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1.
Artigo em Inglês | MEDLINE | ID: mdl-31605387

RESUMO

BACKGROUND: A central nosological problem concerns the etiological relationship of emotional dysregulation with ADHD. Molecular genetic risk scores provide a novel method for informing this question. METHODS: Participants were 514 community-recruited children of Northern European descent age 7-11 defined as ADHD or non-ADHD by detailed research evaluation. Parents-rated ADHD on standardized ratings and child temperament on the Temperament in Middle Childhood Questionnaire (TMCQ) and reported on ADHD and comorbid disorders by semi-structured clinical interview. Categorical and dimensional variables were created for ADHD, emotional dysregulation (implicating disruption of regulation of both anger-irritability and of positive valence surgency-sensation seeking), and irritability alone (anger dysregulation). Genome-wide polygenic risk scores (PRS) were computed for ADHD and depression genetic liability. Structural equation models and computationally derived emotion profiles guided analysis. RESULTS: The ADHD PRS was associated in variable-centered analyses with irritability (ß = .179, 95% CI = 0.087-0.280; ΔR2  = .034, p < .0002), but also with surgency/sensation seeking (B = .146, 95%CI = 0.052-0.240, ΔR2 =.022, p = .002). In person-centered analysis, the ADHD PRS was elevated in the emotion dysregulation ADHD group versus other ADHD children (OR = 1.44, 95% CI = 1.03-2.20, Nagelkerke ΔR2  = .013, p = .033) but did not differentiate irritable from surgent ADHD profiles. All effects were independent of variation in ADHD severity across traits or groups. The depression PRS was related to oppositional defiant disorder but not to ADHD emotion dysregulation. CONCLUSIONS: Irritability-anger and surgency-sensation seeking, as forms of negative and positively valenced dysregulated affect in ADHD populations, both relate principally to ADHD genetic risk and not mood-related genetic risk.

2.
Mol Psychiatry ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628418

RESUMO

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.

3.
Transl Psychiatry ; 9(1): 242, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582733

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder caused by an interplay of genetic and environmental factors. Epigenetics is crucial to lasting changes in gene expression in the brain. Recent studies suggest a role for DNA methylation in ADHD. We explored the contribution to ADHD of allele-specific methylation (ASM), an epigenetic mechanism that involves SNPs correlating with differential levels of DNA methylation at CpG sites. We selected 3896 tagSNPs reported to influence methylation in human brain regions and performed a case-control association study using the summary statistics from the largest GWAS meta-analysis of ADHD, comprising 20,183 cases and 35,191 controls. We observed that genetic risk variants for ADHD are enriched in ASM SNPs and identified associations with eight tagSNPs that were significant at a 5% false discovery rate (FDR). These SNPs correlated with methylation of CpG sites lying in the promoter regions of six genes. Since methylation may affect gene expression, we inspected these ASM SNPs together with 52 ASM SNPs in high LD with them for eQTLs in brain tissues and observed that the expression of three of those genes was affected by them. ADHD risk alleles correlated with increased expression (and decreased methylation) of ARTN and PIDD1 and with a decreased expression (and increased methylation) of C2orf82. Furthermore, these three genes were predicted to have altered expression in ADHD, and genetic variants in C2orf82 correlated with brain volumes. In summary, we followed a systematic approach to identify risk variants for ADHD that correlated with differential cis-methylation, identifying three novel genes contributing to the disorder.

4.
Mol Psychiatry ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492941

RESUMO

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

5.
J Am Coll Health ; : 1-9, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498751

RESUMO

Objective: The prevalence of stimulant medication misuse is rising in college students. Motivations to use stimulant medications differ from motivation to use other substances such as alcohol or cannabis. However, no previous research has examined the impact of achievement goal orientation on stimulant misuse in college students. Participants: 309 college students (mean age = 18.9; 117 males) without an ADHD diagnosis were invited to participate. Methods: Participants completed an online research questionnaire that assessed factors associated with stimulant medication misuse as well as achievement goal orientations (Learning and Performance Orientations). Results: Approximately 12% endorsed a history of stimulant misuse within the past year. More males (17.1%) than females (9.4%) reported stimulant misuse. Those with and without a history of stimulant misuse differed on Performance Orientation (misuse > no misuse) yet were comparable on Learning Orientation. Conclusions: Having a higher Performance Orientation independently predicted stimulant misuse.

