Attention-Deficit Hyperactivity Disorder

1. Attention-Deficit Hyperactivity Disorder By Chris Golner April 19, 1999 Biochemistry/Molecular Biology Seminar

2. ADHD Statistics • 3-5% of all U.S. school-age children are estimated to have this disorder. • 5-10% of the entire U.S. population • Males are 3 to 6 times more likely to have ADHD than are females. • At least 50% of ADHD sufferers have another diagnosable mental disorder.

3. Outline • History of ADHD • Symptoms and Diagnosis: DSM-IV criteria • Possible causes • Treatments • Stimulants • Outcome

4. History of ADHD • Mid-1800s: Minimal Brain Damage • Mid 1900s: Minimal Brain Dysfunction • 1960s: Hyperkinesia • 1980: Attention-Deficit Disorder • With or Without Hyperactivity • 1987: Attention Deficit Hyperactivity Disorder • 1994-present: ADHD • Primarily Inattentive • Primarily Hyperactive • Combined Type

5. Diagnosing ADHD: DSM-IV • Inattentiveness: Has a minimum of 6 symptoms regularly for the past six months. Symptoms are present at abnormal levels for stage of development • Lacks attention to detail; makes careless mistakes • has difficulty sustaining attention • doesn’t seem to listen • fails to follow through/fails to finish projects • has difficulty organizing tasks • avoids tasks requiring mental effort • often loses items necessary for completing a task • easily distracted • is forgetful in daily activities

6. Diagnosing ADHD: DSM-IV • Hyperactivity/ Impulsivity: • Fidgets or squirms excessively • leaves seat when inappropriate • runs about/climbs extensively when inappropriate • has difficulty playing quietly • often “on the go” or “driven by a motor” • talks excessively • blurts out answers before question is finished • cannot await turn • interrupts or intrudes on others Has a minimum of 6 symptoms regularly for the past six months. Symptoms are present at abnormal levels for stage of development

7. Diagnosing ADHD: DSM-IV • Additional Criteria: • Symptoms causing impairment present before age 7 • Impairment from symptoms occurs in two or more settings • Clear evidence of significant impairment (social, academic, etc.) • Symptoms not better accounted for by another mental disorder

8. Problems of Diagnosis • Subjectivity of Criteria • Inconsistent evaluations--presence of symptoms usually given by teacher or parent • Study by Szatmari et al (1989) showed that the number of diagnosed cases of ADHD decreased 80% when observations of parent, teacher and physician were used rather than just one source • Symptoms in females more subtle---leads to underdiagnosis

9. ADHD and the Brain • Diminished arousal of the Nervous System • Decreased blood flow to prefrontal cortex and pathways connecting to limbic system (caudate nucleus and striatum) • PET scan shows decreased glucose metabolism throughout brain Comparison of normal brain (left) and brain of ADHD patient.

10. ADHD and the Brain II • Similarities of ADHD symptoms to those from injuries and lesions of frontal lobe and prefrontal cortex • MRIs of ADHD patients show: • Smaller anterior right frontal lobe • abnormal development in the frontal and striatal regions • Significantly smaller splenium of corpus callosum • decreased communication and processing of information between hemispheres • Smaller caudate nucleus

11. What causes ADHD? • Underlying cause of these differences is still unknown; there is much conflicting data between studies • Strong evidence of genetic component • Predominant theory: Catecholamine neurotransmitter dysfunction or imbalance • decreased dopamine and/or norepinephrine uptake in brain • theory supported by positive response to stimulant treatment • Recent study indicates possible lack of serotonin as a factor in mice

12. Dopamine in the Brain Scientific American Http//www.sciam.com/1998/0998issue/0998barkely.html#link1

13. Genetic Linkages to ADHD • Twin studies by Stevenson, Levy et al, and Sherman et al indicate an average heritability factor of .80 • Biederman et al reported a 57% risk to offspring if one parent has ADHD. • Dopamine genes • DA type 2 gene • DA transporter gene (DAT1) • Dopamine receptor (DRD4, “repeater gene”) is over-represented in ADHD patients

14. DRD4 • DRD4 is most likely contributor • DRD4 affects the post-synaptic sensitivity in the prefrontal and frontal cortex • This region of cortex affects executive functions and attention • Executive functions include working memory, internalization of speech, emotions, motivation, and learning of behavior

