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Effects of total sleep deprivation on urinary cortisol, self-rated arousal, and mood in depressed patients
Psychiatry Research, 34:149-162 Elsevier
149
Effects of Total Sleep Deprivation on Urinary Cortisol, Self-rated Arousal, and Mood in Depressed Patients Antoinette Received 1990.
L. Bouhuys,
Frans Flentge, and Rutger H. Van den Hoofdakker
June 26, 1989; revised version received November
21, 1989; accepted February
10,
Abstract. The possibility that the clinical response to total sleep deprivation (TSD) is mediated by dimensions of arousal was investigated in a group of 16 depressed patients. Self-reports of activation, stress, and mood were assessed 3 days before, during, and 2 days after TSD. Urinary cortisol excretion and responses to the dexamethasone suppression test (DST) were also measured. TSD increased cortisol excretion in depressed patients and advanced the time of the maximal excretion of cortisol. No such changes have been reported for normal subjects. Neither the increased excretion nor the time shift was related to the mood response to TSD. The DST results were also unrelated to this response. Indications that the mood response to TSD may be mediated by dimensions of arousal are the significant relationships between this response and the responses of subjective stress and activation to TSD. The TSD-induced cortisol increase was not related to the subjective arousal response to TSD. The increased cortisol excretion itself could be predicted by the averaged baseline levels of subjective stress: the lower the stress levels before TSD, the larger the cortisol response to TSD. Key Words. Sleep deprivation,
depressives,
cortisol,
arousal.
About 50% of patients with endogenous depression respond to total sleep deprivation (TSD) with clinical improvement (Gerner et al., 1979; Gillin, 1983; Elsenga and Van den Hoofdakker, 1987). The mechanisms underlying these mood changes are unknown. One hypothesis is that the response to TSD might be related to TSDinduced changes in arousal (Van den Burg and Van den Hoofdakker, 1975). A number of factors support the plausibility of this explanation. The presence or absence of sleep is related to the course of arousal (Horne, 1978). Moreover, the relationships between primary dimensions of emotions (depressed mood) and arousal (activation and stress or anxiety) are widely recognized (Thayer, 1978b; relationships Tellegen, 1985; Van den Hoofdakker et al., 1989). Consequently, between mood, sleep, and wakefulness might be explained by the interaction of sleep and wakefulness with dimensions of arousal. This explanation can be pursued in
Antoinette L. Bouhuys, Ph.D., is Senior Behavior Researcher; Frans Flentge is Senior Lecturer; and Rutger H. Van den Hoofdakker, M.D., Ph.D., is Professor of Psychiatry and Head, Department of Biological Psychiatry, Academic Hospital, University of Groningen, The Netherlands. (Reprint requests to Dr. A.L. Bouhuys, Dept. of Biological Psychiatry, Psychiatric University Clinic, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.) 01651781/90/
$03.50 @ 1990 Elsevier Scientific
Publishers
Ireland
Ltd.
150 various ways. We previously reported on the covariation of mood and self-reported arousal measures before, during, and after TSD (Van den Hoofdakker et al., 1989) and on the predictive value of arousal-related observed behavior and the subsequent response to TSD (Bouhuys et al., 1985, 1988, 1989). These studies support the suggestion that the clinical response to TSD is mediated by dimensions of arousal. This suggestion is further examined in the present report. Cortisol excretion in response to psychological stress is often considered to be an indicator of arousal (Lundberg and Forsman, 1979; Davies et al., 1981; Forsman and Lundberg, 1982; Vaemes et al., 1982; Sinyor et al., 1983). Depressive patients excrete more cortisol than controls and depressive patients in remission (Stokes et al., 1984; Souetre et al., 1988; Goetze and Tolle, 1987; Linkowski et al., 1987; Holsboer, 1988), suggesting that they are in a relatively high state of arousal or show an increased sensitivity of the adrenals to stimulation by adrenocorticotropic hormone (ACTH) (Amsterdam et al., 1983; Mendlewicz and Linkowski, 1987). In addition, the diurnal pattern of cortisol secretion in depressed patients has been reported to show an early timing in the acute phase of the illness in comparison with the remitted state (Linkowski et al., 1985; Goetze and Tblle, 1987). The phase-advance hypothesis of depression (Wehr and Goodwin, 1981) has been used to interpret these findings. There is evidence suggesting that the suppression of cortisol excretion after dexamethasone is negatively related to the clinical response to TSD (Nasrallah and Coryell, 1982; Kasper et al., 1983; Kuhs, 1985) and to the severity of depression (Klein et al., 1984; Sangal et al., 1984; Arana et al., 1985; Miller and Nelson, 1987). The aim of the current study is to report on relationships between biochemical and psychological measures of arousal and mood in relation to TSD. The first question concerns the effect of TSD on the various arousal measures, i.e., self-reported stress and activation, overall cortisol excretion, and phase position of the cortisol distribution pattern. The second question deals with the interrelationships of these measures. The third question examines the ability of arousal measures to predict the mood response to TSD. Finally, dexamethasone suppression test (DST) results are related to mood and arousal responses to TSD.
