Age effects on autism heritability and etiological stability of autistic traits.

BACKGROUND: Autism and autistic traits onset in childhood but persist into adulthood. Little is known about how genetic and environmental factors influence autism and autistic traits into adulthood. We aimed to determine age effects on the heritability of clinically diagnosed autism and the etiological stability of autistic traits from childhood to adulthood using twin methods. METHODS: From 23,849 twin pairs in the Swedish Twin Register born between 1959 and 2010, we identified 485 individuals (1.01%, 31.5% female) with a clinical autism diagnosis. We estimated and compared the relative contribution of genetic, shared, and nonshared environmental influences to autism in childhood and adulthood. We further used multivariate twin analysis with four measurement points among 1,348 twin pairs in the longitudinal Twin Study of Child and Adolescent Development to assess the phenotypic and etiological stability of autistic traits - measured with three scales from the Child Behavior Checklist - from childhood to adulthood. RESULTS: Autism heritability was comparable from childhood, (96% [95% CI, 76-99%]) to adulthood (87% [67-96%]). Autistic traits were moderately stable (phenotypic correlation = 0.35-0.61) from childhood to adulthood, and their heritability varied between 52 and 71%. We observed stable as well as newly emerging genetic influences on autistic traits from ages 8-9 to 19-20, and unique nonshared environmental influences at each age. CONCLUSIONS: Genetic factors are important for autism and autistic traits in adulthood and separate genetic studies in adults are warranted.

Association of intellectual disability with violent and sexual crime and victimization: a population-based cohort study.

BACKGROUND: Intellectual disability (ID) is associated with violent and sexual offending and victimization, but the importance of neuropsychiatric comorbidity and severity of disability remains unclear. METHODS: In a register-based cohort study of people born in Sweden 1980-1991 (n = 1 232 564), we investigated associations of mild and moderate/severe ID with any, violent and sexual crimes, and with assault victimization, stratified by comorbid autism and attention deficit hyperactivity disorder (ADHD). We defined ID by attendance at a special school or registered diagnosis and obtained data on criminal convictions and injuries or deaths due to assaults from nationwide registers until end of 2013. RESULTS: Compared to people without ID, autism or ADHD, men and women with mild or moderate/severe ID and comorbid ADHD had elevated risks of violent crimes [range of hazard ratios (HRs) 4.4-10.4] and assault victimization (HRs 2.0-7.7). Women with mild ID without comorbidities or with comorbid autism also had elevated risks of violent crimes and victimization (HRs 1.8-4.6) compared to women without ID, autism or ADHD. The relative risks of sexual offending and victimization were elevated in men and women with ID without comorbidities (HRs 2.6-12.7). The highest risks for sexual offending in men (HRs 9.4-11.0) and for sexual assault victimization in women (HRs 11.0-17.1) related to ID and comorbid ADHD. CONCLUSIONS: The elevated risk of violent offending and assault victimization in people with ID is largely explained by comorbid ADHD, whereas ID is independently associated with sexual crimes and victimization, even though absolute risks are low.

A twin study of genetic and environmental contributions to attention-deficit/hyperactivity disorder over time.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time. METHODS: We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time. RESULTS: We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%-65%. No statistically significant changes in variance in screening diagnoses were observed. CONCLUSIONS: The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses.

Melatonin use and the risk of self-harm and unintentional injuries in youths with and without psychiatric disorders.

BACKGROUND: Sleep disorders in youth have been associated with increased risks of injury, including suicidal behavior. This study investigated whether melatonin, which is the most common medication for sleep disturbances in youth in Sweden, is associated with a decreased risk of injury. METHODS: This population-based cohort study included 25,575 youths who initiated melatonin treatment between ages 6 and 18. Poisson regression was used to estimate rate of injuries in the year prior to and following melatonin treatment initiation. A within-individual design was used to estimate relative risks by comparing injury risk in the last unmedicated month with injury risks in the 12 months after medication initiation. Analyses were stratified by sex, injury type, psychiatric comorbidities and age at melatonin-treatment initiation. RESULTS: While body injuries, falls and transport accident rates were comparable in the year before and after melatonin-treatment initiation, the risk of self-harm was highest in the months immediately prior to medication, and decreased thereafter. This was particularly prominent among adolescents with depression and/or anxiety, with females displaying greater absolute risks than males. Compared to the last unmedicated month, the 12 months post medication initiation had decreased relative risks for self-harm, with an IRR [95% CI] in the month following melatonin-treatment initiation of 0.46 [0.27-0.76] among adolescent females with psychiatric disorders, after excluding antidepressant users. CONCLUSIONS: Decreased risk of intentional self-harm was observed following melatonin-treatment initiation among females with depression and anxiety, suggesting that sleep interventions could be considered in an effort to reduce risk of self-harm in this population.

