- Email: [email protected]
Hyperactivity Disorder
SYMPOSIA 10.0 – 10.3
SYMPOSIUM 10 ADVANCES IN THE NEUROBIOLOGY OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER AND RELATED DISORDERS Joseph Biederman, MD, Massachusetts General Hospital, 55 Fruit Street, Yawkey Bldg 6 Floor 6900, Boston, MA 02114-2696; James J. McGough, MD Objectives: The goal of this session is to advance knowledge on the neurobiology of ADHD and related disorders. Methods: This group of studies relied on individual datasets to address the specific scientific issues examined. Results: Dr. Stephen V. Faraone used data from the ADHD subgroup of the Psychiatric Genomics Consortium and the iPSYCH-SSI-Broad ADHD group to conduct a new analysis on the genetics of ADHD. The final sample size comprises 17,893 individuals with ADHD and 31,174 control subjects. Results showed several loci with genomewide significance and evidence for a significant polygenic background of common DNA variation and provided the first genomewide significant findings for biological mechanisms that have not been implicated in ADHD until now. Dr. Thomas J. Spencer examined the therapeutic potential of coadministering the mixed opioid antagonist naltrexone with methylphenidate (MPH) by conducting a 6-week double-blind, placebocontrolled RCT of naltrexone in adults with ADHD who received open treatment with therapeutic doses of MPH. The coadministration of naltrexone with MPH did not interfere with the clinical effectiveness of MPH for ADHD. Dr. Mai Uchida used resting-state fMRI to examine the neural basis of emotional dysregulation in a sample group of children at risk for major depression. Results showed that children at-risk manifest atypical functional connectivity in the default mode, cognitive control, and affective networks, which could represent biomarkers of risk for depression in the young. Dr. Amy Yule used familial risk analysis to re-examine the association between ADHD and SUDs, with attention given to proband sex. Results revealed that ADHD and SUDs in the proband were associated consistently with a significant risk for the same and opposite addictive (drug or alcohol) disorder in relatives independently of proband sex, indicating a common familial risk between ADHD and SUDs. Dr. Joseph Biederman’s study assessed the implications of autism traits (ATs) in a large sample group of youth with ADHD of both sexes without a diagnosis of autism by relying on a unique profile of the Child Behavior Checklist to define ATs. Results showed that a substantial minority of children with ADHD manifests ATs, and those exhibiting them have greater severity of illness and dysfunction. Conclusions: This group of studies provides new insights into the neurobiology and pharmacology of ADHD and related disorders.
ADHD NEPSYC http://dx.doi.org/10.1016/j.jaac.2016.07.173
Results: We found several loci meeting genome-wide significance and also found evidence for a significant polygenic background of common DNA variation. One of the significant findings implicates the FOXP2 gene, which had been implicated previously in cognitive functions and brain regions relevant to ADHD. Conclusions: Our results provide the first genome-wide significant findings for ADHD. These findings implicate biological mechanisms that, up until now, have not been implicated in the disorder. The substantial polygenic background of ADHD shows that the effects of common ADHD DNA variants are, individually, very small yet, as a group, account for much of the disorder’s heritability.
ADHD GS OTH http://dx.doi.org/10.1016/j.jaac.2016.07.174
10.2 EFFECT OF AN OPIOID RECEPTOR ANTAGONIST ON STIMULANT TREATMENT OF ADULTS WITH ATTENTION-DEFICIT/ HYPERACTIVITY DISORDER Thomas J. Spencer, MD, Psychiatry, Massachusetts General Hospital, 55 Fruit Street, YAW6900, Boston, MA 02114-2621 Objectives: Preclinical studies have shown that methylphenidate (MPH) activates mu opioid receptors, which are linked to euphoria. It is possible that mu opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. The main aim of this study was to assess whether the combination of naltrexone with MPH is safe and effective and whether it preserves the clinical benefits of stimulants. We hypothesized that the coadministration of naltrexone would not affect the therapeutic potency of stimulants in the treatment of subjects with ADHD. Methods: We conducted a 6-week double-blinded, placebo-controlled, randomized clinical trial of naltrexone in adults with ADHD who were receiving open treatment with therapeutic doses of MPH. Subjects were adults with ADHD, preselected by the experience of euphoria with a test dose of MPH. Results: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria on a baseline visit were started in the open trial of MPH and randomized to naltrexone or placebo. Thirty-one subjects completed to week three, and 25 subjects completed through week six. Throughout the course of six weeks of blinded naltrexone and open MPH treatment, the coadministration of naltrexone with MPH did not interfere with the clinical effectiveness of MPH for ADHD symptoms. In addition, the combination of naltrexone and MPH did not produce any increase in adverse events over MPH alone. Conclusions: Our findings provide further support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential. Such a nonaddictive form of stimulant treatment for ADHD could minimize diversion and misuse concerns by prescribers and consumers.
