It is well-known that depression is a leading cause of disability. In the United States, it is estimated that approximately 16% of the population will meet criteria for major depressive disorder (MDD) in their lifetime, with women being 1.7 times more likely than men to develop the disorder (24). The predominance of women in those with MDD has generated considerable research focusing on the endocrine/biological differences between males and females and the increased risk of MDD during periods of reproductive changes and events in women. In the Study of Women’s Health Across the Nation (SWAN), a multicenter, multiethnic, community-based cohort study of women, we have shown that that change in menopausal status from pre- to early perimenopause and late perimenopause is independently associated with increased risk of a high level of depressive symptoms (5). Thus, the menopausal transition represents a period of vulnerability to depression that would benefit from better methods of prevention and intervention, particularly nonpharmacological approaches.
We were particularly interested in the possible protective role that moderate-intensity physical activity (PA) might have on depression in midlife women and the persistence of this association across time. The public health-recommended dose of 150 min of moderate-intensity PA weekly has been associated with multiple health benefits (19). Cross-sectional studies in midlife women consistently demonstrate positive association between PA and positive mood, vigor, and general well-being (8,9,11,15,28,44,45) and negative association with negative symptoms, such as depression, anxiety, and perceived stress (11,13,28,35,46), but the study populations, covariates, PA measures, and depression outcomes varied. The Melbourne Women’s Midlife Health Project looked longitudinally at change in well-being (rather than depression or depressive symptoms) and found a marginally significant positive association with change in well-being and PA over a 3-yr follow-up period (18). In the Belgian National Health Interview Survey of more than 6800 adults age 25–64 yr of age, for women, positive correlations were found for self-reported walking and emotional well-being, different from men with positive correlations between vigorous activity and mood (1).
Randomized trials of exercise show that women in exercise groups report improvements in mood symptoms, relative to controls, with structured supervised programs for several hours per week over several months, including aerobic and strength training (14,27,39,42). For example, Dennerstein et al. (11) compared the public health guidelines recommendation of 150 min of moderate-intensity PA weekly with a lower dose of PA and found that after 12 wk of supervised exercise in individuals with MDD, only the dose meeting public health guidelines was associated with reduced depressive symptoms at a rate similar to other antidepressant interventions. A community based controlled trial of strength training using elastic bands with women with mean age of 68 yr demonstrated improvements in strength but not in mental health functioning (10). In an intervention study on sedentary midlife African-American women, adherence to a community-based walking program at moderate intensity was associated with lower depressive symptoms at 6 months (47). Trivedi et al. (38), in the TReatment with Exercise Augmentation for Depression (TREAD) study, tested the efficacy of two different doses of aerobic exercise in patients with MDD who had not remitted with antidepressant medication and found a trend toward a higher remission rate in the higher-dose exercise group. Furthermore, they concluded that higher-dose exercise may be better for women without a family history of mental illness. Researchers in the United Kingdom used accelerometers to correlate objectively measured level of PA with daily positive emotional style but not psychophysiological stress responses in 40 healthy females (age 28.7 ± 6.1 yr) (30). Of interest, using cut points for the accelerometer data, the positive correlation with daily mood was found for light- and moderate-intensity but not vigorous-intensity PA.
SWAN provides the opportunity to examine in midlife women the independent association between naturally occurring changes in PA and changes in depression across time, adjusting for covariates that might confound this association The current analyses tested the hypothesis that a level of PA that approximates the public health recommendation of 150 min·wk-1 of moderate-intensity PA (referred to here as “meeting PA guidelines”) is longitudinally associated with lower levels of depressive symptoms over 10 yr, independent of potential confounders. In addition, we tested the hypothesis that women who reported some exercise but not at a level that approximates the public health recommended dose (“below PA guidelines”) would also report fewer depressive symptoms over 10 yr than women with no reported exercise or sports activity (“inactive”). Results of this evaluation can increase our understanding of the extent to which PA may be useful in managing depression in midlife women and how persistent the relation may be over midlife, a time of vulnerability.