Individuals With Eosinophilic Esophagitis Are at Greater Risk of Later Psychiatric Disorder.

INTRODUCTION: Several gastrointestinal and allergic diseases have been linked to psychiatric disease, but there are limited data on psychiatric disease in eosinophilic esophagitis (EoE). Our aim was to study the association between EoE and later psychiatric disorders. METHODS: This was a population-based nationwide cohort study. Individuals with EoE diagnosed during 1989-2017 in Sweden (n = 1,458) were identified through the ESPRESSO histopathology cohort that represents all gastrointestinal biopsy reports in Sweden's 28 pathology departments. Individuals with EoE were matched with up to 5 reference individuals on sex, age, county, and calendar year (n = 6,436). Cox proportional hazard modeling estimated adjusted hazard ratios (HRs). In a secondary analysis, we compared individuals with EoE with their siblings to adjust for intrafamilial confounding. RESULTS: The median age at EoE diagnosis was 39 years, and 76% of the enrolled individuals with EoE were male. During a median follow-up of 4 years, 106 individuals with EoE (15.96/1,000 person-years) developed a psychiatric disorder compared with 331 reference individuals (10.93/1,000 person-years), corresponding to an HR of 1.50 (95% confidence interval = 1.20-1.87). The increased risk was seen in the first 5 years of follow-up, but not thereafter. The highest relative risks were seen in individuals diagnosed with EoE in childhood. Compared with siblings, individuals with EoE were at an increased risk of psychiatric disease (HR = 1.62; 95% confidence interval = 1.14-2.31). EoE was linked to mood disorders, anxiety disorder, and attention-deficit hyperactivity disorder. DISCUSSION: Individuals with EoE may be at greater risk of psychiatric disease than their siblings and the general population. This risk needs to be considered in clinical care to detect, prevent, and treat comorbidity.

Etiological links between autism and difficulties in initiating and maintaining sleep: a familial co-aggregation and twin study.

BACKGROUND: Difficulties initiating and maintaining sleep (DIMS) are frequent features of autism, yet little is known about why these conditions co-occur. One possibility is that they share etiological factors, yet this hypothesis remains to be tested using quantitative genetic designs. We thus investigated etiological links between autism and DIMS using familial co-aggregation and twin methods. METHODS: Twins, siblings, half-siblings, and cousins of 50,097 individuals with autism were identified from Swedish population registries. Their risk of DIMS, defined through diagnoses of insomnia and/or melatonin prescriptions, was then estimated. Twin analyses conducted on 15,279 child and adolescent twin pairs investigated etiological links between DIMS and ASD. RESULTS: 22.8% of autistic individuals had DIMS. Monozygotic co-twins of individuals with autism were most at risk of DIMS compared to the reference group (OR = 6.6 [2.5-17.4]), followed by dizygotic co-twins (OR = 2.6 [1.5-4.5]) and full siblings (OR = 2.5 [2.4-2.6]). Half-siblings and cousins of individuals with autism were least likely to have DIMS relative to the reference group (OR range = 1.3-1.5). Twin analyses estimated a correlation of 0.57 (0.53-0.61) between autism and DIMS, with a genetic correlation of 0.62 (0.60-0.68). These overlapping genetic factors explained 94% of the covariance between these conditions. Autistic traits also showed genetic overlap with DIMS. CONCLUSIONS: Our results suggest that shared genetic mechanisms underlie autism and DIMS, which may lead them to co-occur. Untangling the etiological overlap between these conditions has potential to assist in understanding the etiology of each condition, as well as their associated outcomes.

Familial risk and heritability of intellectual disability: a population-based cohort study in Sweden.

BACKGROUND: Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown. METHODS: A population-based family cohort study of 4,165,785 individuals born 1973-2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equation modeling was used to estimate heritability. RESULTS: Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30-408.53) for monozygotic twins, 16.47(13.32-20.38) for parents, 14.88(12.19-18.16) for children, 7.04(4.67-10.61) for dizygotic twins, 8.38(7.97-8.83) for full siblings, 4.56(4.02-5.16) for maternal, 2.90(2.49-3.37) for paternal half-siblings, 3.03(2.61-3.50) for nephews/nieces, 2.84(2.45-3.29) for uncles/aunts, and 2.04(1.91-2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74-6.46) and more severe ID (mild RR 9.15, 8.55-9.78, moderate RR 8.13, 7.28-9.08, severe RR 6.80, 5.74-8.07, and profound RR 5.88, 4.52-7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25-1.41 for brothers vs. sisters and RR 1.49, 1.34-1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93-0.98) of the variance in liability attributed to genetic influences. CONCLUSIONS: The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiological studies in ID.

