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

Study Overview
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Brief Summary
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The purpose of this study is to examine the efficacy of atomoxetine (ATX) treatment for the mild to moderate cognitive disturbances frequently experienced by women during the menopause transition. In addition, we seek to determine, using the Brown Attention Deficit Disorder Scale (BADDS), whether and to what degree peri- and early post-menopausal women experience cognitive disturbances which overlap with the impairments of executive function characteristic of adults with attention deficit disorder (ADHD).

Detailed Description
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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.

Official Title
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A Controlled Trial of Atomoxetine in the Treatment of Mild to Moderate Cognitive Difficulties in Menopausal Women

Conditions
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Menopause, Cognitive Disturbances

Intervention / Treatment
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* Drug: atomoxetine
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Atomoxetine<br>Subjects were enrolled into a double-blind, placebo-controlled cross over study where they will receive ATX 40mg/d x 1 week, then 80mg/d x 5 weeks or placebo (PBO) for 6 weeks, followed by a 4-week wash out period that is followed by an additional 6 weeks of treatment in the alternate condition. The 4-week washout period include a 4-day taper in the first week. Subjects undergo assessments of cognition, mood, and menopausal symptoms prior to randomization, after 6 weeks in the first treatment condition (ATX or PBO) and then finally after the second 6-week period of the alternate treatment condition. Subjects are monitored every other week to assess medication compliance and side effects. Subjects will be instructed to take one capsule of ATX 40mg/d or placebo per day. If tolerated, the number of pills of ATX will be increased to 2 per day at the end of Week 1 of both Trials A and B. Subjects will remain on two capsules per day for the remaining 5 weeks of Trials A and B. | Drug: atomoxetine<br>* Subjects will receive ATX 40mg/d x 1 week, then 80mg/d x 5 weeks followed by a 4-week wash out period that is followed by an additional 6 weeks of treatment in the alternate condition. The 4-week washout period include a 4-day taper in the first week.<br>* Other names: Strattera;|
| Placebo Comparator: Placebo<br>Subjects were enrolled into a double-blind, placebo-controlled cross over study where they will receive ATX 40mg/d x 1 week, then 80mg/d x 5 weeks or placebo (PBO) for 6 weeks, followed by a 4-week wash out period that is followed by an additional 6 weeks of treatment in the alternate condition. The 4-week washout period include a 4-day taper in the first week. Subjects undergo assessments of cognition, mood, and menopausal symptoms prior to randomization, after 6 weeks in the first treatment condition (ATX or PBO) and then finally after the second 6-week period of the alternate treatment condition. Subjects are monitored every other week to assess medication compliance and side effects. Subjects will be instructed to take one capsule of ATX 40mg/d or placebo per day. If tolerated, the number of pills of ATX will be increased to 2 per day at the end of Week 1 of both Trials A and B. Subjects will remain on two capsules per day for the remaining 5 weeks of Trials A and B. | Drug: placebo<br>* Subjects will receive placebo equivalent for 6 weeks followed by a 4-week wash out period that is followed by an additional 6 weeks of treatment in the alternate condition. The 4-week washout period include a 4-day taper in the first week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brown Attention Deficit Disorder Scale | Raw scores for 5 clusters (organizing/activating, attention/concentration, alertness/effort/processing, managing affect interference, and working memory/recall) on the BADDS were converted to T scores which range from 50-99, with higher scores meaning greater impairment. | Baseline and after 6 weeks intervention | 
| BADDS Total Score | The total BADDS ranged from 0-120 with higher scores meaning greater problems with memory, attention and focus. | Baseline and after 6 weeks intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure |  | Baseline and after 6 weeks intervention | 
| Heart Rate |  | Baseline and after 6 weeks intervention | 
| Weight |  | Baseline and after 6 weeks intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menopause, Cognition