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Zusammenfassung. Hintergrund: Eine Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Kindesalter stellt einen Risikofaktor für Substanzmissbrauch und Störungen durch Substanzgebrauch (Substance Use Disorder, SUD) in der Pubertät und dem (frühen) Erwachsenenalter dar. ADHS und SUD treten auch häufig bei therapiesuchenden Jugendlichen auf, was die Diagnosestellung und Therapie erschwert sowie mit schlechten Behandlungsergebnissen verbunden ist. Forschungsergebnisse über die Wirkung der Behandlung von ADHS im Kindesalter auf die Prävention von SUD im Jugendalter sind nicht eindeutig und Studien über die Diagnose und Behandlung von Jugendlichen mit ADHS und SUD sind selten. Daher reicht die verfügbare Evidenz allgemein nicht aus, um starke Behandlungsempfehlungen zu rechtfertigen. Fragestellung: Ziel dieser Arbeit war es, eine Konsenserklärung auf der Grundlage von wissenschaftlichen Daten und klinischen Erfahrungen zu erhalten. Methodik: Es wurde eine modifizierte Delphi-Studie durchgeführt, um basierend auf der Kombination von wissenschaftlichen Daten und klinischer Erfahrung mit einer multidisziplinären Gruppe von 55 Expert_innen aus 17 Ländern einen Konsens zu erzielen. Die Expert_innen wurden gebeten, eine Reihe von Aussagen über die Wirkung der Behandlung von ADHS im Kindesalter auf die SUD bei Jugendlichen sowie über das Screening, die Diagnostik und die Behandlung von Jugendlichen mit komorbidem ADHS und SUD zu bewerten. Ergebnisse: Nach drei iterativen Bewertungsrunden und der Anpassung von 37 Aussagen wurde ein Konsens über 36 dieser Aussagen erzielt, die sechs Bereiche repräsentieren: allgemein ( n = 4), Risiko der Entwicklung einer SUD ( n = 3), Screening und Diagnostik ( n = 7), psychosoziale Behandlung ( n = 5), pharmakologische Behandlung ( n = 11) und komplementäre Behandlungen ( n = 7). Der Einsatz von Routinescreenings auf ADHS wird bei adoleszenten Patient_innen in einer Suchtbehandlung ebenso wie Routinescreenings auf SUD bei jugendlichen Patient_innen mit ADHS in allgemeinpsychiatrischen Therapiesettings empfohlen. Langwirksame Stimulanzien werden als Behandlung der ersten Wahl von ADHS bei Jugendlichen mit gleichzeitiger ADHS und SUD empfohlen. Die Pharmakotherapie sollte vorzugsweise in psychosoziale Behandlung eingebettet werden. Die einzige nichtkonsentierte Aussage betraf die Notwendigkeit von Abstinenz vor Beginn einer pharmakologischen Behandlung bei Jugendlichen mit ADHS und gleichzeitigem SUD. Im Gegensatz zur Mehrheit verlangten einige Expert_innen eine vollständige Abstinenz vor Beginn einer pharmakologischen Behandlung, einige waren gegen die Verwendung von Stimulanzien bei der Behandlung dieser Patient_innen (unabhängig von Abstinenz), während einige sich gegen die alternative Anwendung von Bupropion aussprachen. Schlussfolgerungen: Diese internationale Konsenserklärung kann von Kliniker_innen und Patient_innen zusammen in einem gemeinsamen Entscheidungsprozess genutzt werden, um die besten Interventionen auszuwählen und die bestmöglichen Ergebnisse bei adoleszenten Patient_innen mit gleichzeitiger ADHS und SUD zu erzielen.

