The Relation Between Cortisol and Mood Disorders
For several decades, strong associations have been made between hypothalamo–pituitary–adrenocortical (HPA) axis dysregulation and mood disorders (1,2). During the 1980s, investigators focused on cross-sectional associations between cortisol and melancholic depression, using the Dexamethasone Suppression Test (DST). It has been reported that approximately 70% of patients meeting criteria for melancholic depression do not show suppressed cortisol secretion after dexamethasone challenge (3). Further studies using the DST have shown that some individuals suffering from mood disorders have positive DSTs even after their clinical depression has improved and that these periods of cortisol nonsuppression correlate with heightened risk of relapse (4). Intermittent nonsuppression has also been used to predict high-risk periods for episode recurrence (5,6).
Recently, interest has turned to more refined testing and the probability that HPA dysregulation may even predate the onset of clinical illness (7). Preliminary data suggest that this dysregulation may be concentrated within the families of individuals with mood disorders (7), suggesting the hypothesis that early abnormalities in cortisol regulation may confer a risk for the future development of mood disorders.
To understand the temporal relation between HPA dysregulation and the onset of bipolar disorder (BD), it is essential to have a reliable and noninvasive test that can be repeatedly administered prospectively and is acceptable to high-risk populations. Promising candidates for such a test include the salivary free cortisol response to waking and the short daytime profile, a test that adds afternoon and evening measurements to the waking values.
This pilot study builds on a long-term naturalistic study of patients with a highly recurrent typical BD stabilized with lithium monotherapy. Using monthly DSTs for more than 6 years, we have already established extended patterns of enhanced cortisol secretion in this group. The goal of this pilot investigation was to apply the salivary cortisol testing to the same group.
The Free Cortisol Response to Waking and the Short Daytime Profile
Salivary cortisol levels are about 5% of the concentrations present in the serum (8,9), representing the unbound fraction. They correlate reliably with serum and cerebrospinal fluid (CSF) levels, lagging the pulsatile pattern of adrenal secretion by approximately 15 minutes (10,11).
The cortisol response to waking is a rapid increase in salivary cortisol levels—at least 2.5 nmol/L above the individual morning baseline. It is normally observed within the first 30 minutes of waking (12). According to preliminary data, enhanced secretion is seen in people reporting chronic anxiety, social stress, and perceived lack of social recognition (12). Wust and others have reported a mean rise of 50% in 509 German control subjects (12).
The cortisol rise is consistent, and a moderate rise is present in 75% of the general population. While women show a virtually identical cortisol rise after awakening, compared with men, they tend to have a significantly delayed decrease (12). The free cortisol response to waking test comprises 4 saliva samples taken at 15-minute intervals, immediately upon waking.The test shows a high degree of intraindividual stability and has been shown to be under substantial genetic influence (12–14).
The short daytime profile comprises 3 salivary tests. The first is taken within 1 hour of waking, and the next 2 are taken at 3:00 PM and 8:00 PM, respectively. Recent observations in large samples suggest that approximately 85% of the general population show a declining pattern from morning to night. However, 15% tend to show a relatively flat short daytime profile, defined as an AM-to-PM decline of less than 5% (14). Investigations into the health implications of a flattened response curve are being actively pursued, and initial data point to a poorer outcome in breast cancer patients showing this pattern, compared with those having a typical AM-to-PM decline in cortisol (15). In contrast to the more stable cortisol response to waking, the short daytime profile has shown a lack of similarity between twin siblings and is believed to be more sensitive to immediate circumstances (16).
Dexamethasone Suppression Tests. Participants took 1 mg dexamethasone at 11:00 PM the night before the test, which was conducted the day following the salivary profile. A blood sample for serum cortisol was drawn at 4:00 PM the next day. Cortisol levels over 138.5 nmol/L were considered positive (3).
The Research and Ethics Committee of the Royal Ottawa Hospital, Ottawa, Canada, approved these procedures.
There was a significant difference between BD patients and our control subjects in the maximum percentage rise of salivary cortisol response to awakening (patient mean 96.11, standard error of the mean [SEM] 32.01; control subject mean 10.60, SEM 10.60; Mann–Whitney U = 16.00, P < 0.03; Table 1). Those showing a waking response also had significantly higher mean cortisol values at 30 minutes after waking, compared with 509 normal subjects described in Wust and others’ study (12) (patient mean 27.1 nmol/L, SD 9.67; control subject mean 22.95 nmol/L, SD 9.13; 1-tail t-test P < 0.001) Baseline values at time zero, immediately upon waking, did not differ significantly between our sample and Wust’s control subjects (12) (patient mean 15.98 nmol/L, SD 7.99; control subject mean 15.12 nmol/L, SD 6.25).
