In longitudinal analyses that spanned 10 years, we found that the odds of experiencing a major depressive episode was significantly greater when women were perimenopausal and postmenopausal than when they were premenopausal, independent of a baseline history of major depression and annually measured very upsetting life events, use of psychotropic medications, reproductive hormone characteristics, BMI, and frequent VMS. These findings are consistent with previous results in the entire SWAN cohort (n=3296) showing that the odds of high depressive symptoms (CES-D score of 16 or higher) were significantly greater as women progressed through the menopausal transition (Bromberger et al, 2007
In the last 3 decades, epidemiological studies of menopause have found no relationship between depressive symptoms and menopausal status (Matthews et al, 1994
; McKinlay et al, 1994; Kaufert et al, 1992
) or in some cases, higher levels of symptoms during perimenopause (Hunter et al, 1992
; Kuh et al, 1997
; Avis et al, 1994
). These studies had numerous methodological limitations, including select or small samples, non-standard measures of depressive symptoms, and inconsistent definitions of menopausal status. Most were cross-sectional. The results of recent longitudinal studies (Freeman et al, 2004
; Maarten et al, 2002
; Cohen et al, 2006
) have more consistently found that the odds of high depressive symptoms were greater during perimenopause than premenopause. Compared to earlier studies, recent studies had larger or more diverse samples, longer and more frequent follow-up, more consistent, careful definitions of menopausal status and used sophisticated analyses that utilized fully the longitudinal data. With one exception (Maarten et al, 2002
), these studies did not find an increased risk for depressive symptoms postmenopause. The null findings may have been due to insufficient power because of the relatively small numbers of women followed through postmenopause. For example, the Penn Ovarian Aging study (POA) (Freeman et al, 2004
) reported an increase in depressive symptoms in the perimenopause and a subsequent decline postmenopause over 4 years of follow-up. However, in this study 73% of the 332 participants remained premenopausal over the 4 years of follow-up.
Three longitudinal studies of menopause have assessed depressive disorders (Freeman et al, 2004
; Cohen et al, 2006
; Schmidt et al, 2004
). The POA found that depressive disorders, were not more likely to occur during the menopausal transition than premenopausal (Freeman et al, 2004
). However, this study was limited by having only 4 years of data collection, only 3% of the sample had reached postmenopause, and the assessment of MDE covered only the past month, making the numbers for postmenopause and MDE too small to determine statistical significance. The POA and Harvard Study of Moods and Cycles reported an increased risk of first onset depressive disorder during perimenopause compared to premenopause over 8 years. (Cohen et al, 2006
). Importantly, neither study included women who had ceased menstruating and only examined a subset of women.
Our findings of an increased risk of MDE during postmenopause and particularly during the first two years after the final menstrual period are similar to those reported in a small longitudinal study (5 years) that followed 29 regularly cycling women in their 40s through one year after their last menses (Schmidt et al, 2004
). In this study, every 3–6 six months detailed measures of menstrual cycles, symptoms, and depression as well as plasma FSH were collected and the SCID was conducted to obtain data on episodes of minor and major depression. Results indicated that women were significantly more likely to experience an episode of clinical depression (primarily minor depression) during the year before or after their final menstrual period than when they were premenopausal.
In our sample, the increased vulnerability to a MDE during and after the menopausal transition was not accounted for by frequent VMS or by levels of or changes in reproductive hormones. Lack of a statistically significant association between frequent VMS and MDE may be due to the short time frame over which we assessed VMS (i.e., past 2 weeks). It is possible that a measure of VMS frequency over a longer period of time may have been more strongly related to major depression onset in the multivariate analysis and may have attenuated the association between menopausal status and MDE, particularly because VMS may wax and wane across a period of time. Nonetheless, future studies should continue to examine the role of VMS in the development of MDEs.
We found no significant associations between any reproductive hormone and MDEs which is consistent with the literature showing no direct associations between depression and serum estradiol (E2) levels (Schmidt et al, 2002
). However, single annual hormone samples have limited ability to provide information about the underlying hormonal dynamics that occur during the menopausal transition. Reproductive hormone secretion, especially that of estradiol, is subject to great variability during the menopausal transition. It has been hypothesized that the fluctuations in reproductive hormones in susceptible women pose a risk for depression. However, we found no association between change or variability in hormones over time with major depression. In contrast, the POA study of first onset depression did report an association between the variability of E2 and FSH measured at two consecutive monthly assessments with high depressive symptoms or depressive disorder (Freeman et al, 2006
). Our null result for testosterone was in contrast to our previously reported associations between high depressive symptom scores (CES-D ≥16) and testosterone levels and changes in these over the first eight years of SWAN in the entire cohort. The conflicting findings may be due to the relatively small sample of women in the current analysis (n=221) compared to the SWAN cohort of more than 3,000 women. Perhaps, T is more likely to be associated with the level of depressive symptoms than to the syndromal cluster represented by MDE.
It is noteworthy that the odds of a MDE were nearly tripled in those with a history of major depression at baseline or at least one very upsetting event at the annual visits (ORs=2.83 and 2.93, respectively) indicating that in addition to and independent of menopausal status, lifetime depression history and the experience of recent life stressors made significant contributions to the risk of a MDE. Both factors are known to be consistently related to major depression (Kendler & Gardner, 2010
) but prior studies of menopause have not assessed their importance relative to the menopausal transition.
In addition to the limitations concerning the measures of VMS and hormones described above, other limitations of the current report are important. Because of the small size of the sample, we were limited in our ability to examine racial/ethnic differences in major depression according to menopausal status and/or history of major depression at study entry. However, in a future paper encompassing a longer period of follow-up we will focus on the characteristics and subgroups of midlife women that may be particularly vulnerable to a MDE. Second, structured interviews, although they improve diagnostic reliability and validity, are subject to subjective recall and interpretation of symptoms.
Finally, we do not know the potential bias introduced by the absence of data on women whom we could not contact or who refused to complete the initial telephone screener. If this group of women included more who were depressed at the time of contact than did the group who participated, there would likely be more cases of major depression during the study. Because our sample is not large enough to determine whether women with a prior history of depression would be more likely to experience a subsequent MDE when they were peri- or post menopausal than premenopausal, we cannot know how our current findings would be affected.
The current study is unique in its ability to assess major depression annually in midlife African American and Caucasian women as they transitioned through perimenopause and postmenopause. We used a standard semi-structured interview to assess MDE during the time between visits and currently which allowed us to account for episodes for the entire 10-year period. The current findings confirm the greater risk for MDEs during the menopausal transition than before. While our data also indicate that the years immediately after the transition are a high risk period for MDEs, these findings warrant confirmation when all SWAN participants become late postmenopausal. Many questions remain regarding the factors that contribute to the elevated risk of MDEs during the menopausal transition and after including the role of reproductive hormone changes and the characteristics of the subgroup of vulnerable women. When all women enrolled in our study complete the menopausal transition, we will be able to address these important questions in further detail.