Participants for the current analysis were from the SWAN. Between 1995 and 1997, SWAN recruited over 3000 women from five ethnic/racial groups who self-identified as Caucasian, African-American, Japanese, Chinese, or Hispanic. Recruiting from seven sites allowed for recruitment of Caucasian women and one specified minority group (African-Americans in Pittsburgh, Boston, the Detroit area, and Chicago; Japanese in Los Angeles; Chinese in the Oakland region; and Hispanics in Newark) at each site. Women age 42–52 yr with an intact uterus and at least one ovary were invited to participate in SWAN as long as they had menstruated in the previous 3 months, were not currently pregnant or breast feeding, and had not used reproductive hormone preparations affecting ovarian or pituitary function in the past 3 months. Several population sampling techniques were used, and institutional review board approval and informed consent were obtained by all sites, as previously described (36). At study entry and annually thereafter, women at all sites completed a standard assessment that included self-administered and interviewer-administered questionnaires assessing sociodemographic, behavioral, psychological, physical, health, and lifestyle characteristics. Interviews and questionnaires were available in English, Spanish, Cantonese, and Japanese. All women provided a written informed consent. Of the 3302 midlife women enrolled in SWAN, this analysis includes data from 2891 participants who provided data on PA level, depressive symptoms, and relevant covariates in one or more annual assessments.
Data for the current study were obtained from self-administered and interviewer-administered questionnaires at baseline and at annual follow-up (F/U) visits for 10 yr. Data on PA were collected at baseline and F/U years 3, 6, and 9. Sociodemographic data including age, ethnicity, marital status, and education were collected at baseline. Time-varying covariates including depressive symptoms, menopausal status, body mass index (BMI), social support, very stressful life events, antidepressant medication use, and hormone replacement therapy (HT), smoking status, frequent hot flashes, or night sweats were assessed at baseline and at each of the following visits.
PA was measured using a version of the Kaiser Physical Activity Survey (KPAS), originally adapted from the Baecke questionnaire (2) that consists of 38 items (37). The KPAS is self-administered, asks about PA in the past year, and assesses PA in four domains (sports/exercise, active living, occupational, and household/caregiving). Most of the items have categorical responses that are combined to provide domain-specific indices and a total score. For this analysis, the results in the sports/exercise domain were used (an open-ended question about participation in most frequent sport or exercise and three questions with categorical responses for frequency, duration, and relative intensity). Women reported a broad range of sports and exercise, including team sports, individual sports, and recreational activities including walking. Women who reported playing sports or exercising more than once a week, for at least 2 h·wk-1, with a moderate or greater increase in HR and breathing, and for more than 9 months per year were classified into the “meeting PA guidelines” group. We considered this level of PA to approximate the public health guidelines recommendation of 150 min·wk-1 of moderate-intensity PA for health benefits (19). Women who reported sports or exercise but not at the frequency, relative intensity, or duration approximating the public health guideline were classified as the “below PA guidelines” group. Women who never reported any participation in sports or exercise were classified as the “inactive” group (referent). The three groups were mutually exclusive. Those who were inactive reported not participating in any sports or exercise. The below PA guidelines group could report sports or exercise activity ranging from a very small or irregular amount of PA to just below guidelines. Likewise, the meeting PA guidelines group could range from just meeting guidelines to very active.
Dependent variables.Depressive symptoms.
Depressive symptoms were measured with the 20-item Center for Epidemiological Studies Depression Scale (CES-D), which assesses the frequency of being bothered by depressive symptoms in the past week on a scale from 0 (rarely) to 3 (most or all of the time) (33). Responses to the 20 items are summed for a total score ranging from 0 to 60. CES-D scores of 16 or higher indicate “high depressive symptoms” with possible clinical implications (3). The CES-D has been shown to be valid and reliable in diverse ethnic populations (22,48).
