Treatment of Executive Dysfunction in Parkinson's Disease

Parkinson's disease (PD), while defined by its motor abnormalities and associated
dopaminergic loss, is invariably accompanied by cognitive impairment. Early in the disease
course, the deficits are characterized by executive dysfunction with difficulties on tasks
that involve information processing, attention, sorting, planning, set-shifting, and working
memory and are subserved by neural connections with prefrontal brain regions. There has been
little effort to identify treatments for these PD-related cognitive impairments, despite
their disabling and distressing effects. Accordingly, the goal of this proposal is to conduct
a small pilot study to determine the effectiveness and tolerability of atomoxetine, a
selective norepinephrine reuptake inhibitor, for the treatment of executive dysfunction in
patients with PD.

Atomoxetine (Strattera) is currently approved by the FDA for treatment of attention deficit
hyperactivity disorder (ADHD) in children and adults. Atomoxetine enhances dopaminergic and
noradrenergic transmission in frontal regions that are also implicated in executive
dysfunction and thus has the potential to improve executive dysfunction in PD as well as
other neurological conditions. Results of the study will be used to develop a larger
placebo-controlled trial of atomoxetine, if appropriate, as well as inform the design of
other clinical trials on potential treatments for cognitive dysfunction in PD.

The overall hypothesis is that atomoxetine will be an effective and safe treatment for
executive dysfunction in PD.

Inclusion Criteria:

1. Men and women with idiopathic Parkinson's Disease, as defined by United Kingdom (UK)
Brain Bank Criteria.

2. Adults, ages 21 to 65 years old.

3. Clinically significant executive dysfunction, as defined by the reported presence of
problems with disorganization, distractibility, task completion, planning or problem
solving that represents a decline from premorbid (pre-PD) status and is confirmed by
the patient's informant.

4. Mini-Mental State Exam (MMSE) score > 26.

5. Absence of Dementia due to Parkinson's Disease, as defined by Diagnostic and
Statistical Manual-IVth edition-Text revision (DSM-IV-TR).

6. Clinical Dementia Rating (CDR) Scale score < 1.

7. Functional Assessment Staging (FAST) score < 4.

8. Hamilton Depression Rating Scale (HDRS) Score < 11.

9. Able to provide informed consent and participate in follow-up visits during the 8-week
study duration.

10. Availability of informant who knows the patient well and is willing to provide
collateral information on the patient's clinical status and response to treatment.

11. On stable antiparkinsonian therapy for 3 months.

12. Any stage of PD severity, e.g., Hoehn and Yahr stage I-V, but must be able to
participate in testing battery and be capable of independent function so as to
manifest executive dysfunction.

13. Stable medical health with stable medication regimen for 3 months.

14. If history of major depression or anxiety disorder, must have stable symptoms and be
on stable therapy for 3 months.

15. For women of childbearing potential, negative pregnancy test and reliable use of
contraception.

Exclusion Criteria:

1. Prior exposure to atomoxetine within the last 6 months.

2. Current problems with urinary hesitancy or urinary retention.

3. Uncontrolled hypertension or tachycardia.

4. Narrow angle glaucoma.

5. Current presence of hallucinations without insight or uncontrolled delusions (patients
with benign visual hallucinations of any sensory modality with insight, e.g., passage
or presence hallucinations, or controlled stable delusions will be enrolled).

6. Illicit substance use or alcohol abuse or dependence within the last 6 months.

7. Current symptomatic Major Depressive Disorder or Anxiety Disorder that warrants
additional treatment, as assessed on clinical interview, or 21-item Hamilton
Depression Scale > 10.

8. For women, current pregnancy or nursing.

9. Current use of potent CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, quinidine.

10. Current use of stimulant or wakefulness therapy, e.g., methylphenidate or modafinil.

11. Current hepatic dysfunction, defined as values of two times or greater than the upper
limit of normal on the aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) hepatic enzymes or any disorder affecting the liver that in the opinion of the
enrolling investigator would interfere with hepatic metabolism of the medication or
interfere with the participant's ability to complete the study.

12. Current use of monoamine oxidase inhibitors that are typically used for treatment of
depression (isocarboxazid, phenelzine, and tranylcypromine).