Clinical trial NCT00611533: Placebo Controlled Study of Atomoxetine in the Treatment of Mild to Moderate Cognitive Difficulties in Menopausal Women
Official title: A Controlled Trial of Atomoxetine in the Treatment of Mild to Moderate Cognitive Difficulties in Menopausal Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Menopause
Cognitive Disturbances
Keywords: Menopause
Cognition
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
First posted: 2008-02-11
Enrollment: 16
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Brown Attention Deficit Disorder Scale
timeFrame: Baseline and after 6 weeks intervention
measure: BADDS Total Score
timeFrame: Baseline and after 6 weeks intervention
Secondary outcomes:
measure: Blood Pressure
timeFrame: Baseline and after 6 weeks intervention
measure: Heart Rate
timeFrame: Baseline and after 6 weeks intervention
measure: Weight
timeFrame: Baseline and after 6 weeks intervention
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
Study officials:
affiliation: Yale University School of Medicine, Department of Psychiatry
name: Cynthia N Epperson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1016/s0197-4580(00)00230-x.
citation: Sherwin BB. Estrogen and cognitive functioning in women. Proc Soc Exp Biol Med. 1998 Jan;217(1):17-22. doi: 10.3181/00379727-217-44200.
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. doi: 10.1001/jama.289.20.2651.
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. doi: 10.1210/edrv.20.3.0364.
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. doi: 10.1001/jama.288.17.2123.