ObjectivesWe investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of ADHD and/or ASD for future longitudinal research.DesignIndividuals with a childhood diagnosis of ADHD/ASD as recorded on routinely available healthcare datasets were compared with matched controls and a sample of directly assessed individuals with ADHD.SettingThis study utilised data from the Welsh Secure Anonymised Information Linkage (SAIL) Databank in Wales, UK. Routinely collected data from primary care, Emergency Department and hospital admissions were linked at person level.ParticipantsAll individuals in Wales, UK born between 01/01/1991 and 31/12/2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using ICD-10 and NHS Read codes and matched to three controls each and 154 individuals with ADHD recruited from an established research study.Outcome measuresRecorded service use for anxiety and depression, alcohol and drug use and self-harm including Emergency Department use in young adulthood (age 16 years to 25).Results7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); % and 0.9% of the population respectively. Cox’s regression analyses showed ADHD was associated with increased risks of anxiety/depression (HR:2.36, 95% CI:2.20,2.53), self-harm (HR: 5.70, 95% CI:5.07,6.40), alcohol (HR:3.95, 95%CI:3.42,4.56), drug use (HR:5.88, 95%CI:5.08,6.80) and Emergency department service use (HR:1.36, 95%CI:1.31,1.41). Those with ASD were at increased risk of anxiety/depression (HR:2.11, 95%CI: 1.91,2.34), self-harm (HR:2.93, 95%CI: 2.45,3.50) and drug use (HR:2.21, 95%CI: 1.66,2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort.ConclusionsOur identification strategy demonstrated the feasibility of establishing a large e-cohort of those with ADHD/ASD with expected patterns of poorer early adult outcomes, demonstrating a valid method of identifying large samples for future longitudinal studies without selective attrition.Article summaryStrengths and limitations of this studyThis study used population wide administrative data from a well-established and comprehensive databankData from both primary and secondary care was combinedThe study utilised a directly assessed sample of those with ADHD to help validate the establishment of the administratively identified sampleNot all individuals had passed through the whole follow up period at the end of the studyStudies utilising administrative data is dependent upon that data having been collected an recorded.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder, yet the interplay between ADHD polygenic risk scores (PRSs) and other risk factors remains relatively unexplored. The authors investigated associations, confounding, and interactions of ADHD PRS with birth-related, somatic, and psychosocial factors previously associated with ADHD.METHODS: Participants included a random general population sample (N=21,578) and individuals diagnosed with ADHD (N=13,697) from the genotyped Danish iPSYCH2012 case cohort, born between 1981 and 2005. The authors derived ADHD PRSs and identified 24 factors previously associated with ADHD using national registers. Logistic regression was used to estimate associations of ADHD PRS with each risk factor in the general population. Cox models were used to evaluate confounding of risk factor associations with ADHD diagnosis by ADHD PRS and parental psychiatric history, and interactions between ADHD PRS and each risk factor.RESULTS: ADHD PRS was associated with 12 of 24 risk factors (odds ratio range, 1.03-1.30), namely, small gestational age, infections, traumatic brain injury, and most psychosocial risk factors. Nineteen risk factors were associated with ADHD diagnosis (odds ratio range, 1.20-3.68), and adjusting for ADHD PRS and parental psychiatric history led to only minor attenuations. Only the interaction between ADHD PRS and maternal autoimmune disease survived correction for multiple testing.CONCLUSIONS: Higher ADHD PRS in the general population is associated with small increases in risk for certain birth-related and somatic ADHD risk factors, and broadly to psychosocial adversity. Evidence of gene-environment interaction was limited, as was confounding by ADHD PRS and family psychiatric history on ADHD risk factor associations. This suggests that the majority of the investigated ADHD risk factors act largely independently of current ADHD PRS to increase risk of ADHD.

Contains fulltext : 287461.pdf (Publisher’s version ) (Open Access) Clinical and genomic studies have shown an overlap between neuropsychiatric disorders and insulin resistance (IR)-related somatic conditions, including obesity, type 2 diabetes, and cardiovascular diseases. Impaired cognition is often observed among neuropsychiatric disorders, where multiple cognitive domains may be affected. In this review, we aimed to summarise previous evidence on the relationship between IR-related diseases/traits and cognitive performance in the large UK Biobank study cohort. Electronic searches were conducted on PubMed, Scopus, and Web of Science until April 2022. Eighteen articles met the inclusion criteria and were qualitatively reviewed. Overall, there is substantial evidence for an association between IR-related cardio-metabolic diseases/traits and worse performance on various cognitive domains, which is largely independent of possible confoundings. The most consistent findings referred to IR-related associations with poorer verbal and numerical reasoning ability, as well as slower processing speed. The observed associations might be mediated by alterations in immune-inflammation, brain integrity/connectivity, and/or comorbid somatic or psychiatric diseases/traits. Our findings provide impetus for further research into the underlying neurobiology and possible new therapeutic targets.

BACKGROUND: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum.METHODS: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers).RESULTS: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism-based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD.CONCLUSIONS: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.