Methods Sixteen drug-free depressed patients (major depression and bipolar disorder; D&WZZZ, American Psychiatric Association, 1980) (12 females and 4 males, mean + SD age = 45.1 f 13.7 years) participated in an extensive study on circadian rhythms in depression. The interval between admission and the start of the experiment was at least 10 days. Once the experimental period began, measurements were taken over a period of 6 days (called days l-6). Only assessments of self-reported arousal and mood, and urinary cortisol measurements are presented here. At the start of the experimental period, the patients had been free of medication for at least 7 days. At that moment the severity of depression was assessed (Hamilton Rating Scale for Depression, HRSD; Hamilton, 1967) by two independent raters (mean zb SD of the 2 scores = 26.0 f 4.6). The patients underwent TSD after 3 baseline days (days l-3). Except during planned sleeping time, naps were not allowed. Self-reported arousal (i.e., stress and activation; Activation-Deactivation Checklist; AD-ACL; Thayer, 1967, 1978a) was assessed at 3-hour intervals, from 7 a.m. until 10 p.m. During TSD, additional scores were collected at 1 a.m. and 4 a.m. Mood (Adjective Mood Scale; AMS; Von Zerssen, 1976, 1986) was assessed thrice daily at 7 a.m., 1 p.m., and 10 p.m. Urine samples were collected at 3-hour intervals from 7 a.m. until 10 p.m. Additional
151 samples were collected during the night preceding the experimental period of 6 days, from 10 p.m. until 4 a.m. and from 4 a.m. until 7 a.m. During TSD two 3-hour samples at 1 a.m. and 4 a.m. were obtained. In order not to interfere with biochemical and behavioral data collection, a DST was performed on day 6. Blood samples were taken before the administration of 1 mg dexamethasone at 11 p.m. To measure the cortisol response, blood samples were collected at 4 p.m. and 11 p.m. on the next day. A patient was defined as a nonsuppressor if one of the cortisol levels at these time points exceeded 140 nmol/l. Patients were under dietary control to ascertain adequate daily food intake. Cortisol was measured by radioimmunoassay with locally prepared rabbit antiserum. Urinary cortisol was first purified on Sep-pack Cl8 columns and isolated on Sephadex LH-20 columns. Plasma cortisol was measured without purification. For technical reasons, some samples were pooled (see Results). Mood and activation scores underwent a trend correction based on the scores of the 3 baseline days, by means of a regression analysis. The effect of TSD on depression, activation, or stress was defined as the difference of the averaged trend corrected scores on the day before and the day after TSD (7 a.m. until 10 p.m.; after minus before). Mood responders to TSD showed a decrease of more than 5 points on the AMS (i- mood response; n = 7). The remaining group showed a 5-point change or less (- mood response; n = 9) (Elsenga and Van den Hoofdakker, 1987). Two effects of TSD on cortisol were distinguished in the excretion level and the excretion pattern: (1) The effect on the level of excretion was defined as the difference of the averaged hourly excretion during the 24-hour period (10 p.m.-IO p.m.) 2 days before TSD and the corresponding 24-hour period during which TSD took place (scores during and after TSD minus score before TSD). (2) The effect on the excretion pattern was defined as the shift of the acrophase. It was measured by comparing the location of the highest value for cortisol excretion among the 3-hour measurements in the baseline 24-hour period with the location of the highest value in the period during which TSD was applied. A shift was defined as the difference of the corresponding clock times at which these maxima occurred (after minus before). The patients were informed about the nontherapeutic character of the experiment. Nonparametric statistical tests were used to evaluate the results. The Wilcoxon matchedpairs test was used for within-group comparisons. Mann-Whitney U tests were used for
between-group comparisons. Spearman rank correlations were also calculated (Siegel, 1956). The confidence level was set at 5% (two-tailed).
