood kidney outcomes. The associations of maternal 25(OH)D levels with childhood eGFR were partly explained by childhood vitamin D status. CONCLUSIONS: Our findings suggest that maternal 25(OH)D levels during pregnancy may influence childhood kidney outcomes. These results should be considered hypothesis generating. Further studies are needed to replicate the observations, to examine the underlying mechanisms and to identify the long-term clinical consequences.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: the Generation R Study.

BACKGROUND: Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma. OBJECTIVE: We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children. METHODS: We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6. RESULTS: Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]. CONCLUSION AND CLINICAL RELEVANCE: Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences.

Sociodemographic and clinical correlates of migrant status in adults with psychotic disorders: data from the Australian Survey of High Impact Psychosis.

OBJECTIVE: The links between migrant status and psychosis have attracted considerable attention in recent decades. The aim of the study was to explore the demographic and clinical correlates of migrant v. Australia-born status in individuals with psychotic disorders using a large community-based sample. METHOD: Data were drawn from a population-based prevalence survey of adults with psychotic disorders. Known as the Survey of High Impact Psychosis (SHIP), it was conducted in seven Australian catchment areas in 2010. Logistic regression was used for the main analyses, examining associations of migrant status with sociodemographic and clinical variables. RESULTS: Of the 1825 participants with psychotic disorders, 17.8% (n = 325) were migrants, of whom 55.7% (n = 181) were male. Compared to Australia-born individuals with psychosis, migrants were more likely to be currently married, to have completed a higher level at school, to have left school later, and to be employed with full-time jobs. Migrants with psychosis were either no different from or less impaired or disadvantaged compared to their Australian-born counterparts on a range of clinical and demographic variables. CONCLUSIONS: In a sample of individuals with psychotic disorders, there was no evidence to suggest that migrant status was associated with worse clinical or socio-economic outcomes compared to their native-born counterparts.