This chapter summarizes the results and discusses the methodological issues related to prevalence studies on Tourette syndrome (TS) conducted during the past two decades. The best estimate for the prevalence of TS in school-age children is between 5 and 7 cases per 1,000. The prevalence of chronic motor tic disorder appears to range from 3 to 8 per 1,000, whereas estimates of prevalence for chronic vocal tic disorder in school-age children are less stable and await further study. Children with chronic tic disorders, even those with mild conditions, have a higher likelihood of other problems, such as attention-deficit/hyperactivity disorder, disruptive behavior, and obsessive–compulsive disorder. The classic two-stage design seems to be an acceptable approach for prevalence studies of TS and related tic disorders; however, this requires sample sizes greater than 5,000 to ensure relatively narrow confidence intervals. From a public health perspective, chronic tics may serve as a marker of neurodevelopmental vulnerability. Community-based studies that improve case finding and register-based studies may also improve our comprehension of the public health impact of tic disorders in children.

OBJECTIVE: Information on mental disorders over time is critical for documenting changes in population burden, and aiding understanding of potential causal and non-causal factors. The aim of this study was to provide temporal changes in the sex- and age-specific incidence rates (IR) of mental disorders diagnosed in Danish hospitals during five decades and investigate whether such changes may be attributable to changes in administrative reporting practice.METHODS: This population-based cohort study included all people living in Denmark between 1970 and 2016. Mental disorders diagnoses were obtained from the Danish Psychiatric Central Research Register. We estimated the IR of each mental disorder (all persons, and sex- and age-specific IRs) and examined the impact of two administrative changes.RESULTS: Our study included 9 107 157 people, followed for 233.0 million person-years. During follow-up, 9.5% were diagnosed with at least one mental disorder. The IR for any mental disorder was 39.0 per 10 000 person-years. Despite fluctuations, this increased between 1970-84 and 2005-2016, from 28.9 to 63.0 per 10 000 person-years. Increases were most pronounced for younger age groups. Administrative changes did appear to influence incidence rates.CONCLUSION: Mental disorder IRs have increased in Denmark since 1970, with age of diagnosis shifting downwards. Both trends were likely impacted by administrative changes, while the latter is likely to be (partly) attributable to earlier detection and increased reporting of child-onset conditions. Our findings may provide valuable context of the epidemiology of mental disorders across age groups for comparison with other studies and populations.

Objective: To estimate phenotypic and familial association between early-life injuries and attention-deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses.Methods: Children born in Denmark between 1995-2010 (n = 786,543) were followed from age 5 years until a median age of 14 years (interquartile range: 10-18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward-treated injuries by age 5. In a subset of ADHD cases and controls born 1995 to 2005 who had genetic data available (n = 16,580), we estimated incidence rate ratios (IRRs) for the association between PRS-ADHD and number of injuries before age 5 and the genetic correlation between ADHD and any injury before age 5.Results: Injuries were associated with ADHD (HR = 1.61; 95% CI, 1.55-1.66) in males (HR = 1.59; 1.53-1.65) and females (HR = 1.65; 1.54-1.77), with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs 3.1% (no injuries). ADHD was also associated with injuries in relatives, with a stronger association in first- than second-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population (IRR = 1.06; 1.00-1.14), with a genetic correlation of 0.53 (0.21-0.85).Conclusions: Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behavior remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD.

Contains fulltext : 287469.pdf (Publisher’s version ) (Open Access) Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

Genome-wide association studies (GWASs) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by examining the age-of-onset distribution and the age of the controls or the age of onset for cases. The age-of-onset distribution may also depend on information such as sex and birth year. In addition, family history is not routinely included in the assessment of control status. Here, we present LT-FH++, an extension of the liability threshold model conditioned on family history (LT-FH), which jointly accounts for age of onset and sex as well as family history. Using simulations, we show that, when family history and the age-of-onset distribution are available, the proposed approach yields statistically significant power gains over LT-FH and large power gains over genome-wide association study by proxy (GWAX). We applied our method to four psychiatric disorders available in the iPSYCH data and to mortality in the UK Biobank and found 20 genome-wide significant associations with LT-FH++, compared to ten for LT-FH and eight for a standard case-control GWAS. As more genetic data with linked electronic health records become available to researchers, we expect methods that account for additional health information, such as LT-FH++, to become even more beneficial.