Childhood-onset type 1 diabetes and attention-deficit/hyperactivity disorder with educational attainment: A population-based sibling-comparison study.

AIM: To examine the association of childhood-onset type 1 diabetes (T1D) and attention-deficit/hyperactivity disorder (ADHD) with educational outcomes from compulsory school to university. METHODS: Using multiple Swedish nationwide registers, we followed up on 1,474,941 individuals born in Sweden from 1981-1995 to December 31, 2013. Associations of T1D and ADHD with achieving educational milestones (from compulsory school to university) and school performances were estimated using logistic and linear regression models and sibling comparison models. RESULTS: Compared to their peers, children with both T1D and ADHD were less likely to achieve any of the educational attainments, including completing compulsory school (adjusted OR [aOR] [95% CI]: 0.43 [0.26, 0.72]), be eligible to and finishing upper secondary school (0.26 [0.19, 0.36], 0.24 [0.17, 0.35], respectively), and starting university (0.38 [0.17, 0.90]). The odds of achieving these educational milestones were substantially lower in children with ADHD alone (aORs: 0.14-0.44), but were slightly worse or no differences in children with T1D alone (aORs: 0.86-1.08). All associations above remained similar in the sibling comparison models. CONCLUSION: Children and adolescents with both T1D and ADHD had long-term educational underachievement, with ADHD being the major contributor. Our findings suggest the importance of assessing ADHD in children with T1D and targeted support for minimising the education gap between the affected children and their peers.

Poor glycaemic control is associated with increased risk of neurodevelopmental disorders in childhood-onset type 1 diabetes: a population-based cohort study.

AIMS/HYPOTHESIS: The aim of this study was to investigate the effect of childhood-onset type 1 diabetes on the risk of subsequent neurodevelopmental disorders, and the role of glycaemic control in this association. We hypothesised that individuals with poor glycaemic control may be at a higher risk of neurodevelopmental disorders compared with the general population, as well as compared with individuals with type 1 diabetes with adequate glycaemic control. METHODS: This Swedish population-based cohort study was conducted using data from health registers from 1973 to 2013. We identified 8430 patients with childhood-onset type 1 diabetes (diagnosed before age 18 years) with a median age of diabetes onset of 9.6 (IQR 5.9-12.9) and 84,300 reference individuals from the general population, matched for sex, birth year and birth county. Cox models were used to estimate the effect of HbA1c on the risk of subsequent neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disability. RESULTS: During a median follow-up period of 5.6 years, 398 (4.7%) individuals with type 1 diabetes received a diagnosis of any neurodevelopmental disorder compared with 3066 (3.6%) in the general population, corresponding to an adjusted HR (HRadjusted) of 1.31 (95% CI 1.18, 1.46) after additionally adjusting for other psychiatric morbidity prior to inclusion, parental psychiatric morbidity and parental highest education level. The risk of any neurodevelopmental disorder increased with HbA1c levels and the highest risk was observed in patients with mean HbA1c >8.6% (>70 mmol/mol) (HRadjusted 1.90 [95% CI 1.51, 2.37]) compared with reference individuals without type 1 diabetes. In addition, when compared with patients with diabetes with HbA1c <7.5% (<58 mmol/mol), patients with HbA1c >8.6% (>70 mmol/mol) had the highest risk of any neurodevelopmental disorder (HRadjusted 3.71 [95% CI 2.75, 5.02]) and of specific neurodevelopmental disorders including ADHD (HRadjusted 4.16 [95% CI 2.92, 5.94]), ASD (HRadjusted 2.84 [95% CI 1.52, 5.28]) and intellectual disability (HRadjusted 3.93 [95% CI 1.38, 11.22]). CONCLUSIONS/INTERPRETATION: Childhood-onset type 1 diabetes is associated with an increased risk of neurodevelopmental disorders, with the highest risk seen in individuals with poor glycaemic control. Routine neurodevelopmental follow-up visits should be considered in type 1 diabetes, especially in patients with poor glycaemic control.

