We found that current depression was associated with increased 24-hour cortisol levels among 693 medical outpatients with known CHD. Participants in the highest quartile of cortisol had a twofold increased odds of having current depression compared with those in the lowest quartile of cortisol. Even after adjusting for age, gender, BMI, smoking, alcohol use, urinary creatinine, comorbid medical conditions, medication use, and cardiac function, cortisol remained independently associated with major depression.
Major depression, especially the melancholic and psychotic subtype, was previously considered to be related to HPA axis alterations in about 50% of medically healthy patients (Nelson and Davis 1997
); however, it was not known whether depression was associated with increased cortisol in patients with CHD. Despite the potentially confounding effects of comorbid illnesses and use of medications that are known to be associated with alterations in cortisol, we demonstrated an association between depression and increased cortisol levels in patients with CHD.
The causal direction between depression and cortisol cannot be determined with our cross-sectional study, however. There are four possible explanations for the observed association between depression and cortisol: 1) depression may lead to increased cortisol, 2) increased cortisol may lead to depression, 3) the relation could be bi-directional, or 4) another factor (or factors) could lead to both depression and elevated cortisol. The first model is supported by findings that certain symptoms of depression, such as sleep disturbances or decreased food intake, lead to increased cortisol (Sapolsky et al 2000
; Spiegel et al 1999
); evidence is also accumulating to suggest that alterations of the HPA axis are involved in the etiology and pathogenesis of depression (Gold and Chrousos 2002
; Holsboer 1999
; Wolkowitz et al 2001
In support of the second model, patients with Cushing's syndrome have a high prevalence of depression, and medical patients chronically treated with synthetic glucocorticoids often develop depression (Wolkowitz et al 2001
). Furthermore, certain classes of antidepressants normalize HPA activity and upregulate glucocorticoid receptors, thereby increasing negative feedback and lowering cortisol before eliciting their clinical effects (Holsboer and Barden 1996
). This suggests that changes within the HPA axis may be causally involved in the antidepressant effects of these medications. Also, increased activity of the HPA axis, as measured by the dexamethasone (DEX)-suppression test or the combined DEX/corticotropin releasing hormone (CRH) test, predicts early relapse in remitted patients with depression (Ribeiro et al 1993
; Zobel et al 2001
). Finally, several small and mostly open studies have shown that cortisol synthesis inhibitors (Wolkowitz and Reus 1999
), CRH-receptor-antagonists (Zobel et al 2000
), and glucocorticoid-receptor antagonists (Belanoff et al 2002
) may have antidepressant effects.
It is also possible that there is a reciprocal relationship between depression and cortisol. Furthermore, other factors such as genetic predisposition or stressful life events could lead simultaneously to an elevation of cortisol and depression.
Elevated cortisol levels have been associated not only with depression but also coronary disease (Koertge et al 2002
; Troxler et al 1977
); we did not observe a cross-sectional association between cortisol and worse cardiac disease severity, however. One potential reason for the differences between our study and those demonstrating a link between cortisol and coronary atherosclerosis is that we did not use angiographic or carotid ultrasound measurements to determine level of atherosclerosis. Because anatomic findings do not necessarily correlate with severity of ischemia or risk of acute coronary syndromes (Ambrose et al 1988
), angiography may be less accurate than functional studies, such as stress echocardiography, in identifying patients who have myocardium at risk for future events. Thus, it is possible that cortisol may be associated with anatomic level of atherosclerotic burden, but not with functional measures of cardiac disease severity, such as ejection fraction, exercise capacity, and inducible ischemia.
Furthermore, a lack of association between cortisol and baseline cardiac function does not rule out the possibility that elevated cortisol levels may contribute to the increased risk of subsequent coronary events associated with depression (Carney and Freedland 2003
). Cortisol could contribute to greater long-term mortality by triggering or worsening acute cardiac events. Cortisol is strongly associated with the release of thromboxane A2, a vasoconstrictor that is released after endothelial injury (Fimognari et al 1996
). Moreover, cortisol has been shown to suppress the release of vasodilators such as nitric oxide and prostacyclin from vascular endothelium (Rogers et al 2002
; Wallerath et al 1999
). Finally, depressed patients show an increased cortisol response to psychological stress (Heim et al 2000
), and mental stress has been shown to induce both cortisol release and cardiac ischemia (Ghiadoni et al 2000
). Therefore, even if cortisol is not associated with worse baseline cardiac function, it is possible that cortisol contributes to worse outcomes in depressed patients by triggering subsequent coronary events.
Several limitations must be kept in mind when appraising our findings. Only 68% (693/1024) of Heart and Soul Study participants were included in this analysis; however, the prevalence of depression was similar in participants who were included or excluded from the analysis. Only 17% of our participants were women, thereby reducing our power to detect interactions by gender and limiting the generalizability of our results. Depressed patients were more likely to use antidepressants, anxiolytics, and anticonvulsants, all of which are known to reduce HPA activity (Holsboer and Barden 1996
); however, adjustment for use of psychotropic medication did not affect the association between cortisol and depression. We relied on participants' self-report of compliance with the 24-hour urinary protocol and have no proof of complete collection; however, we tried to enhance compliance by visiting the subjects' home environment by requesting that they repeat any urine collection that seemed incomplete and by excluding any samples that were < 500 mL or otherwise deemed inadequate.
Because the psychiatric interviews were administered by lay research assistants, we cannot rule out the possibility that there were some inaccuracies concerning the diagnosis; however, our research assistants received extensive training, and the DIS is considered the gold standard diagnostic instrument for assessment of depression by lay interviewers in epidemiologic studies (Robins et al 1981
). Finally, most of the cortisol values in our sample were within the normal range and were not related to worse cardiac function; however, the Heart and Soul Study is an ongoing prospective study that will follow patients to determine whether greater cortisol at baseline predicts worse outcome at follow-up in patients with CHD.
In summary, we found that depression was associated with elevated cortisol levels in medical outpatients with CHD. Although elevated cortisol levels were not associated with worse cardiac disease severity in our cross-sectional analysis, increased cortisol levels may still contribute to the increased risk of CHD events in patients with depression.