Background Problems with sustained attention, impulsivity, and hyperactivity are the most prominent symptoms of attention-deficit hyperactivity disorder (ADHD), but many children with this diagnosis also present with poor organizational skills that are important in relation to school. These problems tend to increase from childhood to adolescence and are often not well managed by medication. Organizational skills training (OST) is a range of behavioral interventions that specifically target organizational skills deficits. Evidence supports the effect of OST on improving organizational skills, inattention, and academic performance in children with ADHD. Because previous clinical trials included mostly children above the age of 8 years, this trial includes children in the age range 6–13 years to expand the knowledge on the effects of OST in younger children. Previous OST research has also shown improvement on inattention in parent ratings; we will investigate if a change in inattention can be confirmed with neurocognitive tests. Finally, little is known about predictors of treatment response in OST. Objectives The primary objective is to investigate if OST has positive effects on organizational skills in children with ADHD. The primary outcome measurement is the parent-rated Children’s Organizational Skills Scale (COSS), collected before and at the end of the 10 week intervention. Secondary and exploratory outcomes include inattention ratings, family and school functioning, and cognitive functions measured before the intervention period, immediately after, and at a 6 month follow-up. Additional objectives are to investigate both neurocognitive outcomes and age as predictors of treatment response. Methods This is a randomized clinical superiority trial investigating the effect of OST vs a treatment-as-usual (TAU) control group for children with ADHD in the age range of 6–13 years. All participants (n = 142) receive TAU. OST is administered in a group format of 10 weekly sessions. Adverse events are monitored by study clinicians during weekly therapy sessions and all assessments. Data analyses will be conducted using mixed linear regression models with random intercepts for patients, adjusted for the stratification variables and the baseline value. Perspectives This study will provide important new knowledge and expand on existing research in the field of non-pharmacological treatment of children with ADHD. OST can potentially have a significant impact on the lives of children with ADHD by helping them learn how to cope with their present deficits and to become more independent and self-reliant. It is also important to investigate predictors of treatment response in order to optimize OST. Trial registration ClinicalTrials.gov NCT03160378. Registered on May 19, 2017.

Background Attention deficit hyperactivity disorder (ADHD) is a highly heritable, neurodevelopmental disorder known to associate with more than double the risk of death compared with people without ADHD. Because most research on ADHD has focused on children and adolescents, among whom death rates are relatively low, the impact of a high polygenic predisposition to ADHD on accelerating mortality risk in older adults is unknown. Thus, the aim of the study was to investigate if a high polygenetic predisposition to ADHD exacerbates the risk of all-cause mortality in older adults from the general population in the UK. Methods Utilising data from the English Longitudinal Study of Ageing, which is an ongoing multidisciplinary study of the English population aged ≥ 50 years, polygenetic scores for ADHD were calculated using summary statistics for (1) ADHD (PGS-ADHDsingle) and (2) chronic obstructive pulmonary disease and younger age of giving first birth, which were shown to have a strong genetic correlation with ADHD using the multi-trait analysis of genome-wide association summary statistics; this polygenic score was referred to as PGS-ADHDmulti-trait. All-cause mortality was ascertained from the National Health Service central register that captures all deaths occurring in the UK. Results The sample comprised 7133 participants with a mean age of 64.7 years (SD = 9.5, range = 50–101); of these, 1778 (24.9%) died during a period of 11.2 years. PGS-ADHDsingle was associated with a greater risk of all-cause mortality (hazard ratio [HR] = 1.06, 95% CI = 1.02–1.12, p = 0.010); further analyses showed this relationship was significant in men (HR = 1.07, 95% CI = 1.00–1.14, p = 0.043). Risk of all-cause mortality increased by an approximate 11% for one standard deviation increase in PGS-ADHDmulti-trait (HR = 1.11, 95% CI = 1.06–1.16, p multi-trait and an increased risk of all-cause mortality was significant in men (HR = 1.10, 95% CI = 1.03–1.18, p = 0.003) and women (HR = 1.11, 95% CI = 1.04–1.19, p = 0.003). Conclusions A high polygenetic predisposition to ADHD is a risk factor for all-cause mortality in older adults. This risk is better captured when incorporating genetic information from correlated traits.

