Abstract
Altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in patients with treatment-resistant depression, although studies have often conflated patients with unipolar and bipolar depression. This is problematic given that the two groups often present with opposed neurovegetative symptom patterns. The aim of this study was to test, for the first time, whether post-awakening cortisol, a highly reliable, naturalistic measure of HPA functioning, could distinguish patients with clearly defined treatment-resistant unipolar (TRUD) and bipolar depression (TRBD). A total of 37 patients with TRUD, 17 patients with TRBD, and 47 healthy controls were recruited. Areas under the curve (AUC) with respect to the ground (g) and increase (i) of post-awakening cortisol concentrations (awakening, +15, +30, +45, +60, +90 min) were measured over two days. Patients with TRUD had higher total cortisol production in the morning hours compared to controls (AUCg, p = 0.01), while they did not differ in terms of the awakening response (AUCi, p = 0.28). By contrast, subjects with TRBD had lower total cortisol when compared to controls by trend (AUCg, p = 0.07), while they did not differ in the awakening response (AUCi, p = 0.15). A direct comparison of TRUD and TRBD revealed differences in the AUCg (p = 0.003) and AUCi (p = 0.03). This finding of comparatively elevated HPA axis activity in the morning in TRUD and attenuated HPA axis activity in TRBD attests to a fundamental biological distinction between unipolar and bipolar depression. It has implications for the understanding and treatment of bipolar depression and in differentiating the two types of depression.
Highlights
Depression is a debilitating condition, with a course that is often recurrent or chronic with a negative impact on both society and the individual[1]
To the best of our knowledge, this is the first time that post-awakening cortisol concentrations were measured in clearly defined TRUD, given that in the McAllister-Williams et al.[17] study all patients had to use serotonergic antidepressants upon study entry, their sample of patients with a treatment resistant major depressive episode is likely to contain a high proportion of patients with TRUD
Our finding of relatively elevated post-awakening cortisol concentrations contradicts the null-finding by McAllister-Williams et al.[17], who may have included cases with TRBD, while being in line with previous research confined to patients with unipolar depression[24,28]
Summary
Depression is a debilitating condition, with a course that is often recurrent or chronic with a negative impact on both society and the individual[1]. There has been extensive research into the link between hypothalamic-pituitary-adrenal (HPA) axis abnormalities and unipolar depression, with findings such as elevated basal cortisol levels, non-suppression of cortisol following dexamethasone administration, and alterations in the cortisol awakening response[4,5], research looking into depressive episodes occurring as part of bipolar disorder—bipolar depression—has been much less extensive[6] This is especially true regarding postawakening cortisol concentrations, with only three published studies comparing patients with bipolar depression to healthy controls, two reporting null-findings[7,8] and one reporting higher levels in patients[9]. Markopoulou et al Translational Psychiatry (2021)11:244 unipolar and bipolar depression within one illness group, confounding results and masking any potential differences between these two forms of depression Certain clinical features, such as hypersomnia, diminished energy levels, diurnal mood variation, psychosis, excessive self-reproach, and low libido are more common in bipolar rather than unipolar depression[10]. Several of these characteristics are encountered in atypical depression, which is characterised by reversed neurovegetative symptoms and seems to exhibit a different endocrine profile compared to melancholic depression, namely hypocortisolemia as opposed to hypercortisolemia[11]
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