The predictive value of cortisol levels on 2-year course of depression in older persons

doi:10.1016/j.psyneuen.2015.10.006

Psychoneuroendocrinology

Volume 63, January 2016, Pages 320-326

https://doi.org/10.1016/j.psyneuen.2015.10.006 Get rights and content

Highlights

•
Studies on the association between cortisol and course of depression in older persons are lacking.
•
In a cohort of currently depressed older persons, we studied the course of illness.
•
As hypothesized, lower cortisol levels predicted unfavorable 2-year course.
•
In depressed older persons, evening cortisol levels may serve as a marker to identify persons at risk for unfavorable course trajectories.

Abstract

Background

Depressive disorders in older persons are associated with an altered functioning of the Hypothalamic–Pituitary–Adrenal (HPA)-axis. In adults, a lower cortisol awakening response is a predictor of a worse prognosis of depression, but to date longitudinal studies in older depressed persons are lacking. We hypothesised that a lower cortisol awakening response is also associated with poorer course of depression in later life.

Methods

Data were derived from the Netherlands Study of Depression in Older Persons (NESDO). Participants with a 6-month Major Depressive Disorder (MDD), who provided 2-year follow-up data, were included (n = 246). Logistic regression analyses were conducted to examine the association between diurnal cortisol levels and depressive status at 2-year follow-up.

Results

Both lower (OR = 3.54; 95% CI = 1.59–7.89) and higher evening cortisol levels (OR = 2.41; 95% CI = 1.09–5.35) at baseline were associated with poorer prognosis of MDD. Low dexamethasone suppression was associated with poorer course (OR = 2.37; 95% CI = 1.09–5.16), but failed to reach significance after additional adjustment for severity and chronicity of MDD (OR = 1.98; 95% CI = 0.89–4.42). Cortisol awakening response was not significantly associated with course. Since smoking has a great impact on cortisol levels, we conducted post-hoc analyses including non-smokers only, indicating that lower evening cortisol levels (OR = 2.83, 95% CI = 1.31–6.13) predicted unfavourable course.

Conclusions

This first longitudinal study on cortisol and prognosis of depression in older persons demonstrates that in particular lower evening cortisol levels may predict poorer course in MDD. This finding may have clinical implications. Evening cortisol values may serve as a marker to identify persons at risk for an unfavourable course.

Introduction

Late-life major depressive disorder (MDD) is a debilitating disease, with prevalence rates varying between 0.9% to 9.4% among older community-dwelling persons, and up to 42% among persons living in institutions (Djernes, 2006). Furthermore, about ten percent of the persons in this age group are suffering from minor depression (Beekman et al., 1999). The prognosis of late-life depression is poor as compared to depressions among younger adults. It was demonstrated that chronicity or recurrence of depression affects one-third of depressed older adults (Cole, 1999). Comijs et al. (2015) have recently shown an even more unfavourable prognosis in a large cohort of depressed elderly. They demonstrated that almost half (48.4%) of the depressed persons in this cohort were still suffering from depression at 2-year follow-up. Early onset of depression, higher severity, co-morbid dysthymia and/or physical chronic diseases alongside older age were identified as predictors of poorer course (Beekman et al., 2001, Comijs et al., 2015, Licht-Strunk et al., 2007). In addition to clinical predictors, previous research aimed to disentangle the pathophysiological processes involved in depression and their contribution to the course of depression.