Background Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of heritable traits distributed in the general population. Due to the focus on children in the literature on ADHD and data constraints, to-date, almost no research focused on the relationship between ADHD-related outcomes in older adults from the general population. As ADHD is a highly heritable disorder, high genetic liability for ADHD may influence several important live domains in older adults; however, this question has not been investigated yet. Methods Using a population representative sample of 6332 individuals aged ≥50 with an average age 64.7 years (standard deviation (SD)=9.3, range=50–101) from the English Longitudinal Study of Ageing, we investigated relationships of genetic propensity to ADHD, as measured using polygenic score (PGS-ADHD), with several important life domains, such as occupational and social function, poor health, intimate relationships and cognition, which was measured employing tests for verbal memory and executive function. Information on physical health and socio-economic circumstances were self-reported by the participants; data on sexual activity and function were collected via the Sexual Relationships and Activities Questionnaire. Results Compared to participants with low PGS-ADHD, older adults with high polygenic predisposition to ADHD were at a greater risk of lower educational attainment (OR=1.29, 95%CI=1.29–1.68, p Conclusion This is the first study to show that having a higher polygenic predisposition for ADHD is associated with poorer health, low socioeconomic status, limited sexual activity, and lower cognitive performance in older adults. These results highlight high polygenic risk for ADHD as an important risk factor poor functioning in several important life domains including poor health.

Objective:\ud Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.\ud \ud Methods:\ud The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h2SNP).\ud \ud Results:\ud Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05–1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27–2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84–0.88) and increased rates of discontinuation (hazard ratio range, 1.19–1.45) and switch (hazard ratio range, 1.40–2.08). h2SNP estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.\ud \ud Conclusions:\ud The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study’s limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.

Contains fulltext : 237253.pdf (Publisher’s version ) (Open Access) Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment, and is associated with poor treatment outcomes. In this study, we provide a systematic review of controlled studies on the effectiveness of pharmacological, psychosocial, and complementary treatments of ADHD in adolescents with and without comorbid SUD. In addition, we review the longitudinal association between pharmacotherapy for childhood ADHD and the development of SUD in adolescence and early adulthood. We conducted a systematic review of the research literature published since 2000 using Medline, PsycINFO, and the Cochrane Database of Systematic Reviews databases to select randomized clinical trials, observational studies, and meta-analyses. The quality of the evidence from each study was rated using the SIGN grading system. Based on the limited evidence available, strong clinical recommendations are not justified, but provisionally, we conclude that stimulant treatment in children with ADHD may prevent the development of SUD in adolescence or young adulthood, that high-dose stimulant treatment could be an effective treatment for adolescents with ADHD and SUD comorbidity, that cognitive behavior therapy might have a small beneficial effect in these patients, and that alternative treatments are probably not effective. More studies are needed to draw definitive conclusions that will allow for strong clinical recommendations 37 p.

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

BackgroundADHD is multifactorial, yet the interplay ADHD polygenic risks scores (ADHD-PRS) and other ADHD associated risk-factors remains relatively unexplored. The aim of this study was to investigate associations, confounding and interactions of ADHD-PRS with birth, somatic and psychosocial risk-factors previously associated with ADHD.MethodsParticipants came from the Danish iPSYCH2012 case-cohort, including a randomly selected general population sample (N=21,578), and all ADHD cases with an ICD-10 diagnosis F90.0 (N=13,697), born in Denmark 1981-2005. We derived ADHD-PRS and identified 25 ADHD risk-factors in Danish national registers. Logistic regression was used to estimate associations of ADHD-PRS with each risk-factors in the general population. Cox models were applied in the full case-cohort to evaluate confounding of risk-factor associations by ADHD-PRS and family psychiatry history, and interactions between ADHD-PRS and each risk-factor.ResultsADHD-PRS was associated with 14 out of 25 ADHD risk-factors in the general population, e.g., maternal autoimmune disorder, mild traumatic brain injury (TBI), and most psychosocial risk-factors. In the full case-cohort, 21 risk-factors were associated with ADHD diagnosis. Adjusting for ADHD-PRS and parental psychiatric history only led to minor attenuations of these associations. Interactions were observed between ADHD-PRS and sex, maternal autoimmune disease, TBI, paternal employment and age at child-birth.ConclusionHigher ADHD-PRS is associated with exposure to certain birth and somatic ADHD risk-factors, and broadly to psychosocial adversity. Evidence of gene-environment interactions were weak and ADHD-PRS and/or family psychiatric history have limited confounding effect on ADHD risk-factor associations, suggesting that majority of the investigated risk-factors act largely independently of ADHD-PRS to increase risk of ADHD.

