Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence

Summary

Levels of the stress-sensitive hormone cortisol increase dramatically in the first 30–40 min after waking, an effect known as the cortisol awakening response (CAR). There is considerable cross-sectional evidence that psychosocial stress is associated with an increased CAR, and the CAR has been found to be altered in the presence of stress-related diseases, including major depressive disorder (MDD). To date, no prospective longitudinal studies have examined whether individual differences in the CAR serve as a premorbid risk factor for MDD. In a sample of 230 late adolescents, clinical diagnoses of MDD were predicted from the CAR as well as other indicators of basal cortisol functioning gathered 1 year earlier, including: waking cortisol levels, bedtime cortisol levels, the size of the CAR, average cortisol, and the slope of the diurnal cortisol rhythm across the waking day. Age and gender, health and health behaviors, baseline neuroticism, exposure to stressful life events and past episodes of mood and anxiety disorders were included as covariates, to help ensure effects are attributable to the CAR rather than related variables. A higher baseline CAR was associated with a significantly increased risk of developing MDD by follow-up, even when excluding individuals with baseline MDD. No other baseline cortisol measures were significant prospective predictors of MDD. In summary, the CAR is a significant prospective risk factor for the development of MDD in young adults, providing some support for the possibility that a heightened CAR may play a role in the etiology of major depressive disorder.

Introduction

Dysregulation of the hypothalamic pituitary adrenal (HPA) axis, one of the body's major stress-sensitive physiological systems, is frequently implicated in the etiology of major depressive disorder (MDD) (Ehlert et al., 2001, Gold and Chrousos, 2002, Holsboer, 2000). Robust cross-sectional associations have been found between the presence of MDD and a variety of alterations of the HPA axis, including elevated cortisol levels, elevated corticotropin releasing hormone (CRH), and impaired negative feedback control of the HPA (Chrousos and Gold, 1992, Ehlert et al., 2001, Thase et al., 2002). It is not yet clearly established in human populations whether such alterations are correlates or consequences of the experience of depressive disorder and/or its treatments, or whether they reflect risk or vulnerability factors that are present prior to the onset of disorder, thus potentially playing a role in the pathophysiology of MDD (Bhagwagar and Cowen, 2007). In support of the latter hypothesis, HPA axis alterations have been found among young people without a history of MDD but who are at risk for MDD due to having a biological parent with a history of disorder (Mannie et al., 2007). The gold standard approach to identifying a risk factor, however, involves measuring HPA axis characteristics prior to the onset of MDD, and then following the same individuals longitudinally to identify whether, and which types of HPA axis alterations are associated with higher rates of the development of MDD over the intervening time period.

The few existing studies taking this prospective longitudinal approach have converged upon similar findings. Although elevated cortisol levels across the full day and especially during the evening hours, are the most frequent cross-sectional correlates of MDD (Angold, 2003, Dahl et al., 1991), it is elevated morning cortisol that is prospectively predictive of depression (Goodyer et al., 2000, Halligan et al., 2007, Harris et al., 2000).

Cortisol diurnal rhythms vary according to individual sleep–wake schedules, being high upon waking, increasing to peak levels approximately 30–40 min after waking, and declining to a nadir around bedtime (Kirschbaum and Helhammer, 2000, Pruessner et al., 1997, Wilhelm et al., 2007). The increase after waking, or cortisol awakening response (CAR), has become the target of considerable interest over the past 10 years for a number of reasons. First, CAR increases are large (on average 50–60% above waking levels) and highly variable across individuals; as a result, individual differences in the size of this indicator can be easily detected and modeled statistically, and are of a magnitude that is likely to be physiologically meaningful (Adam et al., 2006, Clow et al., 2004). The substantial CAR increases occur on top of already elevated wake-up cortisol levels, and hence have the potential to have strong impacts on the relatively low affinity central glucocorticoid receptor systems that have been implicated in the development of MDD (Holsboer, 2000, van Rossum et al., 2006). Second, there is evidence of both genetic and psychosocial contributions to the size of the CAR (Schulz et al., 1998, Wüst et al., 2000), making it a candidate mechanism for both genetic and environmental pathways to the development of depression. In particular, a larger CAR has been associated with higher levels of both acute and chronic life stress (Adam et al., 2006, Schlotz et al., 2004). It has been theorized that CAR increases are designed, in the short term, to help people meet the anticipated demands of their upcoming day, but that too large, too small, or frequently or chronically elevated CARs may be detrimental to health and functioning over the longer term (Adam et al., 2006).

Because all of the past prospective studies examined morning cortisol levels at fixed clock times (8 AM), rather than in relation to person-specific wake-times (Halligan et al., 2007), they were not in a position to identify whether the size of the cortisol awakening response serves as a risk factor for MDD. As a result, there are no existing prospective longitudinal studies examining whether an elevated CAR is associated with increased risk for future MDD. Studies examining cross-sectional associations between the CAR and depression have found mixed results: some have found significantly lower CARs in individuals with current MDD diagnoses (Huber et al., 2006, Stetler and Miller, 2005), whereas others have found current MDD or high depressive symptoms to be associated with higher CARs (Bhagwagar et al., 2005, Pruessner et al., 2003). As noted earlier, however, how the HPA axis looks in the presence of current MDD disorder, and the premorbid individual differences in the HPA axis that are predictive of the later onset of MDD may not be the same, especially if changes in the HPA axis occur with the development of, or in response to the experience of MDD. Indeed, theorists of the role of the HPA axis in the development of depression argue that depressive symptoms emerge by way of HPA axis changes (Ehlert et al., 2001) in response to extreme or chronic stress exposure. Thus, to identify HPA axis risk factors for MDD, it is important to assess which aspects of premorbid (pre-change) HPA axis function are associated with the later emergence of MDD.

In the current study, using prospective data from a large sample of older adolescents (aged 16–18 years), we examined whether baseline differences in CARs were predictive of new onsets of MDD over the subsequent year. The possible effects of baseline and past episodes of MDD were accounted for in our analyses, and a wide variety of health and lifestyle covariates known to influence cortisol and MDD were examined. We also compared the predictive value of the CAR with several other indicators of basal HPA axis functioning, examined whether the predictive value of the CAR varied by gender, and conducted a number of robustness tests, such as examining whether our results varied when we excluded rather than covaried individuals with baseline MDD, and predicting to a larger outcome group including individuals with subclinical MDD symptoms. Given that several known risk factors for MDD including high levels of life stress, sadness, and loneliness are associated with elevated, rather than blunted CARs (Adam et al., 2006, Chida and Steptoe, 2009, Clow et al., 2004, Schulz et al., 1998), we hypothesized that youth with higher baseline CARs would be at increased risk of developing MDD by follow-up.