Results Effects of TSD on Depressive Mood. Fig. 1 demonstrates the effects of TSD on depressive mood, for responders (n = 7) and nonresponders (n = 9). The results confirm numerous earlier findings that TSD can induce shortlasting moodswings in about 50% of depressive populations (see Gillin, 1983). The suggestion from Fig. 1 that patients who responded well to TSD were those with diurnal variation of mood will be dealt with elsewhere (Reinink et al., 1990). Effects of TSD on Measures of Arousal. The averaged scores of stress and of activation on the day before TSD (17.3 f 3.8 [SD] and 19.3 + 3.8 [SD], respectively) did not differ from the scores on the day following TSD (25.7 + 4.3 [SD] and 18.7 + 4.8 [SD], respectively) (Wilcoxon, n = 16). Fig. 2 depicts the time course of urinary cortisol excretion in the baseline (“before”) and the TSD conditions (“after”). The average secretion of cortisol over the total interval (10 p.m.-10 p.m.) was significantly increased (Wilcoxon: p < 0.001, n = 16). This effect is mainly due to an increase during the 10 p.m.-4 a.m., 4 a.m.7 a.m., and 4 p.m.-IO p.m. intervals (Wilcoxon: p < 0.008, n = 1 I; p < 0.001, n = 15; p < 0.005, n = 16, respectively).
152 Fig. 1. Severity of depressed mood (AK) in patients with different mood responses to total sleep deprivation (TSD) l
+
o -
mood
mood
TSD toTSD
resp. resp.
to
depression 60
36
28
20 7
13
22
7
13
22
7
13
time Responders: n = 7: nonresponders:
22
7
13
22
7
13
22
7
(hours)
n= 9
Fig. 2. Course of the mean (k SEM) excretion of cortisol over 24 hours before and after total sleep deprivation (TSD) in 16 depressed patients PC.001 * L
2 r 2
•I before TSD
24-
Cl after 20-
5 16 -
1Opm
4am
loam Time
Two-tailed Wilcoxon matched pairs test was applied.
4pm
10pm
TSD
153
Average 24-hour cortisol production (7 a.m.-7 a.m.) on baseline days 1 and 2 was compared with the production over the same interval on the day of TSD and the 2 subsequent days. Only on the day during TSD was the cortisol production significantly increased (Wilcoxon: p < 0.002, n = 16). In each patient, the position of the maximum (highest value) of the cortisol excretion curve during the baseline condition was compared with that during the TSD condition. The maximum shifted from 8:58 a.m. + 2:04 (SD) before TSD to 653 a.m. f 1:59 (SD) after TSD (Wilcoxon: p < 0.02, II = 13). Relationships Between Mood and Arousal Responses to TSD. Table 1 shows that only the stress response and the activation response to TSD were significantly related to the mood response to TSD. No relationships were found between the mood response to TSD and the cortisol excretion response to TSD (also see Fig. 3). The cortisol excretion over the interval from 10 p.m. to 10 p.m. before TSD was compared to the same interval starting at 10 p.m. on the night of TSD in patients who improved after TSD and patients who did not. Also a more detailed analysis of the relation between cortisol data (i.e., changes in the 3-hour cortisol excretions after TSD) and the mood response to TSD did not reveal significant results.
Table 1. Correlations between mood and arousal responses to total sleep deprivation (TSD) (n = 16) 1 1. Mood response to TSD
-
2. Activation response
2
3
4
0.5662
-0.76E3
0.318
-0.024
0.336
0.434
-0.057
-
0.068
0.090
-
-0.358 -
-
3. Stress response 4. Cortisol excretion response 5. Peak shift of cortisol maxima
5'
7. n = 13. 2. p < 0.05. 3. p < 0.01.
Fig. 3. Urinary cortisol levels in depressed patients with different mood responses to total sleep deprivation (TSD) EZI+ mood resp. to TSD (n ~7) 0
_ mood resp.
to TSD
(n-9)
20 2
18
g
14
$
12 16 i
T
before
TSD
after
TSD
154
Moreover, Table 1 shows that the shift in the cortisol excretion maximum was not correlated with the change in mood after TSD. Fig. 4 illustrates changes in peak position and their relation to the mood response to TSD. The position of the maximum was not significantly correlated with the severity of the depression (averaged day scores): before TSD this correlation was r = 0.289 (n = 13) and after TSD r = 0.466 (n = 13).