Since decades, the central role of the Hypothalamic–Pituitary–Adrenal (HPA)-axis in the pathogenesis of depression was acknowledged (e.g. Gibbons and McHugh, 1962). However, the majority of studies on cortisol and depression in older persons had a cross-sectional design, limiting insight into the association between HPA-axis functioning and course trajectories of depressive disorders. Some studies focused on the association between cortisol and the onset of depression or depressive symptoms later in life (e.g. Nabeta et al., 2014, Chinthapalli, 2014, Geoffroy et al., 2013), however studies on the predictive value of HPA-axis functioning on the course of current depressive disorders in older persons are lacking. Likewise, the majority of studies on adults examine the impact of HPA-axis functioning on either onset or recurrence of depression (Bockting et al., 2012, Lok et al., 2012, Hardeveld et al., 2015, Dedovic and Ngiam, 2015, Vrshek-Schallhorn et al., 2013). One study examined the association between cortisol and course trajectories of both depression and anxiety disorders in an adult population (aged 18–65 years). It demonstrated that a lower cortisol awakening response was associated with an unfavourable course of illness (Vreeburg et al., 2013). Finally, it has been suggested that an impaired signaling pathway via corticosteroid-activated mineralocorticoid and glucocorticoid receptors would lead to an impaired negative feedback regulation of the HPA system. This could cause high levels of cortisol, which in turn may be associated with unfavorable course of depression (Schüle et al., 2009). Hence, the Dexamethasone Suppression test (DST) was propagated as a putative predictor for course of depressive disorders (e.g. Schweitzer et al., 1987, Charles et al., 1989). However, since then, results from research on its predictive value were inconclusive, and research among older persons is lacking.

Although Bremmer et al. (2007) and Penninx et al. (2007) demonstrated a U-shaped association with both lower cortisol levels and higher cortisol levels being associated with depression in a cross-sectional population based study, a recent meta-analysis (Belvederi Murri et al., 2014) and our own findings (Rhebergen et al., 2015) could not replicate this. Nevertheless, when studying the predictive value of cortisol on the course of depression in older persons, one needs to take a possible U-shape into account, since neglect of this non-linear association may potentially mask underlying associations.

The Netherlands Study of Depression in Older Persons (NESDO) gives us the opportunity to investigate the association between cortisol and longitudinal course of late-life depressive disorders. The aim of this study is to examine the predictive value of cortisol on the 2-year course of depression in older persons, aged 60–93 years. To address the issue of a putative non-linear association, cortisol measures will be divided into tertiles, including lower, average or higher cortisol levels. We hypothesize that lower cortisol levels, a lower awakening response and lower Dexamethasone Suppression ratio may predict an unfavourable course trajectory of depressive disorders in older persons, as compared to average or higher cortisol levels or Dexamethasone Suppression ratio.

Section snippets

Study sample

Data were obtained from the Netherlands Study of Depression in Older Persons (NESDO; Comijs et al., 2011; http://nesdo.amstad.nl). NESDO is a longitudinal cohort of 378 currently depressed persons and 132 persons without a lifetime depression diagnosis aged 60–93 years (n = 510). Respondents were recruited from five different regions in the Netherlands. Both patients from mental health care institutes and patients from general practitioners participated, enabling inclusion of both healthy control

Results

Baseline characteristics are presented in Table 1. The mean age in our study population was 70.2 (±7.3) years, 63.8% were female and 103 persons (41.9%) were still diagnosed with MDD at 2-year follow-up. Chronic depression and higher depression severity at baseline were associated with persistence of depressive disorder at follow-up. Table 1 also shows that the persons with MDD at 2-year follow-up were more likely to have at baseline either low or high evening cortisol levels and to have a

Discussion

To date, findings on the predictive value of cortisol levels for the course of depression are scarce and not unequivocal, and prospective studies on older persons are lacking. In this study we aimed to gain insight in the prognostic value of cortisol levels on the course of major depressive disorder in older persons. Both higher and lower evening cortisol levels at baseline were associated with poorer course of MDD. Post-hoc analyses, with exclusion of smokers, demonstrated that in particular

Conflict of interest

We state that there are no conflicts of interest. Funding sources had no role in study design, in the collection, analysis and interpretation of the data, in writing the report and in the decision to submit the article for publication.

Contributors

All authors contributed sufficiently to the development of the analysis-plan, the analyses of the data, the writing of the article and all authors agree with transference of the copy right to Psychoneuroendocrinology.

Funding

NESDO is funded through the Fonds NutsOhra (project 0701-065), Stichting tot Steun VCVGZ, NARSAD, The Brain and Behavious 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

Acknowledgement

None.