Covariates were chosen for inclusion in statistical analyses because of their established relation with PA and/or relevance to the possible relation between PA and depressive symptoms based on the literature (4,6,16,23). Standard self-report questions frequently used in epidemiological studies were used to assess most of the covariates. Age was self-reported in years. Cigarette smoking (yes/no) and hot flashes (present <6 d or >=6 d in the previous 14 d) were self-reported. Interviewer-administered questions included race/ethnicity self-identification as African-American, Chinese, Hispanic, Japanese, or Caucasian (referent category). Respondents were classified to high education (some college education or higher) or not. Marital status was defined as either married and/or living as married or not married. Menopausal status was considered in two groups: premenopausal/early perimenopausal versus late perimenopausal/postmenopausal (no menstrual bleeding for at least 3 months/12 months). Antidepressant medication and HT use was based on use in the past month. BMI was calculated from measured height and weight using a standardized protocol. Psychosocial variables included social support, four items from the Medical Outcomes Study Social Support Survey, summed and used continuously with possible scores ranging from 0 for least social support to 16 for most social support (34) and stressful life events based on a checklist of 18 life events rated according to how stressful they were. The number of very stressful events since the last study visit was categorized as 0, 1, or 2 or more.
Four assessment TIME PAIRs were created and used in the analyses, linked to the four available PA measurements, as PA was not measured annually. We paired PA measured at baseline, F/U visit 3, F/U visit 6, and F/U visit 9 with CES-D in the following visit (F/U visit 1, F/U visit 4, F/U visit 7, and F/U visit 10) for TIME PAIR 0, TIME PAIR 1, TIME PAIR 2, and TIME PAIR 3 analyses, respectively. Each TIME PAIR analysis included baseline variables and time-varying covariates collected at each of the four PA visits. This allowed us to examine whether the association between PA and depressive symptoms changed over time, independent of the effect of the covariates.
Participant characteristics at TIME PAIR 0 were summarized using mean (SD) for continuous variables and n (%) for categorical variables for the overall cohort and by PA group. Group differences were tested using ANOVA for continuous variables and chi-square tests for categorical variables. To summarize changes of depressive symptoms and PA, the proportions of participants with high depressive symptoms and of those meeting PA guidelines were computed in each TIME PAIR. Similarly, the proportions of participants with high depressive symptoms and of those below PA guidelines were computed in each TIME PAIR. Persistence of high depressive symptoms was defined as having high depressive symptoms over at least two consecutive TIME PAIRs (0 and 1, 1 and 2, or 2 and 3). Similarly, persistence of meeting PA guidelines was defined as meeting PA guidelines over at least two consecutive TIME PAIRs (0 and 1, 1 and 2, or 2 and 3).
The associations between PA and depressive symptoms in the four TIME PAIRs were assessed using mixed effects logistic regression (20). PA and covariates collected at a given visit were included as time-varying predictors of depressive symptoms in the subsequent visit year. All analyses included baseline time-invarying covariates. A random intercept for each participant represented her depressive tendency over time, e.g., the greater the exhibition of high depressive symptoms, the higher the random intercept. Therefore, the mixed model provides the association between PA and depressive symptoms, controlling for participants’ depressive tendency. To determine whether the associations between PA and depressive symptoms were similar over TIME PAIRs, two models were run, one that allowed for associations to vary by TIME PAIRs and another with a fixed association across TIME PAIRs. This step was taken to determine the feasibility of performing the analyses, assuming a fixed association. The final analyses were conducted first as bivariate models without including any covariates and then as multivariable models controlling for covariates. All statistical tests were two tailed, with statistical significance set at P < 0.05. All analyses were conducted using SAS 9.2 (SAS Institute, Cary, NC).
Among 2891 total eligible participants, the number of participants providing data included in TIME PAIR 0, TIME PAIR 1, TIME PAIR 2, and TIME PAIR 3 was 2682, 1951, 1554, and 1447, respectively. Because one of the variables in TIME PAIR 0 was missing (either baseline PA measurement, a time-varying covariates or CES-D at follow-up visit 1) in 209 participants, their data were included in TIME PAIR 1, TIME PAIR 2, and/or TIME PAIR 3 when all variables were completed. Table 1 shows the overall characteristics of the cohort and by PA level at TIME PAIR 0 for 2682 participants (2891 - 209 = 2682). At baseline, the participants were 46 yr of age on average, with 49% self identifying as Caucasian. They were well educated, with 77% reporting education beyond high school. Their mean BMI was 28.0 (SD, 7.1). One-fifth of the participants (20.0%, n = 535) had high depressive symptoms (CES-D, >=16). Only 17% reported meeting PA guidelines. There were statistically significant PA group differences for multiple covariates, such that among women meeting PA guidelines, lower average BMI and higher average social support were each associated with a lower proportion of participants who reported high depressive symptoms (Table 1).
