Adult AD/HD (Attention Deficit/Hyperactivity disorder) in Norway

1. Adult AD/HD (Attention Deficit/Hyperactivity disorder) in Norway From clinical characterization to molecular mechanisms

2. Project staff • Jan Haavik: prof. of biochemistry / mol. biology; adult psychiatrist • Christopher Gillberg: professor of child & adolescent psychiatry • Per M. Knappskog: professor, molecular genetics • Stefan Johansson: research scientist in genetics • Anne Halmøy: MD: adult psychiatrist, PhD student • Kenneth Hugdahl: professor of neuropsychology • Per Bergsholm: ass. professor of adult psychiatry, Førde • Ole Bernt Fasmer: ass. professor of adult psychiatry, Bergen • Astri Lundervold: ass. professor of psychology • Helene Halleland: psychologist, PhD student • Margaretha Dramsdahl: MD, adult psychiatrist • Elisabeth Landaas: medical student • Kaya Jacobsen: medical student International ADHD genetics network/ Stephen V. Faraone, professor, SUNY Upstate Medical University Financial support: Research Council of Norway Helse-Vest / University of Bergen/ Lundbeckprisen/Dobbeltkompetanseprosjektet

3. Plan for this presentation • Background/aims • The research questions in my project • How can this contribute to our understanding of ADHD in adults?

4. The AD/HD diagnosis • Core symptoms: • Attention deficit • Hyperactivity • Impulsivity • A common, often disabling condition, but still poorly understood • Reserved for children? • No specific test – imprecise diagnostic criteria

5. Why study AD/HD in Norway? • Most studies from the USA • The registry of ”expert teams”; unique source of ”real” patients • 5000 patients from 1997-2005! • The Norwegian population; ethnically homogeneous - suitable for genetic studies

6. Why study AD/HD in adults? • World wide prevalence in children 3-7% • ~50 % will persist into adulthood • Little knowledge from adults • Treatment with stimulants equally efficient as in children • Diagnosing ADHD in adults; an everyday-clinical-challenge • Heterogeneity in clinical aspects and therapeutical response • Subgroups with different etiologies and treatment needed? • Persistence into adulthood; • The most severe cases? Subgroup with a stronger genetic component?

7. Phase I (2004-2006) Recruitment of 500 already diagnosed patients from expert teams + 500 controls Screening questions (for doctors and for patients + controls) Rating scales: Adult ADHD Self Report Scale (ASRS-18) Wender Utah Rating Scale (WURS-25 ) TEMPS-A, 21 questions MDQ (16 questions) Blood/spit samples for DNA extraction and protein analysis

8. Phase II (2005-2007) Selection of patients for further diagnosis & testing (n=100) Clinical psychiatric interviews: MINI+, K-SADS (patients & controls) Questionnaires: TCI, migraine (HUNT) Summary of tests: D-KEFS (45 min) –Verbal Fluency Test –Design Fluency Test –Colour-word Interference Test –Sorting Test –Tower Test PASAT (10 min) Attentional Network Test (30 min) Word recognition and matrices from WASI (20 min) California Verbal Learning Test – II (20 min) Benton’s Visual Memory Test (5 min) • Neuropsychological tests: • sMRI • fMRI Subclassification of ”endophenotypes” for further study

9. Phase III (2006-2012) Defined ”endophenotypes” • Association studies against known candidate genes • Linkage studies in affected families • Proteomic studies Input from collaborating groups New candidate proteins/mutations/mechanisms Further validation: Functional studies on isolated proteins, in cell culture and animals Diagnostic & therapeutic implications

10. CD/ODD ? Bipolar I HD Bipolar II Autism spectrum? DAMP? ? What is ”ADHD”? HD ADHD ADD

11. Endophenotyping • Phenotype; • (often imperfect) indicator of the genotype • Endophenotype; • A measurable component unseen by the unaided eye along the pathway between disease and distal genotype(Gottesman et al, Am J Psych 2003) • A simpler clue to genetic underpinnings than the disease syndrome itself • Can clarify classification and diagnosis and foster the development of animal models

12. Criteria for endophenotypes Willcutt, 2006

13. How do we get to these endophenotypes? • ”Decompose” AD/HD in subgroups by different parameters: • Symptom profile • Comorbidity • Environmental (pre-and perinatal) risk-factors • fMRI • Neuropsychology • Then compare subgroups with the genetic characteristics

14. Can neuropsychological measures be valuable for endophenotyping? • Neuropsychological endophenotypes are valuable in our search for genetic correlates of ADHD • Few studies on cognitive endophenotyping in ADHD • Most have focused on aspects of executive functioning

15. Which neuropsychological measures can be used for endophenotyping? • Some candidate endophenotypes: • Working memory • Spatial • Verbal • Inhibition • Processing speed • Organization • Planning • Set shifting • Respons variability • Reaction time • Attention

16. Attention as an endophenotype for ADHD • Attention Network Test • Attention as an organ system • Look at subcomponents of attention

17. How can this knowledge contribute to our understanding of ADHD? • Decide level of functioning on different areas • Divide into more appropriate subgroups • More precise diagnostic criteria • More specific treatment

18. Bergen University/ hospital campus Bridging the gap between basic science and clinical medicine Clinical practice Clinical research Basic research