References (42)

A.T.F. Beekman et al.
Emergence and persistence of late life depression: a 3-year follow-up of the longitudinal aging study Amsterdam
J. Affect. Disord.
(2001)
M. Belvederi Murri et al.
HPA axis and aging in depression: systematic review and meta-analysis
Psychoneuroendocrinology
(2014)
C.L. Bockting et al.
Lower cortisol levels predict recurrence in remitted patients with recurrent depression: a 5.5 year prospective study
Psychiatry Res.
(2012)
S.H. Booij et al.
Chronicity of depressive problems and the cortisol response to psychosocial stress in adolescents: the TRAILS study
Psychoneuroendocrinology
(2013)
M.A. Bremmer et al.
Major depression in late life is associated with both hypo- and hypercortisolemia
Biol. Psychiatry
(2007)
G.A. Charles et al.
Persistent cortisol non-suppression after clinical recovery predicts symptomatic relapse in unipolar depression
J. Affect. Disord.
(1989)
N.O. Dmitrieva et al.
A day-centered approach to modeling cortisol: diurnal cortisol profiles and their associations among U.S. adults
Psychoneuroendocrinology
(2013)
J.L. Gibbons et al.
Plasma cortisol in depressive illness
J. Psychiatry Res.
(1962)
F. Hardeveld et al.
Glucocorticoid and mineralocorticoid receptor polymorphisms and recurrence of major depressive disorder
Psychoneuroendocrinology
(2015)
D.M. Kriegsman et al.
Self-reports and general practitioner information on the presence of chronic diseases in community dwelling elderly: a study on the accuracy of patients’ self-reports and on determinants of inaccuracy
J. Clin. Epidemiol.
(1996)

A. Lok et al.

Longitudinal hypothalamic–pituitary–adrenal axis trait and state effects in recurrent depression

Psychoneuroendocrinology

(2012)

H. Nabeta et al.

Association of salivary cortisol levels and later depressive state in elderly people living in a rural community: a 3-year follow-up study

J. Affect. Disord.

(2014)

A.J. Oldehinkel et al.

Urinary free cortisol excretion in elderly persons with minor and major depression

Psychiatry Res.

(2001)

B.W. Penninx et al.

Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the hypothalamo–pituitary–adrenal axis

Am. J. Geriat. Psychiatry

(2007)

J.C. Pruessner et al.

Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change

Psychoneuroendocrinology

(2003)

D. Rhebergen et al.

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

Psychoneuroendocrinology

(2015)

N. Vogelzangs et al.

Cardiovascular disease in persons with depressive and anxiety disorders

J. Affect. Disord.

(2010)

S.A. Vreeburg et al.

Associations between sociodemographic, sampling and health factors and various salivary cortisol indicators in a large sample without psychopathology

Psychoneuroendocrinology

(2009)

S.A. Vreeburg et al.

Salivary cortisol levels and the 2-year course of depressive and anxiety disorders

Psychoneuroendocrinology

(2013)

H.U. Wittchen

Reliability and validity studies of the WHO-composite international diagnostic interview (CIDI): a critical review

J. Psychiatry Res.

(1994)

C.E. Wright et al.

Physiological correlates of cognitive functioning in an elderly population

Psychoneuroendocrinology

(2005)

Cited by (10)

