Placebo Controlled Study of Atomoxetine in the Treatment of Mild to Moderate Cognitive Difficulties in Menopausal Women

Decline in cognitive function, and in particular memory, is a frequent complaint for which
menopausal women seek clinical intervention. While there is a wealth of preclinical evidence
demonstrating the neuroprotective and cognitive enhancing role of estradiol (Wise et al.,
1999; Jezierski & Sohrabji, 2001), recent publicity from the Women's Health Initiative Study
has made gynecologists and menopausal women concerned about using estrogen therapy (ET) to
address their cognitive complaints as well as other symptoms of menopause (WHI Writing
Group, 2002). Decades of data suggesting that estrogen enhances cognitive function in women
undergoing surgical or natural menopause (Sherwin et al., 1998) has been all but forgotten
in the wake of the results of the WHI. Further, recent findings from a naturalistic study
suggesting that having used estrogen replacement therapy for three years before the mean age
of 70 years significantly reduced the risk of Alzheimer's Disease (AD; Zandi et al., 2002)
did not receive sufficient attention in the lay press or in scientific circles to allay
concerns. Most recently, conjugated equine estrogen plus medroxyprogesterone acetate
(PremPro®) use daily is associated with a small increased risk for dementia (Schumaker et
al., 2003).

Now that clinicians and women have become hesitant to utilize ET, they find themselves
between the proverbial rock and a hard place as there have been no studies demonstrating
efficacy of any other agent in the treatment of mild to moderate cognitive difficulties in
healthy non-demented menopausal women. Thus, it is timely and crucial to investigate other
pharmacologic strategies aimed at improving cognitive function in this population.

Interestingly, many of the cognitive complaints detected in menopausal women including,
short-term memory, organization of tasks, sustaining focus and concentration, and regulating
emotions, overlap with symptoms frequently reported by adults with ADHD (Warga, 1999; Brown,
2000). That ATX has demonstrated efficacy in the treatment of ADHD provides a compelling
rationale for investigating the treatment of menopause-related declines in memory and
cognitive function. Thus, this will be the first double-blind, placebo-controlled,
cross-over clinical trial to obtain preliminary data for the efficacy of ATX in the
treatment of mild to moderate cognitive disturbances in menopause aged women. Women who are
in the early menopause have been chosen for this study as clinical and preclinical data
suggest that long periods of hypoestrogenism may be associated with poorer response to
intervention with ET. Therefore, we believe that this population may be more likely to
respond to treatment with ATX than women who have been postmenopausal for many years.

Inclusion Criteria:

- Menopausal subjects between the ages of 45 and 60 years;

- Physically healthy with no major medical illnesses;

- No history within the past 5 years of a DSM-IV psychiatric or substance abuse
diagnosis by structured diagnostic interview (SCID);

- Subjects will be determined to be either peri or post-menopausal;

- Subjects must be within 5 years of their last menstrual period;

- Subjective report of cognitive disturbances of at least mild to moderate severity;

- All subjects must be of at least average intelligence as determined using the
Wechsler Abbreviated Scale of Intelligence (WASI).

Exclusion Criteria:

- Clinical evidence of dementia and/or signs of dementia on the Mini-Mental Status Exam
(MMSE score of <22);

- History of familial dementia;

- Use of any psychotropic medication within the previous 6 months;

- Use of any estrogen replacement therapy within the previous 6 months;

- Current pregnancy;

- Signs of an unstable medical or neurological disorder.