6.
JAMA Psychiatry ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31389973

RESUMO

Importance: A previous register-based study reported elevated all-cause mortality in attention-deficit/hyperactivity disorder (ADHD), but cause-specific risks and the potential associations of psychiatric comorbidities remain unknown. Objectives: To investigate the all-cause and cause-specific mortality risks in ADHD and to explore the potential role of psychiatric comorbidities. Design, Setting, and Participants: This prospective cohort study used Swedish national registers to identify 2 675 615 individuals born in Sweden from January 1, 1983, through December 31, 2009, as the study population, among whom 86 670 individuals (3.2%) received a diagnosis of ADHD during follow-up. Follow-up was completed December 31, 2013, and data were analyzed from October 2018 through March 2019. Exposures: Attention-deficit/hyperactivity disorder identified by first clinical diagnosis or first prescription of ADHD medications as recorded in Swedish registers. Clinical diagnosis of psychiatric comorbidity was available in the National Patient Register. Main Outcomes and Measures: All-cause and cause-specific mortalities and hazard ratios (HRs) using Cox proportional hazards regression models. Results: In the overall cohort of 2 675 615 individuals, 1 374 790 (51.4%) were male (57 919 with an ADHD diagnosis) and 1 300 825 (48.6%) were female (28 751 with an ADHD diagnosis). Mean (SD) age at study entry was 6.4 (5.6) years. During follow-up, 424 individuals with ADHD and 6231 without ADHD died, resulting in mortality rates of 11.57 and 2.16 per 10 000 person-years, respectively. The association was stronger in adulthood (HR, 4.64; 95% CI, 4.11-5.25) compared with childhood (HR, 1.41; 95% CI, 0.97-2.04) and increased substantially with the number of psychiatric comorbidities with ADHD (HR for individuals with only ADHD, 1.41 [95% CI, 1.01-1.97]; HR for those with ≥4 comorbidities, 25.22 [95% CI, 19.60-32.46]). In adulthood, when adjusting for early-onset psychiatric comorbidity, the association between ADHD and risk of death due to natural causes was attenuated substantially and was no longer statistically significant (HR, 1.32; 95% CI, 0.94-1.85). When adjusting for later-onset psychiatric disorders, the association was attenuated to statistical nonsignificance for death due to suicide (HR, 1.13; 95% CI, 0.88-1.45) but remained statistically significant for death caused by unintentional injury (HR, 2.14; 95% CI, 1.71-2.68) or other external causes (HR, 1.75; 95% CI, 1.23-2.48). Conclusions and Relevance: Psychiatric comorbidity appears to play an important role in all-cause and cause-specific mortality risks in ADHD. In adulthood, early-onset psychiatric comorbidity contributed primarily to the association with death due to natural causes, whereas later-onset psychiatric comorbidity mainly influenced death due to unnatural causes, including suicide and unintentional injury. These findings suggest that health care professionals should closely monitor specific psychiatric comorbidities in individuals with ADHD to identify high-risk groups for prevention efforts.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31468149

RESUMO

The objective of this study was to investigate the stability and predictive utility of autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD). Participants were referred youth with and without ADHD, without a diagnosis of autism spectrum disorder, and their siblings, derived from identically designed longitudinal case-control family studies of boys and girls with ADHD. Subjects were assessed with structured diagnostic interviews and measures of social, cognitive, and educational functioning. The presence of ATs at baseline was operationalized using a unique profile of the Child Behavior Checklist (CBCL) consisting of an aggregate T score of ≥ 195 on the Withdrawn, Social, and Thought Problems subscales (CBCL-AT profile). At the follow-up, 83% of the ADHD youth with a positive AT profile at baseline continued to have a positive CBCL-AT profile. The presence of a positive CBCL-AT profile at baseline in youth with ADHD heralded a more compromised course characterized by a greater burden of psychopathology that emerged at an earlier age, along with poorer interpersonal, educational, and neurocognitive outcomes. Findings indicate a high level of persisting ATs in ADHD youth over time, as indexed through the CBCL-AT profile, and the presence of this profile prognosticates a compromised course in adult life in multiple domains of functioning.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31421235

