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Diurnal Activity and Pulsatility of the Hypothalamus-Pituitary-Adrenal System in Male Depressed Patients and Healthy Controls

Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany

Address all correspondence and requests for reprints to: Michael Deuschle, M.D., Central Institute of Mental Health, J5, 68159 Mannheim, Germany.

	Abstract

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There is only sparse and ambiguous information about circadian and pulsatile secretion features of the hypothalamus-pituitary-adrenocortical system in depression. We studied 15 severely depressed (Hamilton Depression Scale 30.4 ± 6.7) male patients (age 22–72 yr; mean, 47.7 ± 14.8) and 22 age-matched male controls (age 23–85 yr; mean, 53.1 ± 18.2). Twenty-four-hour blood sampling from 0800–0800 h with 30-min sampling intervals was performed; from 1800–2400 h, blood was drawn every 10 min. Multivariate analysis of covariance, with the covariate being age, revealed mean 24-h cortisol (315.9 ± 58.5 vs. 188.2 ± 27.3 nmol/L) and mean ACTH (7.82 ± 1.94 vs. 5.79 ± 1.28 pmol/L) to be significantly increased in depressed patients. The frequency of cortisol (2.6 ± 0.7 vs. 1.3 ± 1.0 pulses/6 h) and ACTH (2.6 ± 1.6 vs. 1.6 ± 1.4 pulses/6 h) pulses during the evening were higher in patients compared to controls. The flattened circadian cortisol variation and reduced time of quiescence of cortisol secretory activity (140 ± 116 vs. 305 ± 184 min) in patients suggest disturbances of circadian functions.

We conclude that increased hypothalamus-pituitary-adrenocortical activity in depression is related to a greater frequency of episodic hormone release, and we hypothesize that the observed circadian changes might be partly due to altered mineralocorticoid and glucocorticoid receptor capacity and function.

	Introduction

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HYPERCORTISOLEMIA is a frequent endocrine sign in depressed patients. Similarly, an ample number of studies have demonstrated dysregulation of the hypothalamus-pituitary-adrenal (HPA) system by applying various challenge tests, such as 1) the dexamethasone suppression test (1, 2, 3), 2) CRH or ACTH stimulation tests (3, 4, 5), or 3) the combined dexamethasone suppression/CRH stimulation test (6, 7).

In contrast to the huge literature about function tests, only little information about the circadian activity and features of pulsatile secretion of ACTH and cortisol at baseline in depressed patients has been communicated.

Several researchers (8, 9, 10, 11, 12) reported increased mean 24-h cortisol plasma concentrations in adult depressed patients and attenuation after antidepressant treatment (13, 14). Also, an age-associated phase advance with earlier acrophase and nadir (15, 10) and earlier first evening cortisol secretory episode (9) were reported. Reduced diurnal amplitude of the 24-h cortisol rhythm relative to the 24-h mean cortisol level supported the idea of circadian alterations in depressed patients (15, 11).

Ambiguous data about pulsatile release of cortisol and ACTH in depressed patients have been reported. Increased (8), unchanged (11, 12), and reduced (15) frequency of pulsatile cortisol release were found. However, the magnitude of the secretory cortisol episodes seemed to be increased (8, 11, 12, 15). The frequency of pulsatile ACTH release in depression was either unchanged (11) or increased (12). Also, circadian plasma ACTH concentrations were found to be either unchanged (11) or increased (10, 14) in depressed patients.

Most of these studies, however, had some significant methodological shortcomings, such as a small number of subjects (8, 13, 12), no matching for age (10), concomitant tricyclic medication (10), or insufficient pulse criteria (8, 15).

Thus, the aim of this study was to assess in a reasonably large number of well characterized, medication-free patients and age-matched controls HPA system activity with special regard to pulsatile and circadian features.

