ADHD pharmacogenetics across the life cycle: New findings and perspectives.

Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder, affecting individuals across the life cycle. Although its etiology is not yet completely understood, genetics plays a substantial role. Pharmacological treatment is considered effective and safe for children and adults, but there is considerable inter-individual variability among patients regarding response to medication, required doses, and adverse events. We present here a systematic review of the literature on ADHD pharmacogenetics to provide a critical discussion of the existent findings, new approaches, limitations, and recommendations for future research. Our main findings are: first, the number of studies continues to grow, making ADHD one of the mental health areas with more pharmacogenetic studies. Second, there has been a focus shift on ADHD pharmacogenetic studies in the last years. There is an increasing number of studies assessing gene-gene and gene-environment interactions, using genome-wide association approaches, neuroimaging, and assessing pharmacokinetic properties. Third and most importantly, the heterogeneity in methodological strategies employed by different studies remains impressive. The question whether pharmacogenetics studies of ADHD will improve clinical management by shifting from trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains unanswered. © 2014 Wiley Periodicals, Inc.

Glutamatergic copy number variants and their role in attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with a strong genetic component. The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. The aim of the present study was to investigate if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. A total of 1038 individuals with ADHD and 1057 subjects without this disorder were investigated. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD (P = 0.326, OR = 1.112, 95% CI = 0.762-1.624). The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples (P = 0.026, OR = 1.824, 95% CI = 1.066-3.121) but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases (P = 0.002, OR = 3.915, 95% CI = 1.631-9.402), but not in individuals without ADHD. Taken together, our results suggest a role for glutamate in ADHD as CNVs in the glutamatergic genes investigated herein were associated with cognitive and clinical characteristics of ADHD individuals.

Assessing undertreatment and overtreatment/misuse of ADHD medications in children and adolescents across continents: A systematic review and meta-analysis.

A controversy exists on whether there is an over or underuse of medications for Attention-Deficit/Hyperactivity Disorder (ADHD). We conducted the first meta-analysis to estimate the rate of ADHD pharmacological treatment in both diagnosed and undiagnosed individuals. Based on a pre-registered protocol (CRD42018085233), we searched a broad set of electronic databases and grey literature. After screening 25,676 abstracts, we retained 36 studies including 104,305 subjects, from which 18 studies met our main analysis criteria. The pooled pharmacological treatment rates were 19.1 % and 0.9 % in school-age children/adolescents with and without ADHD, respectively. We estimated that for each individual using medication without a formal ADHD diagnosis, there are three patients with a formal diagnosis who might benefit from medication but do not receive it in the US. Our results indicate both overtreatment/misuse of medication in individuals without ADHD and pharmacological undertreatment in youths with the disorder. Our findings reinforce the need for public health policies improving education on ADHD and discussions on the benefits and limitations of ADHD medications.

Are ADHD medications under or over prescribed worldwide?: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, characterized by age inappropriate and impairing levels of inattention and/or hyperactivity/impulsivity. Pharmacotherapy is an important part of the ADHD multimodal treatment. The extent to which ADHD is pharmacologically over or under treated worldwide is controversial. We aimed to estimate the pooled worldwide rate of ADHD pharmacological treatment in individuals with and without the disorder. METHOD AND ANALYSIS: We will include published or unpublished studies reporting the rates of ADHD pharmacological treatment in participants with and without ADHD of any age group. Population-based, cohort, or follow-up studies, as well as data from insurance health system and third-party reimbursements will be eligible. Searches will be performed in a large number of electronic databases, including Medline, Embase, CINAHL, Cochrane, PsycINFO, Web of Science, and Scopus. The primary outcome will be the prevalence of ADHD pharmacological treatment in individuals with ADHD and without ADHD. Two independent reviewers will perform the screening, and data extraction process. Study quality/bias will be assessed with the Newcastle-Ottawa scale by 2 independent reviewers. To test the robustness of the findings, we will perform a series of sensitivity and meta-regression analysis. Analyses will be performed with R and STATA software. ETHICS AND DISSEMINATION: No IRB approval will be necessary. The results of this systematic review and meta-analysis will be presented at international conferences and published in peer-reviewed journals. REGISTRATION AND STATUS: PROSPERO 2018 CRD42018085233.

Genetics of attention-deficit/hyperactivity disorder: an update.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting children, adolescents, and adults. The prevalence is estimated at 5 to 7% of school-aged children and 2.5 to 5% of adults. The phenotype is complex and heterogeneous, presenting variable clinical features, developmental course, and outcome. The genetic susceptibility to ADHD is attributed to both common and rare variants from a broad range of genes related mainly to neurotransmission and neurodevelopment pathways. However, it has been difficult to identify the genetic risk variants that account for the high heritability of this disorder. In this paper, we present recent findings from molecular genetics studies on both child and adult ADHD. Challenges and future directions for ADHD genetic studies are reviewed and discussed.

Genetics of attention-deficit/hyperactivity disorder: current findings and future directions.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting 5.29% of children worldwide. It presents a heterogeneous clinical expression, and both environmental and genetic factors are involved in the etiology. Despite high heritability estimates, identification of genes that confer susceptibility to ADHD has been a slow and difficult process. The first genetic studies targeted dopaminergic genes, but the effects were small and only explained a small portion of ADHD heritability. Recent studies focus on the identification of novel genes and pathways that may underlie ADHD. The main goal of this review is to present evidence from genome-wide association, copy number variation and family-based studies of genetic susceptibility to ADHD. The challenges involved to disclose ADHD susceptibility genes will be reviewed in order to provide directions for future studies.