RESUMO

OBJECTIVE: Genomic discoveries should be investigated in generalizable child psychiatric samples to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined: 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRS) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRS with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRS manifest a distinctive clinical profile. METHOD: Participants were 433 youth, ages 7 to 18, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD GWAS to date. We replicated key findings in 5140 adult patients from a local health system biobank. RESULTS: Among referred youth, ADHD PRS associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (OR's ∼1.4; R2's ∼2-3%) as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRS associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than those with low burden (beta's∼.2). CONCLUSION: Among child and adolescent outpatients, ADHD polygenic risk associated with ADHD and related phenotypes as well as clinical severity. Results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.

9.
Int J Methods Psychiatr Res ; : e1794, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310449

RESUMO

OBJECTIVES: This study aims to ascertain whether the differences of prevalence and severity of attention deficit hyperactivity disorder (ADHD) are true or whether children are perceived and rated differently by parent and teacher informant assessments (INFAs) according to gender, age, and co-occurring disorders, even at equal levels of latent ADHD traits. METHODS: Use of latent trait models (for binary responses) to evaluate measurement invariance in children with ADHD and their siblings from the International Multicenter ADHD Gene data. RESULTS: Substantial measurement noninvariance between parent and teacher INFAs was detected for seven out of nine inattention (IA) and six out of nine hyperactivity/impulsivity (HI) items; the correlations between parent and teacher INFAs for six IA and four HI items were not significantly different from zero, which suggests that parent and teacher INFAs are essentially rating different kinds of behaviours expressed in different settings, instead of measurement bias. However, age and gender did not affect substantially the endorsement probability of either IA or HI symptom criteria, regardless of INFA. For co-occurring disorders, teacher INFA ratings were largely unaffected by co-morbidity; conversely, parental endorsement of HI symptoms is substantially influenced by co-occurring oppositional defiant disorder. CONCLUSIONS: Our findings suggest general robustness of Diagnostic and Statistical Manual of Mental Disorders ADHD diagnostic items in relation to age and gender. Further research on classroom presentations is needed.

10.
J Adolesc Health ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31350122

RESUMO

PURPOSE: The aim of the study was to help quantify the protective effects of stimulant treatment on important functional outcomes in attention-deficit/hyperactivity disorder (ADHD) using the number needed to treat (NNT) statistic and examine whether these effects are moderated by sex. METHODS: Subjects were derived from three independent samples, two similarly designed case-control, 10-year prospective follow-up studies of boys and girls with and without ADHD grown up and a cross-sectional randomized clinical trial of lisdexamfetamine on driving performance and behavior. For all studies, subjects were evaluated with structured diagnostic interviews. To measure psychopharmacologic treatment in the follow-up studies, we collected information about each subject's stimulant medication use, age at onset, and age at termination of treatment. Subjects in the driving study underwent two driving simulation assessments (premedication and after 6 weeks of treatment on lisdexamfetamine or placebo). For each outcome, we ran a logistic regression model that included an interaction between sex and treatment status. Lifetime rates were used to calculate the NNT statistic. We also calculated adjusted NNT statistics that accounted for sex, age, socioeconomic status, and family intactness. RESULTS: The NNTs were very low, ranging from 3 to 10. No interaction effects with sex were detected (all p > .05). The adjusted NNTs mostly remained the same with the exception of any substance use disorder, which increased after controlling for age. CONCLUSIONS: Stimulants have strong protective effects on functional outcomes in youth with ADHD that are not moderated by sex. These results support the critical importance of early identification and treatment of children with ADHD of both sexes.