	Subjects and Methods

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Subjects

This study was approved by the local ethics committee, and all subjects gave informed written consent. Only male in-patients with major depression were included in this study. Inclusion criteria were 1) major depression according to DSM-III-R (16), 2) at least 18 points on the 21-item Hamilton Depression Scale (17), 3) no history of substance abuse or dependency, 4) exclusion of neurological or relevant medical diseases, and 5) no psychotropic drugs for at least 7 days before the study, except chlorohydrate given in cases of sleep difficulties.

The healthy control group was obtained by newspaper advertisement. A standardized psychiatric interview gave no evidence for an individual or family history of psychiatric disorders in the normal controls. In all subjects, a thorough physical examination and routine laboratory test, including magnetic resonance imaging, electrocardiogram, and electroencephalogram, revealed no sign of physical illness.

Fifteen male depressed patients [age, 22–72 yr (mean, 47.7 ± 14.8); body mass index, 16.5–33.3 kg/m² (mean, 24.3 ± 4.4); HAMD, 18–44 (mean, 30.4 ± 6.7)] and 22 healthy male volunteers [age, 23–85 yr (mean, 53.1 ± 18.2); body mass index, 21.0–28.4 kg/m² (mean, 24.9 ± 2.1)] participated in this study.

Methods

24-h blood sampling. All subjects underwent a 24-h blood sampling period, starting at 0800 h. Blood was drawn through an indwelling forearm catheter at 30-min intervals for measurement of plasma ACTH and cortisol concentrations. Between 1800–2400 h, blood was sampled at 10-min intervals. Between all blood samplings, the tubing system was kept patent by saline infusion at a rate of 50 mL/h. Each sample was immediately centrifuged and stored at -20 C for cortisol and at -80 C for ACTH measurement. Subjects remained sedentary in bed, food was given at fixed schedules, mineral water was given ad libitum, and lights were off at 2300 h. Patients and controls spent the time mostly reading or watching television. Daytime napping was not allowed.

Hormone assays. Cortisol was measured using a commercial RIA (ICN Biomedicals, Costa Mesa, CA). The precision criteria (intraassay variation, 4–7% at a concentration of 40 ng/mL) of this method were routinely monitored longitudinally. The plasma ACTH concentration was measured by immunoradiometric assay using a commercial kit (Nichols Institute, San Juan Capistrano, CA). The intra- and interassay variabilities were less than 8%.

Statistical analysis. In the cortisol and ACTH profiles sampled every 10 min, analysis of pulsatile secretion was performed with the Pulsar program (18). The following G values were used for ACTH: G(1), 3.50; G(2), 2.00; G(3), 1.50; G(4), 1.20; and G(5), 1.00; the following G values were used for cortisol: G(1), 3.80; G(2), 2.60; G(3), 1.90; G(4), 1.50; and G(5), 1.20.

The following parameters of the diurnal cortisol and ACTH profiles were calculated: minimal 24-h ACTH (ACTH MIN), mean 24-h ACTH (ACTH MEAN), maximal 24-h ACTH (ACTH MAX), relative diurnal variation (ACTH VAR) expressed as the change in ACTH (ACTH DELTA; ACTH MAX minus ACTH MIN) divided by ACTH MEAN, number of ACTH pulses in 6 h (ACTH PUL), and amplitude of ACTH pulses (ACTH AMPL). For cortisol, the respective parameters were used. The nadir time of ACTH and cortisol (cortisol NADIR and ACTH NADIR) was defined as the time of the lowest plasma hormone concentration at night. The quiescent period of cortisol was defined according to Linkowski et al. (11) as starting when concentrations lower than 50% of the cortisol MEAN occurred in more than two consecutive samples and ending when concentrations higher than 50% of the cortisol MEAN occurred in more than two consecutive samples. Total quiescent time was defined as the entire time when the plasma cortisol concentration was lower than 50% of the cortisol MEAN. We used samples collected every 30 min for all but pulsatile parameters.

