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Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases.

ABSTRACT: OBJECTIVE:ObjectiveaaWe evaluated the distribution of alpha-2A adrenergic receptor (ADRA2A) and catechol-o-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) among ADHD subtypes and other homogeneous patient populations including treatment-resistant cases and patients with high symptom severity. METHODS:Methodsaa121 ADHD patients aged 6-18 years were included in the study. Diagnosis and subtypes designation were confirmed using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and symptoms were evaluated using the Conners' Parent (CPRS) and Teacher Rating Scales (CTRS). The response to methylphenidate was assessed objectively using the Clinical Global Impression-Severity Scale (CGI-S) and Global Assessment of Functioning Scale (GAS) as well as the Continuous Performance (CPT) and Trail Making tests (TMT-A, B). Patients were genotyped for ADRA2A (rs1800544) and COMT (rs4680) SNPs by PCR/RFLP and compared to a gender-matched control group. RESULTS:Although there was no association of COMT (rs4680) SNP with symptoms or diagnosis, the ADRA2A polymorphism, low socioeconomic status (SES), and comorbid psychiatric diagnosis were all associated with poor response to methylphenidate in logistic regression analysis. CONCLUSION:Clinicians may consider adjuvant strategies when these negative factors are present to increase the success of tailored ADHD treatments in the future.

SUBMITTER: Unal D

PROVIDER: S-EPMC4965653 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases.

Unal Dilek D Unal Mehmet Fatih MF Alikasifoglu Mehmet M Cetinkaya Arda A

Psychiatry investigation 20160725 4

<h4>Objective</h4>ObjectiveaaWe evaluated the distribution of alpha-2A adrenergic receptor (ADRA2A) and catechol-o-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) among ADHD subtypes and other homogeneous patient populations including treatment-resistant cases and patients with high symptom severity.<h4>Methods</h4>Methodsaa121 ADHD patients aged 6-18 years were included in the study. Diagnosis and subtypes designation were confirmed using the Kiddie Schedule for Affective Disord ...[more]

PMID: 27482244

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Project description:Attention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55-66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD. Integrating the neuroimaging-derived phenotypes with genomics deciphers various neurobiological pathways that can be leveraged for the development of novel clinical biomarkers, new treatment modalities as well as therapeutic interventions for ADHD patients. In this review, we discuss the neurobiology of ADHD with particular emphasis on structural and functional changes in the ADHD brain and their interactions with complex genomic variations utilizing imaging genetics methodologies. We also highlight the genetic variants supposedly allied with the development of ADHD and how these, in turn, may affect the brain circuit function and related behaviors. In addition to reviewing imaging genetic studies, we also examine the need for complementary approaches at various levels of biological complexity and emphasize the importance of combining and integrating results to explore biological pathways involved in ADHD disorder. These approaches include animal models, computational biology, bioinformatics analyses, and multimodal imaging genetics studies.