11.
J Psychiatr Res ; 117: 15-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31272014

RESUMO

The objective of this study was to investigate the prevalence and clinical correlates of ADHD patients with mind wandering. 255 consecutively referred 18- to 55-year-old adults of both sexes with ADHD were assessed. Subjects completed a demographic interview, the Mind Wandering Questionnaire (MWQ), the ADHD Rating Scale (ADHD RS), the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A), the Social Responsiveness Scale - Second Edition (SRS-2) Adult Self-Report Form, the Adult Self-Report (ASR), the Barkley Emotional Dysregulation Scale, and the Quality of Life Enjoyment & Satisfaction Questionnaire (Q-LES-Q). We used receiver operator characteristic (ROC) curves to identify the optimal cut-off on the MWQ to categorize patients as having high-versus low-level mind wandering and compared demographic and clinical characteristics between the two groups. Participants were categorized by ROC analysis as having high- (N = 127) and low-level (N = 128) mind wandering based on an MWQ total score ≥ or < than 24, respectively. Compared with low-level mind wandering participants, those with high-level mind wandering had significantly more Inattentive and Hyperactive symptoms (all p < 0001), worse executive functioning as measured by the BRIEF-A, more impaired mean (all p ≤ 0.001) and dichotomized scores (t-score ≥65) (all p < 0.005) on subscales and composite ASR scales, more impaired scores on the Barkley Emotional Dysregulation Scale (p < 0.001), and more impaired quality of life scores. High-level mind wandering is prevalent in adults with ADHD and is associated with more severe ADHD symptoms, more executive function deficits, more emotional dysregulation, higher levels of associated psychopathology, and more impaired quality of life.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31326580

RESUMO

OBJECTIVE: To review all literature on the nonmedical use (NMU) and diversion of prescription stimulants to better understand the characteristics, risk factors, and outcomes of NMU and review risk-reduction strategies. METHOD: We systematically searched PubMed, PsycINFO, and SCOPUS from inception to May 2018 for studies containing empirical data about NMU and diversion of prescription stimulants. Additional references identified by the authors were also assessed for inclusion. RESULTS: 109 studies met inclusion criteria. NMU and diversion of stimulants are highly prevalent; self-reported rates among population samples range from 2.1%-58.7% and 0.7%-80.0%, respectively. A variety of terms are used to describe NMU, and most studies have examined college students. Whereas most NMU is oral, non-oral NMU also occurs. The majority of NMU is associated with no, or minor, medical effects; however adverse medical outcomes, including death, occur in some individuals, particularly when administered by non-oral routes. Although academic and occupational performance enhancement are the most commonly cited motivations, there is little evidence that academic performance is improved by NMU in individuals without ADHD. CONCLUSION: NMU of stimulants is a significant public health problem, especially in college students, but variations in the terms used to describe NMU and inconsistencies in the available data limit a better understanding of this problem. Further research is needed to develop methods that detect NMU, identify individuals at greatest risk, study routes of administration, and devise educational and other interventions to help reduce occurrence of NMU. Colleges should consider including NMU in academic integrity policies.

13.
J Atten Disord ; 23(11): 1219-1228, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31169052

RESUMO

Objective: To describe consequences of the nonmedical use (NMU) of prescription amphetamines (AMPs). Method: Data from the U.S. National Poison Data System yielded four groups: intravenous NMU (IV NMU) intentionally injected AMP, Nasal NMU intentionally inhaled AMP but did not inject, Oral NMU intentionally ingested AMP, and controls reported unintentional oral exposure to AMP. Results: The Nasal NMU group was at greater risk of admission to a health care facility. All NMU groups were at greater risk for adverse clinical effects. IV NMU had the greatest number of adverse effects, followed by Nasal and Oral NMU. Nasal NMU had a greater risk for major medical outcomes versus Oral NMU. The IV NMU group was 21.9 times more likely to die from AMP NMU than controls. Oral NMU conferred a significantly greater risk of suicide attempts. Conclusion: Oral and nonoral NMU of AMP are associated with significant risks of morbidity and mortality.