Multivariate analysis of covariance (MANCOVA), with diagnosis (depressed patient vs. healthy control) as independent variable and age as covariate, was applied to test the significance of covariate and factor effects on the dependent variables. The dependent variables were the above-mentioned parameters of diurnal and pulsatile cortisol and ACTH profiles. An equal to 0.05 was accepted as the nominal level of significance. For a significant diagnostic effect, univariate F tests followed to identify the parameters contributing significantly to that effect. The univariate F tests were carried out at a reduced level of significance (adjusted level according to the Bonferroni procedure) for keeping the type I error less than or equal to 0.05. Data are reported as the mean ± SD.

	Results

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MANCOVA revealed a diagnosis effect (F_1,34 = 0.194; P < 0.002). Major depression was significantly associated with increased ACTH MIN (3.33 ± 1.48 vs. 2.33 ± 1.03 pmol/L), ACTH MEAN (7.82 ± 1.94 vs. 5.79 ± 1.28 pmol/L), and ACTH MAX [17.90 ± 6.56 vs. 12.40 ± 2.75 pmol/L (by univariate F tests with df = 1,34, P < 0.05); Fig. 1]. The respective cortisol parameters MIN (106.8 ± 39.2 vs. 52.1 ± 25.7 nmol/L), MEAN (315.9 ± 58.5 vs. 188.2 ± 27.3 nmol/L), and MAX (617.5 ± 89.9 vs. 478.1 ± 86.4 nmol/L) were also reasonably increased (by univariate F tests, P < 0.05; see Table 1 and Fig. 2).

View larger version (22K): [in this window] [in a new window]   Figure 1. Diurnal profiles of mean plasma cortisol in depressed patients and healthy controls (mean ± SEM).

View larger version (22K): [in this window] [in a new window]   Figure 2. Diurnal profiles of mean plasma ACTH in depressed patients and healthy controls (mean ± SEM).

ACTH DELTA (14.56 ± 5.77 vs. 10.06 ± 2.77 pmol/L) and cortisol DELTA (510.7 ± 69.5 vs. 426.3 ± 93.8 nmol/L) were higher in depression, but cortisol VAR (1.7 ± 0.3 vs. 2.3 ± 0.6) was decreased in depressed patients compared to that in the healthy control group (by univariate F tests).

One elderly control subject and one young depressed patient did not have a quiescent period as defined above and could, therefore, not be included in the analysis of the quiescent period. Although there was no effect of diagnosis on cortisol nadir time and beginning of the quiescent period, the duration of the quiescent period (2:20 ± 116 vs. 5:05 ± 184 h ± min), and total quiescent time (3:16 ± 151 vs. 6:05 ± 163 h ± min) were significantly shorter in depressed patients compared to control values.

There was an age-associated increase in cortisol MIN and cortisol MEAN in patients and controls alike. Also, ACTH VAR, cortisol VAR, duration of the quiescent period, and total quiescent time decreased with advancing age in both groups (by univariate F tests with df = 1,34 for the regression effects, P < 0.05).

	Discussion

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The main finding of this study is that the well known heightened activity of the HPA system in depressed patients is due to an increase in the frequency of pulsatile HPA activity, but not in the amplitude of ACTH or cortisol pulses. Second, the nadir time of cortisol and the onset of the quiescent period of cortisol were not different between the two groups studied. Third, the duration of the cortisol quiescent period and the diurnal variability in cortisol (cortisol VAR) was reduced in depression, suggesting a disturbance of circadian function. Interestingly, the effects of aging were similar to the effects of diagnosis, but were of a much lesser degree.

Our results support the hypothesis of a suprapituitary-driven hypercortisolemia in depression with an elevated pituitary set-point in depressed patients, as we found consistently increased diurnal ACTH plasma concentrations in concert with hypercortisolemia.