BACKGROUND: Type 2 diabetes was related with larger cognitive decline. However, other glycemic dysregulations showed inconsistent results. Our aim was to examine longitudinal associations between diabetes/glycemic status and cognitive function in older adults with metabolic syndrome. METHODS: We conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. Participants were categorized by diabetes status (no-diabetes, prediabetes, and 1c) levels were measured and antidiabetic medications were recorded. Linear and logistic regression models, adjusted by potential confounders, were fitted to assess associations between glycemic status and changes in cognitive function. RESULTS: Prediabetes status was unrelated to cognitive decline. However, compared to participants without diabetes, those with ≥5-year diabetes duration had greater reductions in the GCF (β=-0.11 [95%CI -0.16;-0.06]), processing speed and executive function measurements. Inverse associations were observed between baseline HOMA-IR and changes in the GCF (β=-0.0094 [95%CI -0.0164;-0.0023]), but also between HbA1c levels and changes in the GCF (β=-0.0610 [95%CI -0.0889;-0.0331]), the Mini-Mental test, and other executive function tests. Poor diabetes control was inversely associated with phonologic fluency. Sulfonylureas, but especially insulin use, were related to cognitive decline.CONCLUSIONS: Insulin resistance, diabetes status, longer diabetes duration, poor glycemic control, and insulin treatment were associated with worsening cognitive function at short-term in a population at high cardiovascular risk.TRIAL REGISTRATION: ISRCTN, ISRCTN89898870. Registered 28 May 2014 - Retrospectively registered, http://www.isrctn.com/ISRCTN89898870

Attention deficit hyperactivity disorder (ADHD) is a complex disorder with heterogeneous clinical presentations that manifest variability in long-term outcomes. The genetic contributions to this clinical heterogeneity, however, are not well understood. Here, we study 14 084 individuals diagnosed with ADHD to identify several genetic factors underlying clinical heterogeneity. One genome-wide significant locus was specifically associated with an autism spectrum disorder (ASD) diagnosis among individuals diagnosed with ADHD and it was not previously associated with ASD nor ADHD, individually. We used a novel approach to compare profiles of polygenic scores for groups of individuals diagnosed with ADHD and uncovered robust evidence that biology is an important factor in on-going clinical debates. Specifically, individuals diagnosed with ASD and ADHD, substance use disorder (SUD) and ADHD, or first diagnosed with ADHD in adulthood had different profiles of polygenic scores for ADHD and multiple other psychiatric, cognitive, and socio-behavioral traits. A polygene overlap between an ASD diagnosis in ADHD and cognitive performance was replicated in an independent, typically developing cohort. Our unique approach uncovered evidence of genetic heterogeneity in a widely studied complex disorder, allowing for timely contributions to the understanding of ADHD etiology and providing a model for similar studies of other disorders.

Attention deficit hyperactivity disorder (ADHD) is a complex disorder with heterogeneous clinical presentations that manifest variability in long-term outcomes. The genetic contributions to this clinical heterogeneity, however, are not well understood. Here, we study 14 084 individuals diagnosed with ADHD to identify several genetic factors underlying clinical heterogeneity. One genome-wide significant locus was specifically associated with an autism spectrum disorder (ASD) diagnosis among individuals diagnosed with ADHD and it was not previously associated with ASD nor ADHD, individually. We used a novel approach to compare profiles of polygenic scores for groups of individuals diagnosed with ADHD and uncovered robust evidence that biology is an important factor in on-going clinical debates. Specifically, individuals diagnosed with ASD and ADHD, substance use disorder (SUD) and ADHD, or first diagnosed with ADHD in adulthood had different profiles of polygenic scores for ADHD and multiple other psychiatric, cognitive, and socio-behavioral traits. A polygene overlap between an ASD diagnosis in ADHD and cognitive performance was replicated in an independent, typically developing cohort. Our unique approach uncovered evidence of genetic heterogeneity in a widely studied complex disorder, allowing for timely contributions to the understanding of ADHD etiology and providing a model for similar studies of other disorders.

