Hypothalamic–pituitary–adrenal axis activity in older persons with and without a depressive disorder
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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2021, Psychiatry ResearchCitation Excerpt :Although the exact relationship of neuroendocrine measures to CNS function remains to be fully established, salivary measurement of glucocorticoids can be a potential window into hypothalamic-pituitary-adrenal (HPA) dysfunction (Clow and Smyth, 2020). While the role of steroid hormones in MDD is highly complicated, HPA hormones such as cortisol and dehydroepiandrosterone (DHEA) appear to play important roles in MDD, including hypercortisolemic states in depressed vs non-depressed individuals (Rhebergen et al., 2015). Notably, a recent meta-analysis of multiple biomarkers identified cortisol as the only consistent factor with a predictive effect on the onset, relapse, and recurrence of MDD (Kennis et al., 2020).
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These two authors contributed equally to the manuscript.