Our study suggests that hypercortisolemia and hypercorticotropinemia in depression are associated with increased evening pulse frequency and not amplitude. This is in partial contrast to an earlier study (8) that attributed elevated plasma cortisol concentrations to a greater frequency and amplitude of episodic cortisol secretion. The shortcomings of this study were ill defined pulse criteria and the fact that the low sampling frequency might not be sensitive enough to detect small pulses. Another group (9) found the number of pulses per 24 h to be decreased in depressed patients. Their pulse criteria (increase of 2 µg/mL in subsequent samples) is equivalent to a G(1) criteria of approximately 9. Therefore, comparison with our results with regard to pulse frequency is difficult because we used a G(1) for cortisol of 3.80. Our G criteria are similar to those used by other researchers (19). Linkowski et al. (11), using a pulse criterion similar to ours, found similar numbers of ACTH and cortisol pulses, but larger cortisol pulses in depressed patients compared to controls. The magnitude of cortisol pulses was smaller after antidepressive treatment (14). Another study (12), using Cluster analysis, again found no difference in the frequency of pulsatile cortisol release, but found a greater magnitude of pulses in depressed patients compared to normal controls. They reported a larger number of ACTH pulses, whereas ACTH pulse amplitude was unchanged in depressed patients. Taken together, our study confirms these findings of more frequent ACTH release in depression. Our finding of an increased frequency of pulsatile cortisol release in depression, which is in contrast to earlier reports, could be due to the fact that we investigated the evening hours, when HPA activity is usually low in healthy controls. This time window may be more sensitive than others (8) in evaluating heightened pulsatile activity of the HPA system, which probably reflects hypothalamic pulsatile CRH release (20).

Our findings are consistent with earlier reports (10, 11, 14, 15) in terms of phase advance and reduced quiescent period when comparing depressed patients with controls. Although the beginning of the quiescent period did not differ between patients and controls, the roughly 50% reduction of duration of quiescent time suggests earlier onset of HPA activity in depressed patients, which is not reflected by the ACTH or cortisol nadir time. This suggests that the quiescent period is a more sensitive parameter to evaluate HPA system phase advance in depressed patients.

We found that aging is associated with increased cortisol MIN, but not MAX. The age-associated changes in basal HPA activity that we found were mostly circadian dysfunctions, such as a flattened ACTH VAR, cortisol VAR, and age-associated decline in the duration of the quiescent period and total quiescent time. These changes resembled depression-related changes and were more pronounced in the healthy control group. The only effect of the covariate age on ACTH that emerged in our study was attenuated diurnal amplitude relative to the 24-h mean. The mean age was nonsignificantly increased in the healthy controls compared to that in the depressed patients. As the effects of aging and depression on the activity of the HPA system are similar, the reported effects of depression might actually be even greater.

Recent animal studies showed that a dual system of mineralocorticoid receptors (MR), predominantly found in hippocampus, and glucocorticoid receptors (GR) control the feedback inhibitory actions of adrenal steroids. The MR has a high affinity for glucocorticoids and is thought to mainly control low basal circadian levels of circulating glucocorticoids. In contrast, the low affinity glucocorticoid receptor (GR) controls high stress levels of corticoids (21, 22). The early first evening cortisol secretory episode and reduced quiescent period in depressed patients, respectively, minimize the time when the high affinity MR is unoccupied. A receptor that is nearly always occupied can hardly fulfill its regulatory function properly. The resulting functional impairment of MR may be related to the restricted ability to control basal and circadian features of HPA activity, which is supported by our findings.

In conclusion, our findings suggest hypercortisolemia and hypercorticotropinemia in depressed patients to be due to increased pulsatile HPA activity at the hypothalamic level, probably reflecting an altered feedback at a central site. A reduced quiescent period of episodic cortisol secretion may prevent cortisol from dissociating from MR at a central site and thus further impair MR functions, such as the control of feedback sensitivity and circadian regulation of the HPA system.

	Acknowledgments

 
We thank Dr. Alexander Yassouridis for statistical support, Ms. Jutta Drancoli for expert technical assistance, and Ms. Vera Rosburg for preparing the manuscript.

Received May 30, 1996.

Revised August 22, 1996.

Accepted September 11, 1996.

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