We estimated the absolute and relative risk of sleep problems in children and adolescents with newly diagnosed neurodevelopmental disorders. This was a population-based cohort study of individuals born in Denmark in 1993-2014 and followed in nationwide registers in 2011-2016. We estimated the 5-year cumulative incidence of sleep problems in incident cases of attention-deficit/hyperactivity disorder (ADHD; n = 12,844), autism spectrum disorder (ASD; n = 8,073), oppositional defiant disorder/conduct disorder (ODD/CD; n = 2,234) and epilepsy (n = 3,709). Hazard ratios (HRs) for sleep problems were estimated by Cox regression. The 5-year risk of sleep problems was highest in ADHD (29.2%; 95% CI, 28.4-30.1), ASD (24.2%; 95% CI, 23.1-25.3) and ODD/CD (27.1% 95% CI, 25.0%-29.2%) and lowest in epilepsy (11.3%; 95% CI, 10.2%-12.6%). For ADHD and ASD, sleep problems were more common in females than in males. Furthermore, sleep problems were predicted by high parental socioeconomic status and varied with the geographical region of residence, suggesting that different clinical practices exist across Denmark and that sleep problems may be more likely to go undetected in families of lower socioeconomic position. Compared with individuals without these disorders, the likelihood of sleep problems was increased in individuals with ADHD (HR, 33.81; 95% CI, 32.78-34.87), ASD (HR, 16.77; 95% CI, 16.15-17.41), ODD/CD (HR, 14.73; 95% CI, 13.88-15.64) and epilepsy (HR, 6.01; 95% CI, 5.67-6.37). After mutual adjustment for comorbidity, HRs were attenuated, especially in ASD, ODD/CD and epilepsy when adjusted for ADHD, suggesting that the increased risk of sleep problems in individuals with ASD, ODD/CD and epilepsy is driven largely by comorbid ADHD.

BackgroundPersons diagnosed with attention-deficit hyperactivity disorder (ADHD) have been found to have an increased risk of suicidal behaviour, but the pathway remains to be thoroughly explored.AimsTo determine whether persons with ADHD are more likely to present with suicidal behaviour (i.e. suicide attempts and deaths by suicide) if they have a comorbid psychiatric disorder.MethodUsing nationwide registers covering the entire population of Denmark, this cohort study of 2.9 million individuals followed from 1 January 1995 until 31 December 2014, covers more than 46 million person-years. All persons aged ≥10 years with Danish-born parents were identified and persons with a diagnosis of ADHD were compared with persons without. Incidence rate ratios (IRRs) were calculated by Poisson regression, with adjustments for sociodemographics and parental suicidal behaviour.ResultsPersons with ADHD were followed for 164 113 person-years and 697 suicidal outcomes were observed. This group was found to have an IRR of suicidal behaviour of 4.7 (95% CI, 4.3–5.1) compared with those without ADHD. Persons with ADHD only had a 4.1-fold higher rate (95% CI, 3.5–4.7) when compared with those without any psychiatric diagnoses. For persons with ADHD and comorbid disorders the IRR was higher yet (IRR: 10.4; 95% CI, 9.5–11.4).ConclusionsThis study underlines the link between ADHD and an elevated rate of suicidal behaviour, which is significantly elevated by comorbid psychiatric disorders. In sum, these results suggest that persons with ADHD and comorbid psychiatric disorders are targets for suicide preventive interventions.Declaration of interestNone.

IMPORTANCE Individuals with mental disorders often develop comorbidityover time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity.OBJECTIVES To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age-and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice.DESIGN, SETTING. AND PARTICIPANTS This population-based cohort study included all individuals born in Denmark between January 1, 190 0, and December 31, 2015, and living in the country between January 1, 20 0 0, and December 31, 2016. The analyses were conducted between June 2017 and May 2018.MAIN OUTCOMES AND MEASURES Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, lOth Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% Cls were calculated using Cox proportional hazards regress on models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated.RESULTS A total of 5 940 778 persons were Included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1[25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% Cl, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years).CONCLUSIONS AND RELEVANCE Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental disorders with a considerable overlap in their genetic etiology. We dissected their shared and distinct genetic architecture by cross-disorder analyses of large data sets, including samples with information on comorbid diagnoses. We identified seven loci shared by the disorders and the first five genome-wide significant loci differentiating the disorders. All five differentiating loci showed opposite allelic directions in the two disorders separately as well as significant associations with variation in other traits e.g. educational attainment, items of neuroticism and regional brain volume. Integration with brain transcriptome data identified and prioritized several significantly associated genes. Genetic correlation of the shared liability across ASD-ADHD was strong for other psychiatric phenotypes while the ASD-ADHD differentiating liability correlated most strongly with cognitive traits. Polygenic score analyses revealed that individuals diagnosed with both ASD and ADHD are double-burdened with genetic risk for both disorders and show distinctive patterns of genetic association with other traits when compared to the ASD-only and ADHD-only subgroups. The results provide novel insights into the biological foundation for developing just one or both of the disorders and for driving the psychopathology discriminatively towards either ADHD or ASD.

