Menopause Live - IMS Updates

Date of release: 14 March, 2011

Postmenopausal depression and dementia: are the 2D’s connected?

The aim of this recent analysis from the Women’s Health Initiative Memory Study (WHIMS) was to examine whether significant depressive symptoms in postmenopausal women increase the risk of subsequent mild cognitive impairment (MCI) and probable dementia [1]. Participants were 6376 postmenopausal women without cognitive impairment aged 65–79 years at baseline (mean 70 years), who were assigned either to receive hormone therapy (conjugated equine estrogens alone (CEE) or CEE + medroxyprogesterone acetate) or placebo. Depressive disorders were assessed using an eight-item Burnam algorithm and the women were followed annually for a mean period of 5.4 years. A central adjudication committee classified the presence of MCI and probable dementia based on an extensive neuropsychiatric examination. About 8% of the postmenopausal women in this sample reported depressive symptoms above a 0.06 cut-point on the Burnam algorithm. Depressive disorder at baseline was associated with greater risk of incident MCI (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.33–2.94), probable dementia (HR 2.03, 95% CI 1.15–3.60), and MCI or probable dementia (HR 1.92, 95% CI 1.35–2.73) after controlling for sociodemographic characteristics, lifestyle and vascular risk factors, cardiovascular and cerebrovascular disease, antidepressant use, and current and past hormone therapy status. Assignment to hormone therapy and baseline cognitive function did not affect these relationships. Women without depression who endorsed a remote history of depression had a higher risk of developing dementia. Thus, the conclusion of this WHIMS analysis was that clinically significant depressive symptoms in women aged 65 and older are independently associated with greater incidence of future MCI and probable dementia.


So many old people have symptoms of depression, and many others have cognitive decline or overt dementia. It is noteworthy that MCI is regarded as a prodromal stage of full-blown dementia, and that every year about 10–15% of those diagnosed as having MCI become demented. The possible association of depression and cognition in the aged has been well investigated. It has been shown that the higher the depression score at baseline, the greater is the risk for future Alzheimer's disease or cognitive impairment [2]. However, an intriguing question is whether the presence of depression is a cause or an early manifestation of cognitive decline. The WHIMS platform allowed a thorough examination of this issue in a large-scale, prospective study using a cohort of old postmenopausal women [1]. Indeed, the study demonstrated that the patients who were depressed had twice the hazard of developing MCI and probable dementia, and this remained significant after adjusting for multiple potential confounding variables. 
The current theories to explain such an association ‘blame’ the excessive release of stress hormones during a depressive episode, which may result in neurotoxic damage and brain atrophy. Another potential mechanism is based on a link between the presence of apolipoprotein E epsilon4 allele genotype, depressive symptoms and accumulation of amyloid in the brain [3]. Interestingly, while previous studies in depressed patients pointed at a smaller hippocampal volume, which was inversely associated with the number of years since the first lifetime episode of depression [4], the WHIMS investigators found that certain frontal regions, rather than the hippocampus, were affected: total ischemic lesion volumes in the basal ganglia and the cerebral white and gray matter were similar in women with and without depression [5]. 
It seems, therefore, that late-life depression is associated with MCI and probable dementia. The remaining important question is, of course, whether early diagnosis and treatment of depression will decrease the chance for future cognitive problems. In a study from Denmark, it was found that persons who purchased antidepressants at least once (n = 687,552) had an increased rate of dementia compared to persons unexposed to antidepressants (n = 779,831) [6]. Continued long-term antidepressant treatment was associated with a reduced rate of dementia; however, not to the same level as the rate for the general population.


Amos Pines
Department of Medicine T, Ichilov Hospital, Tel-Aviv, Israel


  1. Goveas JS, Espeland MA, Woods NF, Wassertheil-Smoller S, Kotchen JM. Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Womens Health Initiative Memory Study. J Am Geriatr Soc 2011;59:57-66.

  2. Wilson RS, Barnes LL, Mendes de Leon CF, et al. Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology 2002;59:364-70.

  3. Irie F, Masaki KH, Petrovitch H, et al. Apolipoprotein E epsilon4 allele genotype and the effect of depressive symptoms on the risk of dementia in men: the Honolulu-Asia Aging Study. Arch Gen Psychiatry 2008;65:906-12.

  4. Bell-McGinty S, Butters MA, Meltzer CC, et al. Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. Am J Psychiatry 2002;159:1424-7.

  5. Goveas JS, Espeland MA, Hogan P, et al. Depressive symptoms, brain volumes and subclinical cerebrovascular disease in postmenopausal women: The Womens Health Initiative MRI Study. J Affect Disord 2011 Feb 23. Epub ahead of print.

  6. Kessing LV, Sndergrd L, Forman JL, Andersen PK. Antidepressants and dementia. J Affect Disord 2009;117:24-9.