Over the decade of data collection in SWAN, different trends in high depressive symptoms and meeting PA guidelines were noted. The proportion of participants with high depressive symptoms decreased, whereas the proportion of those meeting PA guidelines increased over time (Table 2). The individuals in the group with high depressive symptoms or meeting PA guidelines were not consistent over time. About half of the participants who had high depressive symptoms in a previous TIME PAIR also had high depressive symptoms in the subsequent TIME PAIR. Similarly, about half to two-thirds of the participants meeting PA guidelines in a previous TIME PAIR engaged in this level of PA in the subsequent TIME PAIR (Table 3).
The relation between PA and high depressive symptoms did not differ over time either in the bivariate analysis (chi-square = 1.7; df = 6; P = 0.94) or multivariate analysis (chi-square = 27.5; df = 33; P = 0.74). Therefore, we present only results of the analysis where we assumed a constant association over time. In unadjusted analyses, PA, either meeting PA guidelines or below, was negatively associated with high depressive symptoms in the following year. Odds of having high depressive symptom for participants meeting PA guidelines and below PA guidelines were about two-thirds (odds ratio, 0.34) and one-third (odds ratio, 0.65) lower, respectively, compared with that in inactive participants. Controlling for covariates, odds ratios for PA meeting guidelines or below PA guidelines, were reduced but still significantly negatively associated with high depressive symptoms. The odds of having high depressive symptoms for participants meeting PA guidelines and below PA guidelines were about half (0.52; 95% confidence interval, 0.40–0.70) and one-fifth (0.81; 95% confidence interval, 0.67–0.98), respectively, compared with that in inactive participants (Table 4). Despite the finding that the individuals in the group with high depressive symptoms or meeting PA guidelines were not consistent over time, the relation between the two variables persisted over the TIME PAIRs.
Married individuals were less likely to report high depressive symptoms, and Japanese and Hispanic individuals were more likely than Caucasians to report high depressive symptoms. Time-varying covariates include the following: current smoker, very upsetting life events, antidepressive medications use, hot flashes, and BMI. These covariates were all positively associated with high depressive symptoms. Higher social support was associated with reduced odds ratios. Menopausal status was not associated with high depressive symptoms in this analysis.
In this study, we assessed whether PA levels, particularly at the dose, frequency, and relative intensity approximating public health guidelines, were longitudinally associated with lower levels of depressive symptoms over 10 yr, independent of potential confounders. To our knowledge, this is the first study exploring the longitudinal relation between PA and depressive symptoms in midlife women over a decade. Consistent with previous studies, we found that PA is inversely related to depressive symptoms, possibly conferring a protective effect. This inverse relation is particularly meaningful during midlife because menopause and its accompanying hot flashes, which can last for a number of years, have been associated with increased risk of potentially clinically significant levels of depressive symptoms (5). Our study demonstrates the positive effects of voluntary exercise and PA on mental health, with greater effect at the dose recommended by the Centers for Disease Control and Prevention (7). Given the high prevalence of depression in the United States, particularly for women, exercise is still not considered a first-line treatment option, even though exercise can be of low cost and low risk, can be sustained indefinitely, and has additional benefits for multiple aspects of physical health and physical function. A 12-wk exercise program for MDD nonremitted with selective serotonin reuptake inhibitor treatment has shown positive outcomes at two different doses of PA (38). This is particularly important to menopausal women who are accumulating greater health risks and disability. Furthermore, our results are strengthened by our analysis demonstrating a persistent relation between PA and mood over time despite the finding that the individuals in the group with high depressive symptoms or meeting PA guidelines were not consistent over time.
