Patterns of salivary cortisol secretion and responses to daily events in patients with remitted bipolar disorder
Introduction
Many patients with bipolar disorders show evidence of increased activity at several levels of the hypothalamic–pituitary–adrenal (HPA) axis during depressive and manic episodes (Linkowski et al., 1994, Schmider et al., 1995, Cassidy et al., 1998, Rybakowski and Twardowska, 1999, Daban et al., 2005). Controversy exists whether these abnormalities are limited to the episodes themselves or might also be present before the onset of bipolar disorder or later, during periods of clinical remission. Offspring of parents with bipolar disorder have been reported to have elevated (Ellenbogen et al., 2006) or normal (Deshauer et al., 2006) basal cortisol levels; in general, studies of basal cortisol secretion in remitted bipolar patients provide little evidence of abnormalities (Cervantes et al., 2001, Watson et al., 2004, Thompson et al., 2005, Deshauer et al., 2006). However, evidence from challenge tests indicates persistent HPA dysfunction after clinical remission from bipolar episodes. For example, remitted bipolar patients have demonstrated intermittent cortisol non-suppression during monthly dexamethasone suppression tests (DSTs) (Deshauer et al., 1999). Moreover, a study using the combined dexamethasone/corticotropin releasing hormone (DEX/CRH) test reported an enhanced salivary cortisol response in symptomatic as well as in remitted bipolar patients, compared to healthy controls (Watson et al., 2004). These findings suggest that cortisol reactivity to psychosocial stressors might also be altered in remitted bipolar patients. Patients with unipolar depression tend to show decreased cortisol responses to laboratory as well as everyday psychosocial stressors (Peeters et al., 2003, Burke et al., 2005), whereas one study found that cyclothymic individuals showed heightened reactivity to a laboratory stressor (Depue et al., 1985). To our knowledge, cortisol reactivity to psychosocial stressors has not been studied in patients with bipolar disorder, either current or remitted. Furthermore, although basal cortisol secretion shows more random variability in individuals with cyclothymia (Depue et al., 1985) and in depressed patients under both naturalistic (Peeters et al., 2004) and controlled conditions (Posener et al., 2004), this indicator of dysregulated HPA activity has not previously been investigated in bipolar patients. In summary, although some studies suggest that HPA axis dysregulation precedes, accompanies and follows bipolar episodes and thus may be a trait characteristic (Daban et al., 2005), there is relatively little information on cortisol secretory patterns in remitted bipolar disorder. Better insight into these patterns may help elucidate whether HPA axis hyperactivity plays a role in the pathophysiology of bipolar disorders (Cousins and Young, 2005). Support for HPA involvement could in turn stimulate the development of therapeutic strategies that target this neuroendocrine system. The glucocorticoid receptor antagonist mifepristone, for example, has been shown to improve cognitive function and attenuate depressive symptoms in bipolar disorder (Young et al., 2004a).
The first aim of the present study was to provide a more complete description of cortisol secretory patterns during the normal daily life of patients with remitted bipolar disorder, in comparison to healthy controls. We therefore conducted an intensive sampling of salivary cortisol with simultaneous registration of daily hassles and uplifts. In the present study, participants collected saliva samples and completed self-report forms 10 times a day for 6 days, which allowed us to examine not only overall cortisol levels, but also the diurnal decline in cortisol levels, short-term reactivity of this hormone to daily stressors, and the degree of apparent random variability. We hypothesized that levels of cortisol secretion in remitted patients would be higher, more variable, and less responsive to daily events than in healthy controls. Our second aim was to investigate whether individual differences in cortisol secretion in the patient group could be explained by the number of previous episodes and the presence of subsyndromal symptoms.