ADHD PPC STIM Supported by Department of Defense Grant W81XWH-12-1-0510 http://dx.doi.org/10.1016/j.jaac.2016.07.175
10.1 GENOME-WIDE ASSOCIATION SCAN OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER Stephen V. Faraone, PhD, SUNY Upstate Medical Univ., 750 E Adams St, Syracuse, NY 13210-1834 Objectives: Although twin and family studies have shown ADHD to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Because prior meta-analysis of genome-wide association scans (GWAS) did not yield genome-wide significant results, we created an international consortium to dramatically increase our sample size. Methods: We used data from the ADHD subgroup of the Psychiatric Genomics Consortium (nine subsamples) and the iPSYCH-SSI-Broad ADHD group. We removed genetic outliers, excluded sample groups not of European origin, and adjusted results with components from a principal component analysis of ancestry (Eigenstrat software). We imputed single nucleotide polymorphism (SNPs) using the 1,000 genomes, phase one European population sample group. The final sample size comprises 17,893 individuals with ADHD and 31,174 control subjects. For each substudy, we imputed HapMap SNPs, computed association test statistics, and transformed them to Z-scores. Then, we combined weighted Z-scores in a meta-analysis.
S272
www.jaacap.org
10.3 ALTERED INTRINSIC FUNCTIONAL BRAIN ARCHITECTURE IN CHILDREN AT FAMILIAL RISK OF MAJOR DEPRESSION Mai Uchida, MD, Psychiatry, Massachusetts General Hospital, 55 Fruit Street, WRN 625, Boston, MA 02114 Objectives: The aim of our study was to identify structural, task-based, and resting-state fMRI-based neural underpinnings of the risk for major depression. Methods: We collected fMRI scans of 38 unaffected children of parents with histories of major depression (at risk children) and 23 age-matched children without histories of major depression (control subjects). We examined structural differences within the two groups. We compared the task-based activation patterns of the two groups while the children were engaged in a simple perceptual-matching task of happy, fearful, and neutral faces. We also compared resting-state functional connectivity between at risk children and control subjects, focusing on regions of interest in the default mode network (DMN), cognitive control network, and affective network.
J OURNAL
OF THE
AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 55 NUMBER 10S OCTOBER 2016
SYMPOSIUM 10 ADVANCES IN THE NEUROBIOLOGY OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER AND RELATED DISORDERS Joseph Biederman, MD, Massachusetts General Hospital, 55 Fruit Street, Yawkey Bldg 6 Floor 6900, Boston, MA 02114-2696; James J. McGough, MD Objectives: The goal of this session is to advance knowledge on the neurobiology of ADHD and related disorders. Methods: This group of studies relied on individual datasets to address the specific scientific issues examined. Results: Dr. Stephen V. Faraone used data from the ADHD subgroup of the Psychiatric Genomics Consortium and the iPSYCH-SSI-Broad ADHD group to conduct a new analysis on the genetics of ADHD. The final sample size comprises 17,893 individuals with ADHD and 31,174 control subjects. Results showed several loci with genomewide significance and evidence for a significant polygenic background of common DNA variation and provided the first genomewide significant findings for biological mechanisms that have not been implicated in ADHD until now. Dr. Thomas J. Spencer examined the therapeutic potential of coadministering the mixed opioid antagonist naltrexone with methylphenidate (MPH) by conducting a 6-week double-blind, placebocontrolled RCT of naltrexone in adults with ADHD who received open treatment with therapeutic doses of MPH. The coadministration of naltrexone with MPH did not interfere with the clinical effectiveness of MPH for ADHD. Dr. Mai Uchida used resting-state fMRI to examine the neural basis of emotional dysregulation in a sample group of children at risk for major depression. Results showed that children at-risk manifest atypical functional connectivity in the default mode, cognitive control, and affective networks, which could represent biomarkers of risk for depression in the young. Dr. Amy Yule used familial risk analysis to re-examine the association between ADHD and SUDs, with attention given to proband sex. Results revealed that ADHD and SUDs in the proband were associated consistently with a significant risk for the same and opposite addictive (drug or alcohol) disorder in relatives independently of proband sex, indicating a common familial risk between ADHD and SUDs. Dr. Joseph Biederman’s study assessed the implications of autism traits (ATs) in a large sample group of youth with ADHD of both sexes without a diagnosis of autism by relying on a unique profile of the Child Behavior Checklist to define ATs. Results showed that a substantial minority of children with ADHD manifests ATs, and those exhibiting them have greater severity of illness and dysfunction. Conclusions: This group of studies provides new insights into the neurobiology and pharmacology of ADHD and related disorders.
