Elsevier

Psychoneuroendocrinology

Volume 100, February 2019, Pages 203-212
Psychoneuroendocrinology

Cortisol, dehydroepiandrosterone sulfate, fatty acids, and their relation in recurrent depression

https://doi.org/10.1016/j.psyneuen.2018.10.012Get rights and content

Highlights

  • Remitted unmedicated recurrent MDD patients had higher cortisol awakening responses.

  • In patients versus controls, awakening DHEAS was inversely related with fatty acids.

  • Findings corroborate persistent changes in HPA axis and metabolism in recurrent MDD.

  • Future research could aid in the development of recurrence-vulnerability biomarkers.

Abstract

Background

Alterations in hypothalamic–pituitary–adrenal (HPA)-axis activity, fatty acid metabolism, and their relation have been associated with (recurrent) major depressive disorder (MDD), although conflicting findings exist.

Aims

To determine whether alterations in HPA-axis activity and fatty acids in recurrent MDD remain during remission (i.e. reflect a potential trait factor). Furthermore, to test the association between HPA-axis activity and fatty acids in patients versus controls.

Methods

We cross-sectionally compared 73 remitted unmedicated recurrent MDD patients with 46 matched never-depressed controls. Measurements included salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) (awakening, evening, and after sad mood induction) and erythrocyte fatty acid parameters: (I) three main fatty acids [omega-3 docosahexaenoic acid (DHA), and the omega-3 eicosapentaenoic acid/omega-6 arachidonic acid (EPA/AA)-ratio], and (II) structural fatty acid indices [chain length, unsaturation and peroxidation].

Results

Patients showed higher cortisol awakening responses (p = 0.006) and lower evening cortisol/DHEAS ratios (p = 0.044) compared to matched controls. Fatty acids did not differ between patients and controls, but HPA-axis indicators were significantly associated with fatty acid parameters in both groups (0.001 ≤ p ≤ 0.043). Patients and controls significantly differed in the relations between awakening DHEAS or cortisol/DHEAS ratios and fatty acid parameters, including unsaturation and peroxidation indices (0.001≤ p ≤ 0.034). Significance remained after correction for confounders.

Conclusions

Our results further support alterations in HPA-axis activity, i.e. a lower baseline, but higher responsiveness of awakening cortisol, in remitted medication-free recurrent MDD patients. Furthermore, the relationship between HPA-axis and fatty acids showed significant differences in recurrent MDD patients versus controls. Prospective research is needed to determine the predictive value of this relationship for MDD recurrence.

Introduction

The overwhelming burden of major depressive disorder (MDD) is mainly due to its recurrent nature (Charlson et al., 2011). Suggested mechanisms underlying the recurrent course of MDD include alterations in endocrinology and metabolism.

From an endocrinological viewpoint, MDD has been extensively associated with hyperactivity of the principal stress system: the hypothalamic–pituitary–adrenal (HPA)-axis (Lok et al., 2012, Stetler and Miller, 2011). However, inconsistencies exist with some studies observing no HPA-axis dysregulation (Ruhé et al., 2015) or even HPA-axis hypoactivity (Ahrens et al., 2008, Bockting et al., 2012, Wichmann et al., 2017). Similarly, effects of sad mood on cortisol have been observed to differ between MDD patients and controls, suggesting a higher HPA-axis responsiveness to stressors in MDD (Huffziger et al., 2013), although a lower responsiveness has been reported as well (Chopra et al., 2008). Potential harms of frequently or chronically high levels of the stress hormone cortisol include hippocampal atrophy, atherosclerosis (McEwen, 2007), and an unbalanced serotonergic and noradrenergic circuitry, resulting in serotonin depletion (Fig. 1) (Kopschina Feltes et al., 2017).

Besides cortisol, adrenal glands secrete the neuroactive steroids dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, combinedly called DHEA(S). While its precise role remains unknown, DHEA(S) is thought to protect against the deleterious effects of elevated cortisol (Maninger et al., 2009). More specifically, while cortisol has catabolic properties, DHEA(S) is believed to have anabolic, neuroprotective, and regenerative effects on the brain (Maninger et al., 2009). Therefore, the cortisol/DHEA(S) ratio has been proposed to indicate HPA-axis balance (Chen et al., 2015). Interestingly, a low DHEAS and high cortisol/DHEAS ratio have been associated with MDD (Mocking et al., 2015a, Zhu et al., 2015), but conflicting results have been reported as well (Hough et al., 2017, Uh et al., 2017). Overall, increasing evidence suggests that HPA-axis alterations may be a trait factor in MDD patients that precede disease-onset (Goodyer et al., 2000), remains during remission, and can possibly predict recurrence (Lok et al., 2012, Mocking et al., 2015a).