15. Treatment • Counseling of individual and family • Stimulants • Tricyclic antidepressants • Bupropion • Clonidine

16. Stimulants • Exact mechanism unknown • Raise activity level of the CNS by decreasing fluctuations of activity or lowering threshold needed for arousal • Similar in structure to NE and DA, and may mimic their actions • At least 75% have positive response with single dose • 95% respond well to stimulant treatment • Include methylphenidate, dextroamphetamine and pemoline

17. Methylphenidate • Is a piperidine derivative commonly known as Ritalin® • Is believed to act as dopamine agonist in synaptic cleft • Stimulates frontal-striatal regions • Dosage (5-20 mg) must be adjusted to each patient • Taken orally, 2-3 times a day as needed • Behavioral effects start within 1/2 hour to hour after ingestion, peaking at 1 and 3 hours • Also comes in Sustained-Release form, whose effects last approximately twice as long.

18. Effects of MPH • Elevates mood • Raises arousal of CNS and cerebral blood flow • Increases productivity • Improves social interactions • Increases heart rate and blood pressure • Has little or no abuse potential

19. Side Effects • Common: • decreased appetite • insomnia • behavioral rebound • head and stomach aches • Also thought to cause temporary height and weight suppression • Mild: • anxiety/ depression • irritability • Rare: • tics (Tourette’s Syndrome) • overfocussing • liver problems or rash (Pemoline only)

20. Outcome • ADHD can persist into adulthood, but usually symptoms gradually diminish • When it persists into adulthood, it usually requires ongoing treatment and counseling • most will develop another disorder (especially learning disability, ODD, depression, and/or conduct disorder) • Without treatment: • antisocial and deviant behavior • increased rates of divorce, moving violations, incarceration, and institutionalization

21. References Barkley, R. Attention-Deficit Hyperactivity Disorder, 2nd Ed. New York: Guilford Press. 1998. 628 pp. Shaywitz, B. and Shaywitz, S. Attention Deficit Disorder Comes of Age: Toward the 21st Century. Austin, TX: Hammill Foundation. 1992. 366 pp. Rie, H.E. and Rie, E.D., Eds. Handbook of Minimal Brain Dysfunctions: A Critical View. New York: John Wiley & Sons. 1980. 744 pp. Faigel, H. Attention Deficit Disorder: A Review. J. of Adolesc. Health, Mar 1995 Vol. 16: 174-84. Cantwell, D.P. Attention Deficit Disorder: A Review of the Past Ten Years. J. of the Am. Acad. Of Child Adolesc. Psychiatry. 1996, Vol 35: 978-87. Seideman, L., Biederman, J., and Faraone, S.V. A Pilot Study of Neuropsychological Function in Girls with ADHD. J. of Am. Acad. of Child Adolesc. Psychiatry, 1997. Vol. 36: 366-73. Seideman, L., Biederman, J., and Faraone, S.V. A Pilot Study of Neuropsychological Function in Girls with ADHD. J. of Am. Acad. of Child Adolesc. Psychiatry, 1997. Vol. 36: 366-73.

22. References Levy, F., Hay D.A., McStephen, M., Wood, C., and Waldman, I. Attention-Deficit Hyperactivity Disorder: A Category or Continuum? Genetic Analysis of a Large Scale Twin Study. J. of Am. Acad. Of Child Adolesc. Psychiatry, 1997, Vol 36: 737-44. Sherman, D.K., Iacono, W.G., McGue, M.K. Attention-Deficit Hyperactivity Disorder Dimensions: A Twin Study of Inattention and Impulsivity-Hyperactivity. J. of Am. Acad. Of Child Adolesc. Psychiatry, 1997, Vol 36: 737-44. Scientific American Online: http://www.sciam.com/1998/0998issue/0998barkley.html#link1 Ritalin Action on Hyperactivity Explained By New Theory http://pharmacology.tqn.com/library/99news/bl9n0155d.htm Approaching a Scientific Understanding of what Happens in the Brain in AD/HD http://www.chadd.org/attnv4n1p30.htm Marx, J. How Stimulant drugs May Clam Hyperactivity. Science, 1999, Vol. 283: 306-08. http://www.sciencemag.org/cgi/content/full/283/5400/306?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Attention+Deficit+Disorder&searchid=QID_NOT_SET&FIRSTINDEX=