Of interest, the menopausal variable in the mixed model is not significant. It may be that PA is a stronger correlate of depressive symptoms than menopausal status. However, this finding may be related to the variable construct we used. It is likely that combining pre- and early perimenopausal as the reference group accounts for the differences in results from the previous analysis. The previous analysis compared premenopausal with early peri-, late peri- and postmenopause (5). Early perimenopause had significantly higher odds of high CES-D than premenopause. In addition, hot flashes are strongly associated with menopausal status, particularly prevalent during late peri- and postmenopause, and are apparently a better predictor of high depressive symptoms than the status variable itself in these analyses. Other covariates were significantly associated with high depressive symptoms. Married individuals and women with education greater than high school were less likely to report high depressive symptoms, and Japanese and Hispanic individuals were more likely than Caucasians to report high depressive symptoms. Over time, smokers, women experiencing very upsetting life events, taking antidepressive medications, having hot flashes, reporting low social support and higher BMI, were at greater risk for high depressive symptoms. The associations observed are consistent with what has been observed in other studies on depression in midlife women (4,17). Importantly, these data suggest that even when common predictors of depression are accounted for, PA, particularly PA that meets guidelines, is associated with reduced risk for high depressive symptoms.
Repeated assessment of the association over time revealed that the magnitude of the association was not affected by chronological age but was constant from a mean age of 46 yr old in TIME PAIR 0, to a mean age of 55 yr old in TIME PAIR 3. Finally, both PA level and level of depressive symptoms changed considerably over time (e.g., about half of subjects meeting PA guidelines at TIME PAIR 0 did not meet it at TIME PAIR 1), suggesting the importance of interventions that not only increase but sustain regular PA. Similarly, it is noteworthy that depressive symptom reports also change over time but persist in about half of the subjects. The importance of the varying symptoms and behaviors may be taken into account by clinicians caring for midlife women who will need to reinforce not only adopting but sustaining healthy behaviors.
Both psychological and physiological mechanisms, including reduced inflammation (32), increased levels of neurotransmitters (specifically dopamine and serotonin), and enhanced brain aminergic synaptic transmission (43), increased endorphin secretion (21), distraction from stressful stimuli (25), and improved self-efficacy and self-esteem (29) may be responsible for these observed protective effects. In the TREAD study, pro-inflammatory cytokines were measured before and after the 12-wk exercise intervention, with higher baseline levels of tumor necrosis factor alpha associated with greater decrease in depression symptoms (32). In addition, a significant positive correlation between change in interleukin-1 beta levels and change in depression symptoms scores was observed. Endocannabinoids, like the endogenous opioids, are known to have anxiolytic and analgesic properties and to be present in elevated concentrations in the body after exercise and may be another plausible mechanism for the physiological basis for the benefits of PA on mental health (12). The positive role of PA in brain health has been linked to increased expression of brain-derived neurotrophic factor, a protein hypothesized to limit or repair the damage caused by stress (26). Exercise is known to increase levels of a number of neurotrophic factors in both experimental animals and humans (41) and induce activity in the prefrontal cortex on neuroimaging that parallels those seen with antidepressant medications (31). Our results suggest that the “dose” of moderate-intensity PA that has been recommended for other health benefits, including increased longevity, decreased risk of cardiorespiratory and metabolic diseases and some cancers (most notably colon and breast cancer), maintenance of energy balance, and improved musculoskeletal health and function (40), also seems to be protective of depressive symptoms.
Given the myriad positive effects of this level of PA, it is likely that for each individual, there is a unique and important benefit to one’s physical and emotional health bestowed by meeting PA guidelines. Sadly, less than half of the population regularly participates in PA at the guideline level linked to health benefits and adherence to PA guidelines is even lower among women age 40–60 yr (7). This finding persists in our current study, with only 17% of participants reporting PA at the “meeting guidelines” level. Maintenance of the recommended level over a decade in midlife is even more challenging. Behavior change models that focus on sustained changes in PA need to be the focus of public health research and clinical care. Sustaining even modest levels of PA may prevent depressive symptoms, so public health messages should support all PA behavior. There may be gender differences relative to PA and mood that should be considered in tailoring these messages.
Strengths of this study include the following: a large multiracial sample of women from a well-characterized cohort study, 10 yr of follow-up data, adjustment for important covariates, an extensive validated PA questionnaire allowing for a calculation of dose of PA approximating public health guidelines, repeated assessments of the association over a decade, which revealed the robust association, and the opportunity to study persistence of the relation between PA and depressive symptoms.