Regarding the metabolic mechanisms that might underlie the pathophysiology of MDD, evidence suggests that alterations in polyunsaturated fatty acids (PUFAs) are important, specifically lower omega-3/omega-6 ratios (Lin et al., 2010, McNamara, 2009, Messamore and McNamara, 2016). Moreover, we previously showed broader alterations in the fatty acid profiles of recurrent MDD patients, including shorter, less saturated, and less peroxidizable fatty acids. These alterations did not only involve PUFAs, but also monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) (Assies et al., 2010, Mocking et al., 2012a, Mocking et al., 2012b). Mechanistically, evidence exists for an essential role of fatty acids in cellular membrane processes, inflammation, and neural signaling (Fig. 1) (Mozaffarian and Wu, 2011, Piomelli et al., 2007). The brain is highly enriched in omega-3 DHA which is considered neuroprotective, due to its, amongst others, stimulation of brain-derived neurotrophic factor (Assies et al., 2014). Omega-3 EPA is the main precursor of anti-inflammatory eicosanoids, while omega-6 AA is considered the main precursor of pro-inflammatory eicosanoids. An imbalance between EPA and AA may lead to inflammatory dysregulation which is thought to be involved in the pathophysiology of MDD (Calder, 2006).

Interestingly, a bidirectional relation between fatty acids and HPA-axis alterations in MDD patients could be expected based on animal and preclinical studies (Chen and Su, 2013, Gounarides et al., 2008, Jazayeri et al., 2010; Delarue et al., 2003). Indeed, our previous cross-sectional research in recurrent MDD patients has shown a relationship between fatty acids and HPA-axis activity (Mocking et al., 2013). More specifically, evening cortisol concentrations were negatively associated with fatty acid unsaturation, chain length, and peroxidizability and these correlations were more negative in recurrent MDD patients compared with never-depressed controls. Our longitudinal research found a more negative relationship of fatty acid unsaturation and peroxidation with awakening cortisol in MDD patients compared with controls and these negative relationships were associated with antidepressant paroxetine nonresponse (Mocking et al., 2015b).

Based on this literature, HPA-axis activity, fatty acid metabolism, and their relationship might play important roles in the pathophysiology of (recurrent) MDD. Given the remaining inconsistencies and limited research on alterations in cortisol, DHEAS, and fatty acid metabolism in MDD during remission, we compared remitted recurrent MDD patients with matched never-depressed controls. We included only psychoactive medication-free subjects to exclude confounding effects of medication. The purpose of this study was to investigate: (I) whether cortisol, DHEAS, and fatty acid metabolism differ in remitted recurrent MDD patients compared to never-depressed controls (pointing to a potential trait factor) and (II) whether the association between cortisol, DHEAS, and fatty acid metabolism differed in remitted recurrent MDD patients as opposed to never-depressed control subjects.

Section snippets

Participants

We detailed the recruitment of the study population in our protocol paper (Mocking et al., 2016). In short, we recruited patients and controls from identical media announcements and from previous studies in several research centers across the Netherlands, including the Depression Evaluation Longitudinal Therapy Assessment (DELTA) study (Bockting et al., 2005). Inclusion criteria for patients were: ≥2 previous MDD episodes, as assessed by the Structured Clinical Interview for DSM-IV (SCID) (

Characteristics of participants

Seventy-three patients and 46 controls initially participated; blood was collected and analyzed from 68 patients and 44 controls, and saliva from 67 patients and 43 controls, respectively. Table 1 shows population characteristics of patients and controls. The median number of previous major depressive episodes was 4 (range = 2–60, interquartile range = 5). Matching was successful for sex, age, educational level, employment status, and ethnicity. Additionally, no significant differences were

Discussion

The current study investigated differences between 68 remitted unmedicated recurrent MDD patients and 44 never-depressed controls in cortisol, DHEAS, fatty acid metabolism, and their relation. Regarding HPA-axis activity, patients exhibited lower baseline salivary cortisol, but higher cortisol and cortisol/DHEAS ratio awakening responses compared to controls. Additionally, patients displayed a lower evening cortisol/DHEAS ratio. Patients did not differ from controls in erythrocyte fatty acid

Conclusion

Compared to never-depressed matched controls, remitted recurrent MDD patients showed a lower baseline, but higher cortisol awakening response, especially relative to DHEAS concentrations. This corroborates with earlier findings of higher HPA-axis responsiveness in MDD and may represent a trait marker for MDD-recurrence-vulnerability that remains during remission. Moreover, awakening DHEAS concentrations were negatively associated with omega-3 fatty acid profiles and fatty acid unsaturation and

Role of the funding source

Funding support for this study was provided by the unrestricted personal grants from the Academic Medical Centre in Amsterdam to Dr. R.J.T. Mocking (AMC PhD Scholarship) and C.A. Figueroa (AMC MD-PhD Scholarship). The DELTA-imaging study is funded by a dedicated grant from the Dutch Brain Foundation (Hersenstichting the Netherlands: 2009(2)-72) to Dr. H.G. Ruhé and Prof. Dr. A.H. Schene. Dr. H.G. Ruhé is supported by a NWO/ZonMW VENI-Grant #016.126.059. None of the funding organizations had any

Author contributions

All authors were involved in conception of the study, interpretation of results, preparation, critical revision, and approval of the final manuscript. C.A.F. and R.J.T.M. were involved in acquisition of the data. D.M.H. and R.J.T.M. performed statistical analyses. D.M.H. and R.J.T.M. had access to all the data in the study and take full responsibility for both the integrity of the data and the accuracy of the data analysis.

Conflicts of interest

All authors report no potential conflicts of interest.

Acknowledgments

We wish to thank the participants of our study as well as the participating psychiatric sites for their recruitment efforts.

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