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

Menopause Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00611533
• Other study ID #: 0403026533
• Status: Completed
• Phase: N/A
• First received: January 29, 2008
• Last updated: January 3, 2017
• Start date: May 2004
• Est. completion date: April 2008

Study information

• Verified date: December 2016
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: April 2008
• Est. primary completion date: April 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 45 Years to 60 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cognitive Disturbances
• Menopause

Intervention

Drug:
• atomoxetine
Twenty subjects will be 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.
• placebo
placebo

Locations

Country	Name	City	State
United States	Yale University School of Medicine	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	Eli Lilly and Company

Country where clinical trial is conducted

United States, 

References & Publications (5)

Jezierski MK, Sohrabji F. Neurotrophin expression in the reproductively senescent forebrain is refractory to estrogen stimulation. Neurobiol Aging. 2001 Mar-Apr;22(2):309-19. — View Citation

Sherwin BB. Estrogen and cognitive functioning in women. Proc Soc Exp Biol Med. 1998 Jan;217(1):17-22. Review. — View Citation

Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J; WHIMS Investigators.. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651-62. — View Citation

Wise PM, Smith MJ, Dubal DB, Wilson ME, Krajnak KM, Rosewell KL. Neuroendocrine influences and repercussions of the menopause. Endocr Rev. 1999 Jun;20(3):243-8. Review. — View Citation

Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC; Cache County Memory Study Investigators.. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002 Nov 6;288(17):2123-9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Women will have a reduction in score on the Brown Attention Deficit Disorder Scale and will perform better on measures of verbal memory and fluency as well as concentration and attention during ATX administration compared to placebo (PBO) administration.		16 weeks	No
Secondary	Brown Attention Deficit Disorder Scale (BADDS)-Adult Version total score and cluster scores from the women participating in this study will be compared to those from an age-matched sample of women with ADD (historical sample).		16 weeks	No