14.
Psychiatr Serv ; 70(10): 874-880, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31242830

RESUMO

OBJECTIVE: The objective of this study was to evaluate rates and correlates of stimulant medication adherence in a sample of pediatric patients using data derived from electronic medical records (EMRs) from a large health care organization in a large metropolitan area. The study relied on a novel definition of medication adherence as a timely renewal of an index prescription determined using the electronically recorded issuance of a stimulant prescription in the EMR ("refill"). METHODS: Prescription and sociodemographic data were extracted from the Partners HealthCare Research Patient Data Registry to calculate adherence to stimulant medication treatment. RESULTS: In the EMR, 2,206 patients with prescriptions for central nervous system stimulant medication were identified. Results showed that 46% of the index prescriptions were refilled within the timeframe necessary for the patient to be considered consistently medicated. A multivariable logistic regression model predicting medication adherence from patient demographic and treatment characteristics yielded an area-under-the-curve statistic of 0.57, indicating that these characteristics predicted adherence only modestly better than chance. CONCLUSIONS: EMR data from a large health care organization showed that 46% of pediatric patients were adherent to treatment with stimulants. Rates of medication adherence were worse among patients receiving care from a primary care provider than among those receiving care from a psychiatrist, in older patients, and in female patients and did not appear to be influenced by racial-ethnic group, economic class, stimulant type, or medication formulation (short or long acting). These findings, which show low rates of medication adherence among children and adolescents with ADHD, suggest the need for efforts to improve these rates.

15.
J Clin Psychopharmacol ; 39(4): 351-356, 2019 Jul/Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31162154

RESUMO

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a prevalent neurobiological disorder associated with a wide range of adverse outcomes. Although large data sets document that stimulants decrease the risks for many ADHD-associated adverse outcomes, compliance with stimulants remains very poor. The main aim of this study was to assess the effectiveness of a novel text messaging-based intervention aimed at improving the poor rate of adherence to stimulant medications in adults with ADHD. METHODS: Subjects were adults with ages 18 to 55, prescribed a stimulant medication for ADHD treatment. For comparators, we identified at a 5-to-1 ratio (age and sex matched) adult patients from the Partners HealthCare electronic medical record who had been prescribed stimulant medications over a 1-year period. We determined whether patients had timely prescription refills, defined as refilled within 37 days, using prescriptions documented in their electronic medical record. RESULTS: Our results showed that 68% of the SMS intervention group refilled their prescriptions in a timely manner. In contrast, only 34% of patients receiving treatment as usual refilled their prescriptions in a timely fashion (odds ratio, 4.04; 95% confidence interval, 2.49-6.56; P < 0.001). CONCLUSIONS: These data indicate that an innovative ADHD-centric text messaging intervention significantly improved patient engagement to treatment with stimulants in adults with ADHD. Findings provide strong support for the use of a readily accessible, inexpensive, and widely available technology to improve the poor rate of adherence to stimulant treatment in adults with ADHD. To the best of our knowledge, this study is the first digital health intervention aimed at improving adherence to stimulant medication for adults with ADHD.

16.
J Clin Psychiatry ; 80(3)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087826

RESUMO

BACKGROUND: Prior follow-up studies of attention-deficit/hyperactivity disorder (ADHD) have mostly been from North America. They have provided a good deal of information about ADHD, but whether these results generalize to population samples and to other countries is not certain. Most prior studies have also not assessed predictors of possible new onsets of ADHD in non-ADHD youth or the validity of subthreshold forms of the disorder. METHODS: 1,012 families were recruited at baseline, when a telephone interview assessed a child in the 6-12 years age range. The interview covered symptoms of ADHD, conduct disorder, and oppositional defiant disorder as well as family living situation, school performance, sleep disturbance, eating habits, use of supplemental iron, and history of ADHD treatment. Nine years later, the persistence of ADHD and its impairments and the emergence of new conditions were assessed. DSM-5 diagnostic criteria were used to diagnose ADHD. RESULTS: 492 of the 1,012 participants seen at baseline were followed up 9 years later, at a mean age of 18 years. At follow-up, 16.7% of the children diagnosed with ADHD at baseline met full criteria for ADHD and 11.1% met criteria for subthreshold ADHD, yielding a persistence rate of 27.8%. Among children not diagnosed with ADHD at baseline, 1.1% met criteria for ADHD at follow-up. The persistence of ADHD and new onsets of ADHD were predicted by several baseline clinical features and by a family history of ADHD. CONCLUSIONS: We replicated predictors of the persistence of ADHD found in prior studies and provide new data about predictors of new ADHD onsets in the population. Our findings about subthreshold ADHD support a dimensional conceptualization of the disorder, highlighting the potential clinical utility of a subthreshold diagnostic category. This study also contributes to the ongoing debate regarding adult-onset ADHD.