Individual differences in latent trait cortisol (LTC): Implications for the onset and course of future depressive symptoms
2022, Psychoneuroendocrinology
Citation Excerpt :
For example, a meta-analysis of cross-sectional studies did not support a link between HPA axis indicators and episode duration among individuals with MDD (e.g., Stetler and Miller, 2011). However, prospective evidence indicates that lower morning and evening cortisol levels each predict greater chronicity of MDD episodes (e.g., Kabia et al., 2016; Vreeburg et al., 2013), suggesting HPA axis regulation may have implications for depression course. In the present study, we sought to construct an across-wave LTC factor using cortisol samples collected over three 3-day measurement waves separated by 6 weeks.
Research suggests that various indicators of hypothalamic pituitary adrenal (HPA) axis activity prospectively predict depression, but few studies have evaluated whether trait indicators of HPA axis activity are related to depression. Further, no prior study has examined links between trait cortisol and psychopathology using a trait indicator that captures HPA axis activity over multiple time points. Here we examined whether we could construct an across-wave latent trait cortisol (LTC) factor using cortisol samples collected over 13 weeks, and whether the across-wave LTC prospectively predicted new depressive symptom onsets and symptom duration. Emerging adults (n = 85; M age = 19.37 years) provided salivary cortisol samples four times a day (waking, 30 min and 45 min post-waking and bedtime) over three 3-day measurement waves separated by 6 weeks. Diagnostic interviews at 3 timepoints (baseline, 1- and 2.5 years post-baseline) assessed lifetime and current depressive symptoms. Results indicated that the across-wave LTC predicted new onsets of depressive symptoms and longer symptom duration. Follow-up tests revealed that the link between the across-wave LTC and new onsets was not significant after adjusting for past depressive symptoms. These findings suggest that an indicator of individual differences in HPA axis regulation has implications for depressive symptom onsets and course.
Association of 11β-hydroxysteroid dehydrogenase type1 (HSD11b1) gene polymorphisms with outcome of antidepressant therapy and suicide attempts
2020, Behavioural Brain Research
Citation Excerpt :
Depression is one of the leading causes of illness and related disability [1]. A vast body of evidence suggests that the stress-related hormone, cortisol, is involved in depression physiopathology in adults [2–7]. This may be related to childhood adverse experiences during early development, which results in adults with increased vulnerability to depression and risk of suicide attempts due to impaired hypothalamus-pituitary-adrenal (HPA) axis function [7–10].
The hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depressive disorders. HSD11B1 encodes 11β-hydroxysteroid dehydrogenase type1 enzyme, responsible for converting cortisone to cortisol. Genetic polymorphisms in HSD11B1 may impact in depression outcome and risk of suicide. This study aimed to assess whether HSD11B1 genotypes and haplotypes are associated with depression risk, severity of symptoms and suicidal attempts, considering early-life stress as an environmental factor.
Here, 142 depressive patients and 103 healthy controls were included. Patients were enrolled from the Affective Disorders ambulatory and day hospital units, both within the University General Hospital of Ribeirao Preto. All subjects were clinically assessed applying the Mini-PLUS International Neuropsychiatric Interview, followed by the 21-item GRID-Hamilton Depression Scale, Childhood Trauma Questionnaire and Beck Scale for Suicidal Ideation (BSI). All subjects underwent antecubital vein puncture to obtain blood for DNA extraction. Genotyping of rs11119328 and rs11811440 were performed using allele-specific oligonucleotide polymerase chain reaction.
We found a significant association of rs11119328 variant genotypes with increased risk for at least one suicide attempt (OR: 7.10, p = 0.049) and an association of variant genotypes of rs11811440 with euthymic mood under optimized pharmacological treatment (OR: 0.05, P = 0.014). These tests included correction for confounding factors. The association of genetic markers with depression risk, GRID-HAM-D₂₁ and BSI scores and the number of suicidal attempts were nonsignificant. Haplotypes combining both markers were not associated with the studied phenotypes.
We conclude that HSD11B1 polymorphisms may be relevant biomarkers for detecting subjects genetically vulnerable to poorer antidepressant response and higher risk of suicide attempts.
Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model