ADHD NEPSYC http://dx.doi.org/10.1016/j.jaac.2016.07.173
Results: We found several loci meeting genome-wide significance and also found evidence for a significant polygenic background of common DNA variation. One of the significant findings implicates the FOXP2 gene, which had been implicated previously in cognitive functions and brain regions relevant to ADHD. Conclusions: Our results provide the first genome-wide significant findings for ADHD. These findings implicate biological mechanisms that, up until now, have not been implicated in the disorder. The substantial polygenic background of ADHD shows that the effects of common ADHD DNA variants are, individually, very small yet, as a group, account for much of the disorder’s heritability.
ADHD GS OTH http://dx.doi.org/10.1016/j.jaac.2016.07.174
10.2 EFFECT OF AN OPIOID RECEPTOR ANTAGONIST ON STIMULANT TREATMENT OF ADULTS WITH ATTENTION-DEFICIT/ HYPERACTIVITY DISORDER Thomas J. Spencer, MD, Psychiatry, Massachusetts General Hospital, 55 Fruit Street, YAW6900, Boston, MA 02114-2621 Objectives: Preclinical studies have shown that methylphenidate (MPH) activates mu opioid receptors, which are linked to euphoria. It is possible that mu opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. The main aim of this study was to assess whether the combination of naltrexone with MPH is safe and effective and whether it preserves the clinical benefits of stimulants. We hypothesized that the coadministration of naltrexone would not affect the therapeutic potency of stimulants in the treatment of subjects with ADHD. Methods: We conducted a 6-week double-blinded, placebo-controlled, randomized clinical trial of naltrexone in adults with ADHD who were receiving open treatment with therapeutic doses of MPH. Subjects were adults with ADHD, preselected by the experience of euphoria with a test dose of MPH. Results: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria on a baseline visit were started in the open trial of MPH and randomized to naltrexone or placebo. Thirty-one subjects completed to week three, and 25 subjects completed through week six. Throughout the course of six weeks of blinded naltrexone and open MPH treatment, the coadministration of naltrexone with MPH did not interfere with the clinical effectiveness of MPH for ADHD symptoms. In addition, the combination of naltrexone and MPH did not produce any increase in adverse events over MPH alone. Conclusions: Our findings provide further support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential. Such a nonaddictive form of stimulant treatment for ADHD could minimize diversion and misuse concerns by prescribers and consumers.
ADHD PPC STIM Supported by Department of Defense Grant W81XWH-12-1-0510 http://dx.doi.org/10.1016/j.jaac.2016.07.175
10.1 GENOME-WIDE ASSOCIATION SCAN OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER Stephen V. Faraone, PhD, SUNY Upstate Medical Univ., 750 E Adams St, Syracuse, NY 13210-1834 Objectives: Although twin and family studies have shown ADHD to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Because prior meta-analysis of genome-wide association scans (GWAS) did not yield genome-wide significant results, we created an international consortium to dramatically increase our sample size. Methods: We used data from the ADHD subgroup of the Psychiatric Genomics Consortium (nine subsamples) and the iPSYCH-SSI-Broad ADHD group. We removed genetic outliers, excluded sample groups not of European origin, and adjusted results with components from a principal component analysis of ancestry (Eigenstrat software). We imputed single nucleotide polymorphism (SNPs) using the 1,000 genomes, phase one European population sample group. The final sample size comprises 17,893 individuals with ADHD and 31,174 control subjects. For each substudy, we imputed HapMap SNPs, computed association test statistics, and transformed them to Z-scores. Then, we combined weighted Z-scores in a meta-analysis.
S272
www.jaacap.org
10.3 ALTERED INTRINSIC FUNCTIONAL BRAIN ARCHITECTURE IN CHILDREN AT FAMILIAL RISK OF MAJOR DEPRESSION Mai Uchida, MD, Psychiatry, Massachusetts General Hospital, 55 Fruit Street, WRN 625, Boston, MA 02114 Objectives: The aim of our study was to identify structural, task-based, and resting-state fMRI-based neural underpinnings of the risk for major depression. Methods: We collected fMRI scans of 38 unaffected children of parents with histories of major depression (at risk children) and 23 age-matched children without histories of major depression (control subjects). We examined structural differences within the two groups. We compared the task-based activation patterns of the two groups while the children were engaged in a simple perceptual-matching task of happy, fearful, and neutral faces. We also compared resting-state functional connectivity between at risk children and control subjects, focusing on regions of interest in the default mode network (DMN), cognitive control network, and affective network.
J OURNAL
OF THE
AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 55 NUMBER 10S OCTOBER 2016