Limitations of this study include recall survey methodology of the dependent and independent variables, no objective measure of PA, and no measure of clinical depression. We were not able to determine the exact volume of exercise, allowing only an approximate comparison between the recommended public health dosing of exercise and our approximation of the recommended amount. We were constrained by the SWAN study protocol, which measured PA on average every 3 yr rather than annually. This led to our paired groupings of PA in 1 yr and CESD in the subsequent year, at TIME PAIRs 0–3. Covariate time frames reflected recall from the past 4 wk, i.e., social support, up to the past 1 yr, i.e., upsetting life events, whereas the time frame of the CESD was the past 1 wk and the KPAS was the past 1 yr. As in all longitudinal studies, participant dropouts played a role and may have biased our sample and hence our findings. The proportion of participants with high depressive symptoms decreased, whereas the proportion of those meeting PA guidelines increased over time, which might reflect a tendency for women with lower depressive symptom levels to continue in the study, whereas those with higher symptom levels dropped out. Likewise, women who were more active may have been more committed to attending follow-up visits than inactive women. Finally, we had very small frequencies of participant data in some of the cells, i.e. Hispanics meeting guidelines, which limited inferences regarding racial differences.
To our knowledge, the current study is the first longitudinal study on PA, at and below PA guidelines, and depressive symptoms to be conducted in a large and diverse sample of midlife women traversing the menopause. The results are independent of multiple relevant and confounding covariates, including BMI, sociodemographics, HT, and antidepressive medication use. Notably, the association between PA and high depressive symptoms was found for both PA groups, meeting or below guidelines, relative to the inactive group and persisted over time. Our findings suggest that motivating midlife women to maintain at least some level of moderate-intensity PA may be protective against depressive symptoms, with some activity better than inactivity. Depression leads to extensive social, emotional and economic impairments, and raising awareness of approaches to prevent or reduce its symptoms at this vulnerable time for women would be extremely valuable, even life changing. Our findings provide another example to share with midlife women and their health care and wellness providers as they make suggestions for robust sustained lifestyle behavior changes that diminish one’s risk of depressive symptoms and their sequelae during midlife, a particularly vulnerable time for women.
We thank the study staff at each site and all the women who participated in SWAN.
The following provided funds for this study: National Institutes of Health, U.S. Department of Health and Human Services, through the National Institute on Aging, the National Institute of Nursing Research, and the National Institutes of Health Office of Research on Women’s Health (grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495).
The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging, National Institute of Nursing Research, Office of Research on Women’s Health, or the National Institutes of Health.
Clinical Centers: University of Michigan, Ann Arbor—Siobán Harlow, PI 2011–present, MaryFran Sowers, PI 1994–2011; Massachusetts General Hospital, Boston, MA—Joel Finkelstein, PI 1999–present; Robert Neer, PI 1994–1999; Rush University, Rush University Medical Center, Chicago, IL—Howard Kravitz, PI 2009–present; Lynda Powell, PI 1994–2009; University of California, Davis/Kaiser—Ellen Gold, PI; University of California, Los Angeles—Gail Greendale, PI; Albert Einstein College of Medicine, Bronx, NY—Carol Derby, PI 2011–present, Rachel Wildman, PI 2010–2011; Nanette Santoro, PI 2004–2010; University of Medicine and Dentistry—New Jersey Medical School, Newark—Gerson Weiss, PI 1994–2004; and the University of Pittsburgh, Pittsburgh, PA—Karen Matthews, PI.
National Institutes of Health Program Office: National Institute on Aging, Bethesda, MD—Winifred Rossi 2012–present; Sherry Sherman 1994–2012; Marcia Ory 1994–2001; National Institute of Nursing Research, Bethesda, MD—Program Officers.
Central Laboratory: University of Michigan, Ann Arbor—Daniel McConnell (Central Ligand Assay Satellite Services).
Coordinating Center: University of Pittsburgh, Pittsburgh, PA—Maria Mori Brooks, PI 2012–present; Kim Sutton-Tyrrell, PI 2001–2012; New England Research Institutes, Watertown, MA—Sonja McKinlay, PI 1995–2001.
Steering committee members are Susan Johnson, current chair, and Chris Gallagher, former chair.
The authors have no conflicts of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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