Psychiatric Disorders in Patients With a Diagnosis of Celiac Disease During Childhood From 1973 to 2016.

BACKGROUND & AIMS: Few studies have explored the link between childhood celiac disease and long-term psychiatric comorbidities. We performed a population-based cohort study of associations between childhood celiac disease and psychiatric disorders and investigated whether risk persists into adulthood. METHODS: We performed a nationwide study in Sweden using data from the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. In this cohort, 19,186 children with a diagnosis of biopsy-verified celiac disease from 1973 through 2016 were identified from Sweden's 28 pathology departments. Each patient was matched with as many as 5 reference children (controls, n = 94,249). Data on psychiatric disorders were obtained from the patient register. We used Cox proportional modeling to estimate hazard ratios (HRs). RESULTS: During a median follow-up period of 12.3 years, 3174 children (16.5%) with celiac disease received a new diagnosis of a psychiatric disorder, compared with 13,286 controls (14.1%). Corresponding incidence rates were 12.2 per 1000 person-years (95% CI, 11.8-12.7) vs 10.3 per 1000 person-years (95% Cl, 10.2-10.5). Childhood celiac disease was associated with a 19% increase in risk of any psychiatric disorder (95% CI, 1.14-1.23); the increase in risk was observed in all childhood age groups. The highest HRs were seen in the first year after celiac diagnosis (HR, 1.70; 95% CI, 1.41-2.05). The risk increase persisted into adulthood (age, >18 y: HR, 1.11; 95% CI, 1.04-1.17). We found increased risks of mood disorders (HR, 1.20; 95% CI, 1.12-1.28), anxiety disorders (HR, 1.12; 95% CI, 1.06-1.19), eating disorders (HR, 1.34; 95% CI, 1.18-1.51), attention deficit hyperactivity disorder (HR, 1.29; 95% CI, 1.20-1.39), and autism spectrum disorder (HR, 1.47; 95% CI, 1.32-1.64). We found no statistically significant risk increase for psychotic disorders, psychoactive substance misuse, behavioral disorders, personality disorders, suicide attempt, or suicide. Celiac disease also was linked to an increased use of psychiatric drugs (HR, 1.34; 95% CI, 1.24-1.43). A conditional logistic regression found that psychiatric disorders also were more common before a diagnosis of celiac disease (odds ratio, 1.56; 95% CI, 1.39-1.76). CONCLUSIONS: Childhood celiac disease is associated with an increased risk of subsequent psychiatric disorders, which persists into adulthood. Mental health surveillance should be integral in the care of celiac disease.

Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders.

BACKGROUND: Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. METHODS: Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp ) and genetic associations (rg ), as well as the contribution of genetic influences to rp . RESULTS: The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg  = 0.73; 95% CI = 0.66-0.79). Moderate genetic correlations were estimated for anxiety disorders (rg  = 0.47; 95% CI = 0.33-0.61), depression (rg  = 0.52; 95% CI = 0.37-0.66), and intentional self-harm (rg  = 0.54; 95% CI = 0.36-0.71). CONCLUSIONS: ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

Celiac Disease Is Associated with Childhood Psychiatric Disorders: A Population-Based Study.

OBJECTIVES: To determine the risk of future childhood psychiatric disorders in celiac disease, assess the association between previous psychiatric disorders and celiac disease in children, and investigate the risk of childhood psychiatric disorders in siblings of celiac disease probands. STUDY DESIGN: This was a nationwide registry-based matched cohort study in Sweden with 10 903 children (aged <18 years) with celiac disease and 12 710 of their siblings. We assessed the risk of childhood psychiatric disorders (any psychiatric disorder, psychotic disorder, mood disorder, anxiety disorder, eating disorder, psychoactive substance misuse, behavioral disorder, attention-deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and intellectual disability). HRs of future psychiatric disorders in children with celiac disease and their siblings was estimated by Cox regression. The association between previous diagnosis of a psychiatric disorder and current celiac disease was assessed using logistic regression. RESULTS: Compared with the general population, children with celiac disease had a 1.4-fold greater risk of future psychiatric disorders. Childhood celiac disease was identified as a risk factor for mood disorders, anxiety disorders, eating disorders, behavioral disorders, ADHD, ASD, and intellectual disability. In addition, a previous diagnosis of a mood, eating, or behavioral disorder was more common before the diagnosis of celiac disease. In contrast, siblings of celiac disease probands were at no increased risk of any of the investigated psychiatric disorders. CONCLUSIONS: Children with celiac disease are at increased risk for most psychiatric disorders, apparently owing to the biological and/or psychological effects of celiac disease.

