Due to the inconsistency in the literature regarding the relationship between cortisol and depressive symptoms (11
), we aimed to understand this association better by studying a large, population-based sample of midlife women. We found that the diurnal slope of salivary cortisol was strongly and independently associated with depressive symptoms in these midlife women. This is a novel finding given that this is a large, generalizable, non-clinical, and community-based epidemiologic sample.
The results of the current study are significant for several reasons. First, they are biologically plausible. Support for this association has been provided by clinical studies aimed at developing hypotheses about the etiology and pathogenesis of depression (33
). Of particular relevance is the hypothesis that depression involves changes in the set point of the HPA system, resulting in altered regulation of cortisol secretory activity via changes in corticotropin-releasing hormone (34
). The suprachiasmatic nucleus (SCN) is one possible mediator of this diurnal cortisol-depression relationship. The SCN is the hypothalamic clock responsible for the rhythmic changes of the stress system, and it appears to have decreased activity in depression (33
). It also has CRH fibers (33
), demonstrating an innate hard wiring for a link between depression, corticosteroids, and diurnal variance. Complex systemic dysregulation involving increased CRH and impaired corticosteroid receptor signaling (34
) may be clinically manifest as impaired diurnal cortisol variation with depression, as we see with our cohort.
Our study also provides a naturalistic, population-based investigation of cortisol response as opposed to more tightly controlled experimental samples (6
) or clinical populations (8
). As noted by Breslau, the suspected association between a disease and a characteristic may be most pronounced in, and often comes from, clinical samples, however, the validity of this association frequently comes from its replication in epidemiological studies (35
Since cortisol is sensitive to, and affected by, a multitude of extraneous influences (36
), measuring cortisol reliably in a population-based sample is especially challenging. Our findings indicate that the association with depressive symptoms is not altered by specific behaviors at the time of saliva sampling that may contaminate the cortisol specimen. It is important to identify reliable, rigorous, low cost, and minimal burden physiologic markers of psychosocial stressors for use in large-scale epidemiologic studies (37
). We have shown that with only three cortisol samples collected at home over the course of a day we can obtain a slope that demonstrates a valid association with depressive symptoms.
Diurnal cortisol is a reliable marker for depressive symptoms even under the influence of the myriad of variables inevitably present in a population-based sample, including differences in sociodemographic factors as well as health and lifestyle behaviors. This supports the independence of the relationship from other known predictors.
Interestingly, the flattened diurnal cortisol slope we found possesses different characteristics than some cortisol rhythm disturbances previously demonstrated. Early timing of the nadir of ACTH-cortisol secretion has been demonstrated in major depressive disorder (38
) and steeper, more rhythmic cortisol slopes driven by elevated morning cortisol has been shown in depressed women with metastatic breast cancer (23
). Our findings, however, illustrate that the dominant effect characterizing flattened cortisol slope seems to be a lower morning cortisol level, which is related in a dose-dependent way to depressive symptoms and does not result in an overall hypercortisolemic state. CES-D scores in this relatively healthy population may reflect less obvious symptomatology than clinical depression, and this blunted or reduced morning rise may be a more subtle, initial sign. In this study of community participants, it appears that a blunting of the diurnal cortisol rhythm is a more sensitive indicator of depression than elevated salivary cortisol levels. Due to the complex and likely bidirectional interaction of cortisol and depressive symptoms, it is difficult to comment on its clinical significance in particular, however, its physiological significance is noteworthy given the disparate findings from previous research.
There may be variation in phenotypes underlying the mechanisms linking psychological processes to health and disease. It has been demonstrated that age, gender, and severity of psychological distress may have varying physiologic manifestations (9
). Certain medical comorbidities may also affect this association as flatter diurnal cortisol slope has been found in depressed people with memory problems (21
) as well as depressed people with coronary artery disease (22
). Understanding these various phenotypes is crucial to targeting populations at risk for adverse health consequences of psychological distress.
Finally, our study population is of clinical importance as midlife women in the late stage of the menopausal transition are particularly vulnerable to depressed mood (39
), with suggestive data that estrogen deficiency (40
) as well as an increasingly testosterone dominated milieu (41
) may contribute to this increased susceptibility. Combined with the loss of protective cardiovascular sex hormones during this time period (42
) as well as already lower bone mineral density in premenopausal women with depression (43
), this particular population is especially susceptible to adverse physiological effects of depression.
There are several limitations to this study. We had a relatively small number of depressed subjects in this population-based sample. However, given that the diurnal cortisol slope has a strong association with depressive symptoms even with this small number, it does not appear to have affected results. While we have awakening times and information on overall sleep problems, we do not have specific information about sleep from the night preceding morning cortisol measurements. It would be interesting to see whether sleep patterns the night before demonstrate an association with cortisol. Nor do we have overnight cortisol levels that, despite its impracticality, would be interesting to have and see whether depressive symptoms affected very early morning cortisol response. Finally, our CES-D and cortisol assessments were separated in time by as many as a few months, which may not be the traditional nature of how this relationship is usually examined. If this in fact introduced error, the direction of bias would be in the null, however, this is not what we found, lending further strength to the relationship we observed. It is unclear whether a flattened diurnal cortisol slope represents a persistent state characteristic of depression or whether this may be more consistent with a trait characteristic. Further studies investigating the temporal relationship between these variables are needed.
Future research should focus on clarifying its clinical significance and determining whether alteration in diurnal cortisol slope may be associated with adverse health consequences observed in depressed individuals (44
). Everson-Rose et al recently showed that increased visceral fat may be one pathway by which depression contributes to excess risk for cardiovascular disease and diabetes (45
); it would be meaningful to examine whether diurnal cortisol slope is a mediator in this relationship.
In conclusion, midlife women from a population-based sample with higher CES-D scores have a significantly flatter diurnal cortisol slope than those with lower scores, even after adjusting for covariates and possibly contaminating behaviors. Further research is needed to examine the health implications of this association.