BACKGROUND: Infectious mononucleosis is a clinical diagnosis characterized by fever, sore throat, lymph node enlargement and often prolonged fatigue, most commonly caused by Epstein-Barr virus infection. Previous studies have indicated that infectious mononucleosis can be followed by depression; however, large-scale studies are lacking. We used nationwide registry data to investigate the association between infectious mononucleosis and subsequent depression in this first large-scale study.METHODS: Prospective cohort study using nationwide Danish registers covering all 1,440,590 singletons born (1977-2005) in Denmark by Danish born parents (21,830,542 person-years' follow-up until 2016); where 12,510 individuals had a hospital contact with infectious mononucleosis. The main outcome measures were a diagnosis of major depressive disorder (ICD-8: 296.09, 298.09, 300.4; ICD-10: F32) requiring hospital contact.RESULTS: Infectious mononucleosis was associated with a 40% increased hazard ratio (HR) for a subsequent depression diagnosis in the fully adjusted model (HR: 1.40, 95% CI: 1.26-1.56;n = 358), when compared to unexposed individuals. The increased risk of being diagnosed with depression was significant to the periods one to four years after the infectious mononucleosis diagnosis (HR: 1.40, 95% CI: 1.17-1.67;n = 121) and ≥ five years (HR: 1.40, 95% CI: 1.22-1.61;n = 207). We did not find any differences according to age (p = 0.61) nor sex (p = 0.30).CONCLUSION: In this largest study to date, infectious mononucleosis in childhood or adolescence was associated with an increased risk of a subsequent depression. Our findings have important clinical implications and identifies youth with infectious mononucleosis as a group at high risk of later depression in young adulthood.

Genome-wide association studies (GWAS) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by examining the age-of-onset distribution and the age of the controls or the age-of-onset for cases. The age-of-onset distribution may also depend on information such as sex and birth year. In addition, family history is not routinely included in the assessment of control status. Here we present LT-FH++, an extension of the liability threshold model conditioned on family history (LT-FH), that jointly accounts for age-of-onset and sex, as well as family history. Using simulations, we show that, when family history and the age-of-onset distribution are available, the proposed approach yields large power gains over both LT-FH and genome-wide association study by proxy (GWAX). We applied our method to four psychiatric disorders available in the iPSYCH data, and to mortality in the UK Biobank, finding 20 genome-wide significant associations with LT-FH++, compared to 10 for LT-FH and 8 for a standard case-control GWAS. As more genetic data with linked electronic health records become available to researchers, we expect methods that account for additional health information, such as LT-FH++, to become even more beneficial.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21566-w

BACKGROUND: Access to green space has been hypothesized to have a beneficial impact on children's mental well-being and cognitive development. The underlying mechanisms of the mental health benefits of green space are not fully understood, but different pathways have been suggested, such as the psychologically restoring capacities of green space, the ability to facilitate physical activity and social cohesion, and the mitigation of exposure to air pollution.OBJECTIVES: In this nationwide cohort study, we investigated associations between residential green space in early childhood and a clinical diagnosis of attention deficit hyperactivity disorder (ADHD).METHODS: The cohort included individuals, who were born in Denmark between 1992 and 2007 ( n = 814,689 ) and followed for a diagnosis of ADHD from age 5, during the period 1997-2016. We used the normalized difference vegetation index (NDVI) as a measure of vegetation greenness surrounding each residential address in a quadratic area of 210 m × 210 m in which the residence was located in the center of the quadrate. Individual exposure to green space was calculated as the average of NDVI surrounding each individual's residential address (or addresses if more than one) between birth and the fifth birthday. Multilevel modeling was used to estimate the incidence rate ratios (IRRs) with 95% confidence intervals (CI) for ADHD, according to exposure level and adjusted for calendar time, age, sex, parental socioeconomic status, neighborhood level socioeconomic status, and urbanicity.RESULTS: Individuals living in areas defined by sparse green vegetation (lowest decile of NDVI) had an increased risk of developing ADHD, compared with individuals living in areas within the highest decile of NDVI ( IRR = 1.55 ; 95% CI: 1.46, 1.65). Adjusting for the known confounders attenuated the result, but the association remained ( IRR = 1.20 ; 95% CI: 1.13, 1.28).CONCLUSION: Our findings suggest that lower levels of green space in residential surroundings, during early childhood, may be associated with a higher risk of developing ADHD. https://doi.org/10.1289/EHP6729.