Section snippets
Participants
Thirty-nine bipolar patients were recruited from lithium clinics in Maastricht and Sittard, The Netherlands. The main inclusion criterion was a primary diagnosis of Bipolar I or Bipolar II Disorder, without rapid cycling, as assessed with the Structured Clinical Interview for DSM-IV (First et al., 1996). Additional inclusion criteria were age between 18 and 65 years, in a state of partial or full remission (according to DSM-IV criteria) for more than 2 months, and under regular treatment
Descriptive characteristics
Of the 78 initial participants (39 patients and 39 controls), four (three patients and one control) were excluded from the analyses due to drop-out or inadequate volume of saliva. None of the participants was excluded from the study because of one of the other exclusion criteria. The final sample thus consisted of 36 patients (of whom 18 men) and 38 controls (of whom 15 men). Use of medication in the patient group was as follows: 15 patients received only lithium; the others used various
Discussion
The main findings of the present study point to subtle alterations in cortisol secretory patterns in remitted bipolar disorder: although daytime cortisol levels and reactivity to daily stressors appeared to be normal, patients showed flatter diurnal slopes and lower autocorrelation between successive cortisol measures than the healthy comparison group. In patients with many previous episodes, disturbances in cortisol secretory patterns appeared to be more widespread, with higher overall
Role of funding source
None.
Conflict of interest
There are no conflicts of interest.
Acknowledgements
We thank Dr. José Sulon, University of Liège, Belgium, for performing the cortisol assays, and Truda Driesen, Lilly Finders, and Frieda van Goethem for research assistance.
References (39)
- et al.
Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression
Neuropsychopharmacology
(2002) - et al.
Depression and cortisol responses to psychological stress: a meta-analysis
Psychoneuroendocrinology
(2005) - et al.
Plasma dexamethasone concentration and cortisol response during manic episodes
Biol. Psychiatry
(1998) - et al.
Hypothalamic–pituitary–adrenal axis and bipolar disorder
Psychiatr. Clin. North Am.
(2005) - et al.
Patterns of DST positivity in remitted affective disorders
Biol. Psychiatry
(1999) - et al.
Daytime cortisol and stress reactivity in the offspring of parents with bipolar disorder
Psychoneuroendocrinology
(2006) - et al.
Medication effects on salivary cortisol: tactics and strategy to minimize impact in behavioral and developmental science
Psychoneuroendocrinology
(2009) - et al.
Salivary cortisol in psychoneuroendocrine research: recent developments and applications
Psychoneuroendocrinology
(1994) - et al.
Chronic stress and stressful life events in the offspring of parents with bipolar disorder
J. Affect. Disord.
(2009) - et al.
Levels and variability of daily life cortisol secretion in major depression
Psychiatry Res.
(2004)
Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder
Psychoneuroendocrinology
The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness
J. Psychiatr. Res.
Combined dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I
Biol. Psychiatry
Diurnal cortisol profiles and evening cortisol in post-pubertal adolescents scoring high on the Children's Depression Inventory
Psychoneuroendocrinology
Cortisol pulsatility and its role in stress regulation and health
Front. Neuroendocrinol.
Circadian secretion of cortisol in bipolar disorder
J. Psychiatry Neurosci.
Is the hypothalamic–pituitary–adrenal axis at last paying dividends?
Validity and reliability of the experience-sampling method
J. Nerv. Ment. Dis.
Cited by (65)
Shared postulations between bipolar disorder and polycystic ovary syndrome pathologies
2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryAlteration in circadian rhythms in bipolar disorder: Mechanisms and implications
2020, Neurobiology of Bipolar Disorder: Road to Novel TherapeuticsInvestigating associations between momentary stress and cortisol in daily life: What have we learned so far?
2019, PsychoneuroendocrinologySocial stress response in adolescents with bipolar disorder
2018, PsychoneuroendocrinologyThe relationship between inflammatory state and quantity of affective episodes in bipolar disorder
2018, PsychoneuroendocrinologyCitation Excerpt :Cortisol is an endogenous corticosteroid that is released in response to stress and regulated via feedback mechanisms in the HPA-axis (Hellhammer, 2009). Studies have shown that patients with BD have abnormally heightened levels of morning cortisol compared to healthy controls (Grishkin et al., 2014) as well as blunted cortisol responses to psychological stress (Havermans et al., 2014; Houtepen et al., 2015). A recent meta-analysis (Grishkin et al., 2014) demonstrated that certain clinical features of BD (e.g. illness chronicity, medication status, mood state) have significant effects on HPA function.