2018, International Journal of Psychophysiology
Citation Excerpt :
The results of the CFA showed no correlation between the two latent constructs HPA Dysregulation and Inflammation, and implied that evening cortisol should be considered as a separate indicator of diurnal cortisol abnormalities (i.e. as an indicator of flattened diurnal cortisol slope). Because prior literature showed that evening cortisol was related to cytokine levels that peak during the night (i.e. IL-6) (Logan and Sarkar, 2012; Nakamura et al., 2010; Vgontzas et al., 2002), and that evening cortisol levels are associated with depression (Hsiao et al., 2010; Kabia et al., 2015), a new model was tested that used only (observed) evening cortisol as an indicator of HPA functioning. The latent construct Inflammation was regressed on depression and evening cortisol (Fig. 2) while controlling for possible confounding variables age, educational status (as a measure of socio-economic status) and gender (O'Connor et al., 2009).
Chronic Fatigue Syndrome (CFS) is a poorly understood illness that is characterized by diverse somatic symptoms, hypothalamic pituitary adrenal (HPA) axis dysfunction and heightened inflammatory indicators. These symptoms are often exacerbated and accompanied by psychological distress states and depression. Since depression is known to be associated with HPA axis dysfunction and greater inflammation, a psychoneuroendocrinological (PNE) model of inflammation was examined in persons diagnosed with CFS in order to uncover underlying biopsychosocial mechanisms in this poorly understood chronic illness.
Baseline data were drawn from two randomized controlled trials testing the efficacy of different forms of psychosocial intervention, and included psychological questionnaires, di-urnal salivary cortisol, and blood samples. Data were analyzed with structural equation modeling (SEM).
The sample (N = 265) was mostly middle-aged (M_age = 49.36 ± 10.9, range = 20–73 years), Caucasian (67.7%), female (81.7%), highly educated (85.5% completed some college, college, or graduate program), and depressed (CES-D M = 23.87 ± 12.02, range 2–57). The SEM supporting a psychoneuroendocrinological model of immune dysregulation in CFS fit the data χ² (12) = 17.725, p = 0.1243, RMSEA = 0.043, CFI = 0.935, SRMR = 0.036. Depression was directly related to evening salivary cortisol and inflammation, such that higher evening cortisol predicted greater depressive symptoms (β = 0.215, p < 0.01) and higher pro-inflammatory cytokines (interleukin-2 [IL-2], IL-6, and tumor necrosis factor-alpha [TNF-α] levels (β = 0.185, p < 0.05), when controlling for covariates.
Results highlight the role of depression, cortisol and inflammation in possible biological mechanisms involved in the pathophysiology of CFS. Time-lagged, longitudinal analyses are needed to fully explore these relationships.
IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity
2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Also dexamethasone administration to humans lowers the brain availability of TRY (Maes et al., 1990a,b,c, d). Increased baseline hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and the loss of the negative feedback loop of glucocorticoids, leading to increased basal serum levels of adrenocorticotrophic hormone (ACTH) and cortisol is one of the biological hallmarks of severe depression (Du and Pang, 2015; Kabia et al., 2015). Patients on prolonged use of glucocorticoids or with Cushing's syndrome, who chronically presents high levels of TDO activity, often experience neuropsychiatric disorders, such as depressive symptoms (Kelly et al., 1980, 1983).
Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-γ, TNFα and IL-1β, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases.
Hypothalamo-Pituitary-Adrenal Axis in Depressive Disorders and Treatment Resistance
2023, Psychiatry (Moscow)
Cortisol Reactivity to a physical stressor in Patients with Depression and Alzheimer’s disease
2022, Dementia e Neuropsychologia

View all citing articles on Scopus

View full text

The predictive value of cortisol levels on 2-year course of depression in older persons

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study sample

Results

Discussion

Conflict of interest

Contributors

Funding

Acknowledgement

J. Affect. Disord.

Psychoneuroendocrinology

Psychiatry Res.

Psychoneuroendocrinology

Biol. Psychiatry

J. Affect. Disord.

Psychoneuroendocrinology

J. Psychiatry Res.

Psychoneuroendocrinology

J. Clin. Epidemiol.

Psychoneuroendocrinology

J. Affect. Disord.

Psychiatry Res.

Am. J. Geriat. Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

J. Affect. Disord.

Psychoneuroendocrinology

Psychoneuroendocrinology

J. Psychiatry Res.

Psychoneuroendocrinology