Patients and our 5 control subjects did not differ significantly in the percentage decline from the peak morning value to the evening values (“AM/PM ratio”; patient mean 79.09, SEM 6.30; control subject mean 83.75, SEM 9.95).
The mean number of DSTs available per patient was 64.9 (SD 36). The patients included in the DST study had between 3.5% and 84.3% positive (DST mean 25.75, SEM 5.00, median 13.5); the values did not correlate significantly either with AM/PM drop (r = 0.132, ns) or with maximum morning rise of salivary cortisol (r = 0.103, ns).
Figures 1, 2, and 3 illustrate a representative example—a woman (Patient 1) we have treated for recurrent bipolar illness for 25 years and whose intermittently positive DSTs we have monitored (Figure 1). Her most recent DST was negative, her AM-to-PM decline was normal (state measures), and she continued to be in full remission (Figure 3). Yet, her morning rise of salivary cortisol (trait-like) was higher than average at 72% (Figure 2), presumably expressing her BD propensity.
Figure 1 Longitudinal Dexamethasone Suppression Test (DST) data on a fully remitted lithium responder for past 5 years who was asymptomatic and treated with lithium throughout
Figure 2 Robust free cortisol response to waking
Figure 3 Salivary cortisol response
In this pilot investigation, euthymic lithium-responsive BD I patients showed significant enhancement of the salivary morning cortisol response to waking, compared with a small group of Canadian healthy control subjects and a large group of German healthy control subjects. The patients had a history of recurrent BD, but when tested, they were experiencing full remission on several years’ treatment with lithium, and their most recent DSTs tended to be normally suppressed. This observation suggests that an excessive cortisol rise in response to waking may be a relatively enduring marker characteristic of bipolar illness, independent of momentary state as reflected by the DST. Conversely, nonsuppressed elevated cortisol in the DST test is considered a useful state marker for many patients with acute depression and mania, as has been established in many studies.
Our observations are consistent with a view that both the DST and the short daytime cortisol profile reflect relatively transient aspects of cortisol regulation, since these tests tended to be normal even when the waking response was abnormal.
The morning cortisol response was not correlated with either the short daytime profile or the percentage of positive DSTs on record. This suggests that, indeed, the morning cortisol rise and the behaviour of cortisol during the day and late afternoon reflect 2 different properties of the HPA axis. The greater-than-expected morning rise of salivary cortisol was present in most tested patients, but not in all. Adjusted methodology could lead to even more patients with a dramatic morning rise. For instance, it will be important in further testings to ensure that the tested patients have slept normally during the night preceding the test and that the first sample is taken immediately after awakening.
Hellhammer and others have observed this problem, and somnographic studies are underway to elucidate the relation between the free cortisol response and sleep problems (Hellhammer, personal communication, 2002). If the rise occurred at a time other than during our specified collection interval, we have under- estimated the proportion of our sample exhibiting the abnormal test. Conversely, it must be kept in mind that 23% of the normal population does not show the waking response at all (12). Individuals with BD not demonstrating a rapid waking response may be a part of that cluster.
If the free cortisol response to waking identifies a vulnerability factor for the illness in such high-risk contexts as family studies (7), it will be essential to determine the retest stability in this population. The initial study design did not take this into account, and future studies will have to address the stability of both normal and abnormal results in BD patients. While restricted by a small sample and limited control subjects, the findings of this pilot study support further investigations into the relation between the free cortisol response to waking and BD.
Funding and Support
This study was supported by the University of Ottawa University Medical Research Fund (UMRF).
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Manuscript received May 2003, revised, and accepted June 2003.
1. Clinical Lecturer, Department of Psychiatry, University of Ottawa, Ottawa, Ontario.
2. Associate Professor, Department of Psychiatry, University of Ottawa, Ottawa, Ontario.
3. Associate Professor, Department of Psychiatry, University of Ottawa, Ottawa, Ontario; Associate Professor, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia.
4. Associate Professor Department of Psychiatry, University of Ottawa, Ottawa, Ontario.
5. Staff psychiatrist, Royal Ottawa Hospital, Ottawa, Ontario.
6. Professor, Department of Psychiatry, University of Ottawa, Ottawa, Ontario.
Address for correspondence: Dr D Deshauer, Mood Disorders Research Unit, Royal Ottawa Hospital, 1145 Carling Avenue, Ottawa, ON K1Z 7K4
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