Higher cortisol levels may proceed a manic episode and are related to disease severity in patients with bipolar disorder
Introduction
Bipolar Disorder (BD) is a severe mental illness, characterized by a chronic and unpredictable course. Understanding the pathophysiological processes is crucial to identify new potential therapeutic targets. Current pharmacological and psychotherapeutic treatment results in long term stability in only one third of BD patients, leaving two thirds in urgent need of novel treatment options (Renes et al., 2014).
Endocrine systems seem to play a role in the pathogenesis of BD. The hypothalamus – pituitary – adrenal (HPA) axis, as one of the key systems, shows an altered functioning, characterized by higher cortisol levels (Belvederi Murri et al., 2016; Cervantes et al., 2001; Daban et al., 2005; Deshauer et al., 2003; Jabben et al., 2011; Langan, McDonald 2009; Linkowski et al., 1994; Schmider et al., 1995) a decrease of number of glucocorticoid receptors (Bei et al., 2009; Fries et al., 2014) and a decreased sensitivity in the negative feedback response (Vieta et al., 1999; Watson et al., 2004) in BD patients as compared to healthy individuals. This has been found during episodes (state phenomenon) and in between episodes (trait phenomenon). Results also indicate a role in the staging of the disease, with a more severe dysregulation in those with a higher number of mood episodes (Watson et al., 2004), suggesting chronicity of both endocrine as mood dysregulation.
However, results concerning HPA-axis functioning in BD have been conflicting and are difficult to interpret and compare across studies, which may be due to 1) heterogeneity of patient groups, with differences in disease type, phase and stage, and, 2) methodological issues regarding the assessment of the functioning of the HPA-axis by using time point measures of cortisol in serum or saliva which are under the influence of the circadian rhythm, diurnal pulsatile secretion, and acute psychological or physiological stress. These constantly changing levels complicate the interpretation of serum and saliva cortisol measurements. By using analysis of cortisol in scalp hair, as a method to monitor chronic HPA axis functioning, we can solve these shortcomings of time point measures. This technique measuring hair cortisol concentrations (HCC) has been proven to be a useful marker of long-term systemic cortisol. (Sauvé et al., 2007; van Uum et al., 2008; Manenschijn et al., 2011)
Until now, only few studies have been published reporting HCC in BD. Our group previously observed higher HCC in BD patients with an older age of onset (Manenschijn et al., 2011). Streit et al. (2016) found higher HCC in BD patients compared to controls (CON) and also found a correlation between manic symptoms and HCC.
The aim of this study is to explore long-term cortisol in relationship to relapses to a manic episode. We included an extensively defined cohort of BD type I patients in a euthymic state, either with or without a manic episode prior to hair sampling in order to distinguish between state and trait. In addition, we explored the severity of the disease, by studying the number of mood episodes and long-term cortisol exposure.
Section snippets
Study design
This study is part of a large case-control study, the Dutch Bipolar Cohort (DBC), investigating genetic and phenotypic information of patients with bipolar disorder type I, first degree relatives and controls (CON). The study design is described in more detail by Vreeker et al. (2016), [PMID: 30303059]. In brief, patients were recruited via clinicians, the Dutch patients’ association for BD, pharmacies and advertisements. Healthy controls were recruited via advertisements and among individuals
Results
In total, 45 BD patients and 17 CON were enrolled in this study (Fig. 1). No differences between groups were found regarding demographics, BMI, corticosteroid use and hair characteristics (Table 1).
Discussion
In this pilot study we found a relationship between increased Hair Cortisol Concentrations (HCC), indicative of increased HPA activity, and a higher probability of a manic episode in BD patients type I. Second, we show a positive association between HCC and the number of previous episodes, representing the disease chronicity.
In the current study we aimed to unravel whether increased cortisol exposure is a condition preceding a mood episode or rather a consequence of a manic or depressive
Declaration of Competing Interest
None.
Financial disclosures
None.
Acknowledgments
EFCvR is supported by an Erasmus MC research fellowship, a fellowship of the Netherlands Brain Foundation (grant number F2011(1)-12), and a Vidi grant of the Netherlands Organization for Scientific Research (grant number 91716453). The Dutch Bipolar Cohort was supported by the National Institute of Mental Health (Grant number: R01MH 090 553).
References (28)
- et al.
Phosphorylation status of glucocorticoid receptor, heat shock protein 70, cytochroom C and Bax in lymphocytes of euthymic, depressed and manic bipolar patients
Psychoneuroendocrinology
(2009) - et al.
The HPA axis in bipolar disorder: systematic review and meta-analysis
Psychoneuroendocrinology
(2016) - et al.
Hypothalamic-pituitary-adrenal axis and bipolar disorder
Psychiatr. Clin. North Am.
(2005) - et al.
Co-occuring manic symptomatology influences HPA axis alterations in depression
J. Psychiatr. Res.
(2011) - et al.
The Stanley foundation bipolar treatment outcome network. I. Longitudinal methodology
J. Affect. Disord.
(2001) - et al.
Evaluation of a method to measure long term cortisol levels
Steroids
(2011) - et al.
Hyper- and hypocortsicolis in bipolar disorder – a beneficial influence of lithium on the HPA-axis?
J. Affect. Disord.
(2017) - et al.
Combined dexamethasone/cortisotropin-releasing hormone test in acute and remitted manic patients, in acute depression and in normal controls
Biol. Psychiatry
(1995) - et al.
Determinants of hair cortisol and hair cortisone concentrations in adults
Psychoneuroendocrin
(2015) - et al.
Perceived stress and hair cortisol: differences in bipolar disorder and schizophrenia
Psychoneuroendocrinology
(2016)
The Stanley foundation bipolar treatment outcome network. II. Demographics and illness characteristics of the first 261 patients
J. Affect. Disord.
Circadian secretion of cortisol in bipolar disorder
J. Psychiatry Neurosc.
The cortisol awakening response in bipolar illness: a pilot study
Can. J. Psychiatry
Structured clinical interview for DSM-IV-TR axis I disorders, research version, non-patient edition. (SCID-I/NP) New York
Biometrics Research
Cited by (17)
The use of biochemical indexes in hair for clinical studies of psychiatric diseases: What can we learn about mental disease from hair?
2023, Journal of Psychiatric ResearchNeuroprogression in bipolar disorder
2022, Biomarkers in Bipolar DisordersDifferential association of cortisol with visual memory/learning and executive function in Bipolar Disorder
2022, Psychiatry ResearchCitation Excerpt :Moreover, other researchers used a novel method measuring fingernails cortisol, which is thought to reflect chronic cortisol exposure, and found no association with memory and executive function tasks in 40 bipolar patients (Herane-Vives et al., 2018). Finally, hair cortisol levels were found slightly higher in BD type I patients compared to controls and particularly elevated in the months prior to a manic relapse (van den Berg et al., 2020) while elevated hair cortisol was associated with cognitive impairment especially in the domain of working memory in a mixed sample of bipolar and schizophrenia patients compared to controls (Aas et al., 2019). Such discrepancies in the literature may be attributed to differences in the cognitive tasks examined, the methodologies to assess cortisol and HPA axis activity and the effect of confounding variables such as medication.