Cortical Excitability: Phenotype and Biomarker in Attention-deficit, Hyperactivity Disorder (ADHD) Therapy

This study will evaluate Short Interval Intracortical Inhibition (SICI) measured by pTMS as
a marker of the hyperactive-impulsive dimension in 120 ADHD 7-12 years, medication-free
children. This study will characterize the effects of a single dose of atomoxetine compared
to placebo on cognitive correlates of SICI change. Participants will be randomized 2:1 to
either atomoxetine or placebo. The study will also characterize the effects of four weeks of
atomoxetine treatment on cortical inhibition and will correlate SICI change with clinical
outcomes.

Inclusion Criteria:

1. Signed informed consent and assent

2. Meets DSM-IV criteria for ADHD, combined or inattentive subtype, based on K-SADS
interview

3. Scores at least 1.5 SD higher than age and gender mean on ADHD RS, keyed to ADHD
subtype (i.e., combined score for the combined subtype, inattentive subscale only for
inattentive subtype, etc.)

4. Age: 7 - 12 years at study entry

5. Findings on physical exam, laboratory studies and ECG are judged to be normal for age
and gender, as determined by study physician at study entry

6. There is not a co-existing medical condition for which TMS or ATX is contraindicated
(for example pheochromocytoma).

7. Pulse and blood pressure within 95% of age and gender mean

8. Full scale IQ >75 (i.e., excluding mental retardation and the lower level of the
borderline range)

9. Able to complete study instruments and swallow capsules

10. Willing to commit to the entire visit schedule for the study

11. No previous treatment with Atomoxetine

12. Must either be naive to ADHD study medication or not doing well on the current ADHD
medication.

Exclusion Criteria:

1. Has one of the following exclusionary diagnoses: autism/ pervasive developmental
disorder, mental retardation, schizophrenia, a psychotic disorder, bipolar disorder,
severe depressive or conduct disorder

2. Has a comorbid disorder that is otherwise allowable, but which requires a treatment
that is not being offered in the study, and should be the primary focus of treatment,
in the opinion of the PI

3. Has a medical or neurologic disorder that would preclude taking the ATX, or which
would potentially confound the assessment of ADHD and/or TMS outcomes, in the opinion
of the PI (for example pheochromocytoma, or for specific purposes of this study
uncontrolled seizure disorder or organic brain syndrome).

4. Taking a systemic medication which might interfere with the metabolism or efficacy
assessment of ATX in this study

5. History of allergic reactions to multiple medications

6. History of alcohol or drug abuse in the past 3 months Has been in a medication
treatment study in the past 30 days

7. Females of childbearing age who are sexually active, do not use acceptable birth
control (double barrier method), or are not abstinent. Abstinence is defined as no
sexual activity for at least 3 months before the start of the study and the intention
to abstain from sexual activity during the study period). Double barrier methods
allowed include: condoms or diaphragms combined with spermicide use, intrauterine
devices (IUD), and oral, transdermal, injectable or implantable hormonal medications
(Ortho-Evra, Norplant, Depo-Provera, and similar prescription products) for at least
one month before entering the study and continuing its use throughout the study.
Birth control pills alone are not acceptable forms of birth control for this study.

8. Has any prior neurological condition that might increase the risk of an adverse event
with TMS. For the purpose of this study we are excluding children with a current or
prior history of epilepsy.