Project description:ImportanceSignificant concern exists over treating youths with attention-deficit/hyperactivity disorder (ADHD) with antipsychotic medications, yet little is known about the factors associated with antipsychotic treatment.ObjectivesTo describe the percentage of youths who fill antipsychotic prescriptions in the year following a new diagnosis of ADHD and characterize the clinical and demographic factors associated with antipsychotic initiation.Design, setting, and participantsA retrospective longitudinal cohort analysis of antipsychotic treatment was performed in 187 563 youths, aged 3 to 24 years, with a new diagnosis of ADHD (without recent diagnosis of any US Food and Drug Administration [FDA]-indicated conditions for antipsychotic treatment). The sample was derived from the 2010 to 2015 MarketScan Commercial Database, with the analysis completed between November 1, 2018, and May 30, 2019.Main outcomes and measuresThe percentage of youths prescribed an antipsychotic in the first year following a new diagnosis of ADHD. Among those prescribed antipsychotic medications, the percentage who received a diagnosis of conduct disorder, oppositional defiant disorder, or a disorder for which 1 or more antipsychotic medication has received an indication for use in youths from the FDA (schizophrenia, bipolar disorder, and Tourette disorder) and the percentage that filled an antipsychotic prescription before filling a stimulant prescription (methylphenidate or amphetamine derivative).ResultsOf the 187 563 youths included in the study, 114 305 (60.9%) were male with a mean (SD) age of 13.74 (5.61) years. In the year following a new ADHD diagnosis, 4869 youths (2.6%; 95% CI, 2.5%-2.7%) with ADHD were prescribed an antipsychotic. Youths treated with antipsychotics with ADHD were more likely than their peers who were not receiving an antipsychotic to have recently received diagnoses of self-harm and/or suicidal ideation (adjusted odds ratio [aOR], 7.5; 95% CI, 5.9-9.6), oppositional defiant disorder (aOR, 4.4; 95% CI, 3.9-4.9), and substance use disorder (aOR, 4.0; 95% CI, 3.6-4.5). The youths who received antipsychotics were also more likely to have received inpatient treatment (aOR, 7.9; 95% CI, 6.7-9.3). During the year following the new ADHD diagnosis, 52.7% (95% CI, 51.3%-54.1%) of youths treated with antipsychotics received a diagnosis for which antipsychotics have either an FDA or evidence-supported indication for their use. Among youths who initiated antipsychotic medications, 47.9% (95% CI, 46.5%-49.3%) did not receive a stimulant prescription between their ADHD diagnosis and antipsychotic initiation. Antipsychotic prescribing was proportionally highest for preschool-aged children (4.3%) and associated with neurodevelopmental disorders (aOR, 3.9; 95% CI, 1.3-11.2) and recent inpatient mental health treatment (aOR, 8.9; 95% CI, 1.7-45.8).Conclusions and relevanceApproximately half of youths with a new ADHD diagnosis may have an evidence-supported indication for an antipsychotic medication. Less than half of these youths received a stimulant; the evidence-supported first line treatment for ADHD, before the antipsychotic was initiated. Use of antipsychotic prescribing appears to be associated with high levels of psychiatric comorbidity.

Project description:Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for attention deficit/hyperactivity disorder (ADHD) specify two dimensions of inattention and hyperactivity-impulsivity symptoms that are used to define three nominal subtypes: predominantly hyperactive-impulsive type (ADHD-H), predominantly inattentive type (ADHD-I), and combined type (ADHD-C). To aid decision making for DSM-5 and other future diagnostic systems, a comprehensive literature review and meta-analysis of 546 studies was completed to evaluate the validity of the DSM-IV model of ADHD. Results indicated that DSM-IV criteria identify individuals with significant and persistent impairment in social, academic, occupational, and adaptive functioning when intelligence, demographic factors, and concurrent psychopathology are controlled. Available data overwhelmingly support the concurrent, predictive, and discriminant validity of the distinction between inattention and hyperactivity-impulsivity symptoms, and indicate that nearly all differences among the nominal subtypes are consistent with the relative levels of inattention and hyperactivity-impulsivity symptoms that define the subtypes. In contrast, the DSM-IV subtype model is compromised by weak evidence for the validity of ADHD-H after first grade, minimal support for the distinction between ADHD-I and ADHD-C in studies of etiological influences, academic and cognitive functioning, and treatment response, and the marked longitudinal instability of all three subtypes. Overall, we conclude that the DSM-IV ADHD subtypes provide a convenient clinical shorthand to describe the functional and behavioral correlates of current levels of inattention and hyperactivity-impulsivity symptoms, but do not identify discrete subgroups with sufficient long-term stability to justify the classification of distinct forms of the disorder. Empirical support is stronger for an alternative model that would replace the subtypes with dimensional modifiers that reflect the number of inattention and hyperactivity-impulsivity symptoms at the time of assessment. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

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Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases.

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Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases.

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