Elsevier

Psychoneuroendocrinology

Volume 51, January 2015, Pages 341-350
Psychoneuroendocrinology

Hypothalamic–pituitary–adrenal axis activity in older persons with and without a depressive disorder

https://doi.org/10.1016/j.psyneuen.2014.10.005Get rights and content

Highlights

  • Older, depressed persons have higher cortisol levels at awakening than non-depressed controls.

  • The stress response system of older, depressed persons is less responsive.

  • No U-shaped association between HPA-axis activity and depression was observed in older persons.

Summary

Background

Altered functioning of the hypothalamic–pituitary–adrenal axis (HPA-axis) has been associated with depression, but findings have been inconsistent. Among older depressed persons, both hyperactivity and hypo-activity of the HPA-axis were demonstrated. However, most studies were population-based studies, with single cortisol measurements, lacking insight into diurnal patterns of HPA-axis functioning. We aim to provide insight into functioning of the HPA-axis, assessed by various salivary cortisol samples, in depressed older adults and non-depressed controls.

Methods

Data were derived from the Netherlands Study of Depression in Older Persons. Cortisol levels of older persons without a lifetime diagnosis of depression and/or anxiety (n = 109) were compared with older persons with a 6-month major depression diagnosis (n = 311). ANCOVA analyses and random coefficient analysis on the four morning cortisol samples were performed. A possible U-shaped association between cortisol and depression status was examined.

Results

Depressed older persons showed higher morning cortisol levels at awakening (T1) and a less dynamic awakening response compared to non-depressed older persons. Dexamethasone suppression did not differ across groups. No U-shaped association between HPA-axis activity and depression was observed.

Conclusion

We demonstrated a hypercortisolemic state and a diminished ability to respond to the stress of awakening among depressed older persons. Previously it was shown, that hypercortisolemic states may indicate a lifelong biological vulnerability for depression. Our findings expand on previous literature by demonstrating that in older persons the HPA-axis may become less responsive to stress, culminating in a further dysregulation of the diurnal cortisol-rhythm, superimposed on – possibly lifelong – hypercortisolemic states.

Introduction

Since the 1960s, the hypothalamic–pituitary–adrenal axis (HPA-axis) has been regarded as a central pathophysiological process involved in depression, even though study findings have not always been consistent. Most studies to date have been performed in adults, but there are several studies available that have been conducted among older persons. Heaney et al. (2010) observed a lower cortisol awakening response (CAR) in older depressed persons compared to younger depressed persons, but no differences between older persons with and without depression were found. In contrast, other studies observed hypercortisolemia in depressed older persons compared to non-depressed older persons (Balardin et al., 2011, Kohler et al., 2010, O’Brien et al., 2004) whereas hypocortisolemia in depressed older persons has also been found (Morrison et al., 2000, Oldehinkel et al., 2001). A recent meta-analysis demonstrated that depression in older persons is associated with diurnal elevations in cortisol as compared to non-depressed older persons (Belvederi Murri et al., 2014).

Moreover, debates on possible non-linear associations between cortisol levels and depression are ongoing. Both Bremmer et al. (2007) and Penninx et al. (2007) demonstrated that depression was associated with both higher and lower cortisol levels in older persons, as compared to non-depressed older persons. It was hypothesized that hypercortisolism might be a sign of a dysregulated stress-response, whereas hypocortisolism might be a sign of exhaustion of the HPA-axis that is associated with frailty (Penninx et al., 2007). Thus far, these issues remain to be settled since most studies on HPA-axis functioning in depressed older persons had limited sample sizes or were derived from population-based studies, lacking a formal depression diagnosis. Finally, due to difficulties to obtain repeated measurements in general population studies, many studies obtained only one cortisol measure, e.g. total cortisol level in urine, thereby limiting a comprehensive insight into the diurnal pattern of cortisol (Miller et al., 2007).

The Netherlands Study of Depression in Older Persons (NESDO) provides an opportunity to study HPA-axis functioning in older persons with and without a formally diagnosed clinical depressive disorder, a sufficient sample size, repeated cortisol measurements, and information on putative confounding variables. The aim of the current study is to examine diurnal salivary cortisol levels according to the cortisol awakening response (CAR), evening cortisol level as well as cortisol level after dexamethasone ingestion, in depressed and non-depressed older persons. In addition, the presence of non-linearity is explored, by examining whether both hypo- and hypercortisolemia are associated with depression.

Section snippets

Study sample

Data were derived from the baseline assessment (April 2007 to September 2010) of the Netherlands Study of Depression in Older Persons (NESDO; http://nesdo.amstad.nl). NESDO was designed to investigate in a prospective design the course of late-life depression and its comorbidities in detail. In short, respondents, aged 60 years or older, were recruited from five regions in the Netherlands. Depressed persons were recruited from both mental health care institutes and general practitioners in

Results

Table 1 summarizes the socio-demographic and clinical characteristics of the study sample. Compared to non-depressed persons, older persons with a depression had lower levels of education (t-test: 6.3 (df 418) p-value < 001), and a poorer physical health, with a higher number of somatic illnesses (Mann–Whitney: U = 13,825.0, p-value = 0.002) and less physical activity (Mann–Whitney: U = 8149.5, p-value < 0.001). Whereas alcohol use was lower (Chi-square: 34.0 (df 2) p-value = 0.001), depressed persons were

Discussion

In this study, we found some modest associations between salivary cortisol and major depression among older persons showing that depressed older persons had higher morning cortisol levels (at awakening (T1)), that – although not significantly – remained higher during the day (at 45 and 60 min after awakening, higher AUCg, and evening levels), as compared to non-depressed older persons. In addition, non-depressed persons had a more dynamic cortisol awakening response than depressed persons, with

Role of funding sources

NESDO is funded through the Fonds NutsOhra (project 0701-065), Stichting tot Steun VCVGZ, NARSAD, The Brain and Behavior Research Fund (grant ID 41080), and the participating universities and mental health care organizations (VU University Medical Center, Leiden University Medical Center, University Medical Center Groningen, University Medical Center, St Radboud, GGZ inGeest, GGNet, GGZ Nijmegen, Lentis, and Parnassia). Funding sources had no role in study design, in the collection, analysis

Conflict of interest

None declared.

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