17.
J Clin Psychiatry ; 80(3)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31090281

RESUMO

OBJECTIVE: Sleep disturbances are a feature of attention-deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate treatment. The authors sought to clarify methylphenidate-associated sleep problems and how studies are affected by confounding factors. DATA SOURCES: Published studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and US Food and Drug Administration websites. Sources were searched from inception to August 2017. STUDY SELECTION: Included were blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings, leading to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3,079 drug-exposed and 2,606 placebo-treated patients. DATA EXTRACTION: Two PhD-level reviewers reviewed each study for inclusion. Four PhD/PharmD-level reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author. RESULTS: Increased pooled relative risks (RRs) were found for methylphenidate-associated sleep-related AEs for insomnia (general), initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the methylphenidate formulation studied (P < .05). After correction for confounding variables, significant differences among drugs were found for initial insomnia, insomnia (general), and sleep disorder (P < .0001) as the other categories could not be tested due to insufficient studies. The findings also show that the RR and its interpretation are constrained by the placebo AE rate. CONCLUSIONS: Several types of insomnia and sleep problems are associated with methylphenidate treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics.

18.
Atten Defic Hyperact Disord ; 11(1): 91-105, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927234

RESUMO

Na+/H+ Exchanger 9 (NHE9) is an endosomal membrane protein encoded by the Solute Carrier 9A, member 9 gene (SLC9A9). SLC9A9 has been implicated in attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), epilepsy, multiple sclerosis and cancers. To better understand the function of NHE9 and the effects of disease-associated variants on protein-protein interactions, we conducted a quantitative analysis of the NHE9 interactome using co-immunoprecipitation and isobaric labeling-based quantitative mass spectrometry. We identified 100 proteins that interact with NHE9. These proteins were enriched in known functional pathways for NHE9: the endocytosis, protein ubiquitination and phagosome pathways, as well as some novel pathways including oxidative stress, mitochondrial dysfunction, mTOR signaling, cell death and RNA processing pathways. An ADHD-associated mutation (A409P) significantly altered NHE9's interactions with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling. An ASD nonsense mutation in SLC9A9, R423X, produced no-detectable amount of NHE9, suggesting the overall loss of NHE9 functional networks. In addition, seven of the NHE9 interactors are products of known autism candidate genes (Simons Foundation Autism Research Initiative, SFARI Gene) and 90% of the NHE9 interactome overlap with SFARI protein interaction network PIN (p < 0.0001), supporting the role of NHE9 interactome in ASDs molecular mechanisms. Our results provide a detailed understanding of the functions of protein NHE9 and its disrupted interactions, possibly underlying ADHD and ASDs. Furthermore, our methodological framework proved useful for functional characterization of disease-associated genetic variants and suggestion of druggable targets.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Mutação , Mapas de Interação de Proteínas/genética , Trocadores de Sódio-Hidrogênio/genética , Humanos
19.
Am J Psychiatry ; 176(3): 228-238, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818988

RESUMO

OBJECTIVE:: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. METHODS:: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. RESULTS:: Analyses revealed a significant negative genetic correlation between ADHD and ICV (rg=-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. CONCLUSIONS:: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

20.
Biol Psychiatry ; 86(1): 56-64, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30926130

RESUMO

BACKGROUND: Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium. METHODS: Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents' genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients' early onset of schizophrenia (≤18 years old) on paternal age was conducted. RESULTS: Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients' early onset of schizophrenia remained (odds ratio = 1.29, p = .04). CONCLUSIONS: The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.

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