Are carriers of CYP21A2 mutations less vulnerable to psychological stress? A population-based national cohort study.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal recessive disorders with an incidence of one in 15 000. About one in 70 individuals in the general population are carriers of a severe CYP21A2 mutation. It has been suggested that this confers a survival advantage, perhaps as a result of increased activity in the hypothalamic-pituitary-adrenal axis. We investigated vulnerability to psychological stress in obligate carriers. METHOD: The Swedish CAH Registry encompasses more than 600 patients. Parents, that is obligate carriers of the CYP21A2 mutation, were identified through the Multigeneration Register. The diagnosis of the child was used as the psychological stressor. Psychiatric diagnoses before and after the birth of a child with CAH were compared to those of controls derived from (i) the general population, (ii) parents of children with hypospadias and (iii) parents of children with diabetes mellitus type 1 (T1DM). RESULTS: Parents of children with CAH had less risk of being diagnosed with any psychiatric disorder (OR, 0·6), an affective disorder (OR, 0·5) or substance misuse (OR, 0·5) after the diagnosis of the child, compared to the general population. Their risk was also decreased compared to parents of a child with hypospadias (OR, 0·6, 0·4 and 0·2, respectively) and parents of a child with T1DM (OR 0·7, 0·6 and 0·2, respectively). The CYP21A2 carriers had a lower risk of developing mood and stress-related disorders after the diagnosis of the child. CONCLUSION: Obligate CYP21A2 carriers had a reduced risk of a psychiatric diagnosis and were less vulnerable to a psychologically stressful situation, at least with respect to receiving a psychiatric diagnosis. This indicates a better ability to cope with psychological stress among heterozygous carriers of severe CYP21A2 mutations, which may contribute to the apparent survival advantage.

Psychiatric Disorders and Health-Related Quality of Life in Children With Type 1 Diabetes Mellitus.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a chronic condition with major effect on health-related quality of life (HRQoL) and mental health. In 1990s, high rates of psychiatric disorders were reported among children with T1DM. Little is known, however, about current prevalence of psychiatric disorders in children with T1DM and the relation between psychiatric diagnosis and HRQoL. OBJECTIVE: The aim of the study was to determine the prevalence of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) psychiatric disorders and the association between psychiatric comorbidity and HRQoL in the pediatric population with T1DM. METHODS: We conducted a cross-sectional study of 207 children, aged 8-18 years, diagnosed with T1DM. The presence of psychiatric disorders has been assessed by the standard diagnostic interview according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria. HRQoL was measured by the general and diabetes mellitus-specific modules of the Paediatric Quality of Life Inventory. RESULTS: Of the evaluated patients, 26.6% (N = 55) met the criteria for psychiatric disorders at the time of evaluation. The most common diagnoses were anxiety (N = 32; 15.5%) and mood disorders (N = 8; 3.9%). One-third of the patients (N = 66, 31.9%) met the criteria for at least 1 psychiatric diagnosis in their lifetime. The presence of psychiatric disorders was related to an elevated hemoglobin A1c level (8.6% vs 7.6%) and a lowered HRQoL level in the general pediatric quality of life inventory. In the diabetes mellitus-specific pediatric quality of life inventory, children with psychiatric disorders revealed more symptoms of diabetes mellitus, treatment barriers, and lower adherence than children without psychiatric disorders. CONCLUSIONS: T1DM in children is associated with a very high prevalence of psychiatric comorbidity, which is related to elevated hemoglobin A1c and lower HRQoL levels.

Hypospadias and increased risk for neurodevelopmental disorders.

BACKGROUND: Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. It has been previously unknown whether this common malformation is associated with increased psychiatric morbidity later in life. Studies of individuals with hypospadias also provide an opportunity to examine whether difference in androgen signaling is related to neurodevelopmental disorders. To elucidate the mechanisms behind a possible association, we also studied psychiatric outcomes among brothers of the hypospadias patients. METHODS: Registry study within a national cohort of all 9,262 males with hypospadias and their 4,936 healthy brothers born in Sweden between 1973 and 2009. Patients with hypospadias and their brothers were matched with controls by year of birth and county. The following outcomes were evaluated (1) any psychiatric (2) psychotic, (3) mood, (4) anxiety, (5) eating, and (6) personality disorders, (7) substance misuse, (8) attention-deficit hyperactivity disorder (ADHD), (9) autism spectrum disorders (ASD), (10) intellectual disability, and (11) other behavioral/emotional disorders with onset in childhood. RESULTS: Patients with hypospadias were more likely to be diagnosed with intellectual disability (OR 3.2; 95% CI 2.8-3.8), ASD (1.4; 1.2-1.7), ADHD (1.5; 1.3-1.9), and behavioral/emotional disorders (1.4; 1.2-1.6) compared with the controls. Brothers of patients with hypospadias had an increased risk of ASD (1.6; 1.3-2.1) and other behavioral/emotional disorders with onset in childhood (1.2; 0.9-1.5) in comparison to siblings of healthy individuals. A slightly higher, although not statistically significant, risk was found for intellectual disability (1.3; 1.0-1.9). No relation between other psychiatric diagnosis and hypospadias was found. CONCLUSIONS: This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability.

Neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency.

We describe a patient with dystonia and psychotic symptoms treated with standard doses of antipsychotics, who developed neuroleptic malignant syndrome (NMS). A 16-year-old male with a history of misuse of dextromethorphan and pseudoephedrine for recreational purpose presented with dystonia and a psychotic episode. Following continuous treatment with olanzapine (10 mg/day), repeated injections of levomepromazine (37.5 mg/day), and a single injection of haloperidol (2.5 mg), the patient developed NMS. Muscular rigidity, fever (up to 41 °C), hypotension (100/70 mmHg), tachycardia (120 beats per minute), tachypnea (26 breaths per minute), elevated leukocyte count (up to 16.6 × 10(3)/µL), and elevated serum creatinine phosphokinase (CPK) (up to 15,255 U/L) were observed. A diagnosis of NMS was made according to the DSM-IV TR criteria. Genotyping revealed that he was homozygous for a non-functional CYP2D6*4 allele. The case highlights the importance of therapeutic drug monitoring in identification and differentiation of drug-induced effects in psychiatric disorder to prevent NMS and its complications. In addition, genotyping of CYP2D6 might be considered in patients with symptoms suggestive of drug toxicity who are treated with neuroleptics metabolized via the CYP2D6 pathway, as carriage of one or more non-functional alleles may increase the risk for adverse reactions, such as NMS.

Substance use-related problems in mild intellectual disability: A Swedish nationwide population-based cohort study with sibling comparison.

Background: Evidence for substance use-related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use-related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. Methods: We conducted a population-based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use-related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use-related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol-related somatic disease, conviction for a substance-related crime, and substance-related death. Results: Individuals with mild intellectual disability had a higher risk of any substance use-related problem compared to the general population (HR, 1.81; 95% CI, 1.72-1.91), both in males (HR, 1.76; 95% CI, 1.65-1.89) and females (HR, 1.89; 95% CI, 1.74-2.05). The risks of substance use-related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21-8.24). The associations were attenuated in the sibling comparison models. Conclusions: Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use-related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use-related problems.

Maternal depressive symptoms predict acute hospitalization among children with type 1 diabetes.

OBJECTIVES: The aim of this study is to examine the impact of a mother's depressive symptoms on the risk of hospital admission of her child due to severe hypoglycemia or diabetic ketoacidosis. MATERIALS AND METHODS: One hundred sixty-six mothers of children with type 1 diabetes (T1DM) were evaluated using the Hamilton Depression Rating Scale (HDRS). All of the children were studied prospectively for acute diabetic complications. The optimal thresholds of HDRS mother's scores for prediction of the risk of child hospitalization were identified using the Receiver Operating Characteristic curve analysis. The time to hospital admissions were compared using the log-rank test for univariate and Cox's proportional hazard models for multivariate analysis of risk factors for hospitalization. RESULTS: At study entry age, diabetes duration and glycated hemoglobin (HbA1c) of the children equaled 13.5 ± 2.6 years, 4.1 ± 1.9 years and 7.8 ± 1.7%, respectively. Throughout the observation period 56 patients required at least one hospitalization due to acute complications. Median time of observation and time to the hospital admission were 46.3 [interquartile range (IQR) 32.2-57.7] and 13.2 (IQR 6.6-20.0) months, respectively. The best cutoff value of maternal depression in HDRS predictive for the risk of child hospitalization was above 12 points. The hazard ratio for hospitalization offered by the cutoff score for mother's depressive symptoms above threshold was 2.73 (95% confidence interval: 1.39-5.36). CONCLUSION: Children with T1DM whose mothers show high level of depressive symptoms are at an elevated risk for hospitalization due to acute diabetic complication.