Fig. 4. Mean and standard deviations of the cortisol peak position in patients with different mood responses to total sleep deprivation (TSD) EZ3+ mood resp. to TSD O-
llr
Prediction
between response
of Mood
mood resp. to TSD
clock time
T
-I-
before
TSD
Response
to TSD.
h=5) (n=8)
after TSD No significant
any of the stress, activation, or cortisol to TSD (Spearman correlations).
relationships were found scores before TSD and the mood
Prediction of Cortisol Responses to TSD. The finding that patients reacted to TSD with an increase and a peak shift of their cortisol production prompted us to investigate relationships between these reactions and the subjective behavioral measures before TSD (see Table 2). Mood. The negative correlation between the average severity of depression only on day 2 before TSD and the peak advance of cortisol suggests that relatively less severely depressed patients are more likely to show a peak advance in cortisol excretion. No significant relations were detected between the severity of depression before TSD and the magnitude of the cortisol excretion response. Stress and activation. The cortisol excretion response was negatively related to baseline levels of stress on each of the 3 days preceding TSD. Fig. 5 visualizes these correlations. Patients were divided into two groups: patients (n = 8) with the highest cortisol response to TSD (-I- cortisol) and patients (n = 8) with the lowest response (- cortisol). Significant rank correlations between the cortisol excretion response and stress levels are indicated. In addition, Table 2 shows that the average level of activation on the first experimental day was positively related to the cortisol excretion response to TSD. Cortisol. Baseline levels of cortisol excretion were not significantly related to either the excretion response or the peak shift response to TSD (Spearman correlations).
155
Table 2. Correlations between self-rated arousal and mood before total sleep deprivation (TSD) (on days 1, 2, and 3) and cortisol responses to TSD(n=16) Stress Assessment time of self-ratings Day 1
7 a.m. 10 a.m.
Mean
Mean
-0.450
-0.347
0.6263
0.387
-0.7034
-0.051
0.375
0.250
-0.6443
-0.068
0.479
0.241
-0.059
0.5433
0.365
Mood Cortisol excretion
Peak shift
-0.394
-0.419
-0.430
-0.172
7 p.m.
-0.5473
0.008
0.324
0.517
10 p.m.
-0.414
0.163
0.394
-0.108
-0.442
0.051
-0.115
0.5703
0.485
-0.477
-0.308
-0.134
0.023
-0.400
-0.5743
-0.741 4 7 a.m.
-0.5473
-0.085
0.298
0.235
10 a.m.
-0.7434
-0.366
0.332
0.238
1 p.m.
-0.6754
-0.484
0.433
0.535
4 p.m.
-0.55a3
-0.379
0.263
0.516 0.295
7 p.m.
-0.5243
-0.291
0.248
10 p.m.
-0.440
-0.291
0.437
0.61 63
-0.467
-0.5943
-0.6473
-0.395
0.419
0.475
-0.396
-0.5823
-0.7324
-0.139
0.261
-0.125
-0.389
-0.397
-0.61 53
-0.068
0.380
0.438 -0.181
-0.5793
7 a.m.
day 3
Peak shift
-0.6553
10 a.m.
Mean
Cortisol excretion
1 p.m.
day 2
Day 3
Peak shift’
4 p.m.
day 1
Day 2
Cortisol excretion’
Activation
1 p.m.
-0.502
-0.234
0.414
0.453
4 p.m.
-0.465
-0.080
0.151
0.220
7 p.m.
-0.092
0.015
0.292
0.451
10 p.m.
-0.339
-0.285
0.421
0.453
-0.234
-0.385
-0.551 3
-0.130
0.383
0.404
-0.315
-0.514
Note. Results are expressed as Spearman correlation coefficients 1. Urinary cortisol excretion (after TSD minus before). 2. Time position of cortisol excretion maximum (after TSD minus before) (n = 13). 3. p < 0.05. 4. p < 0.01.
DST. Patients were classified as nonsuppressors (n = 8) and suppressors (n = 7). These groups were compared with respect to the various mood, arousal, and cortisol levels. No differences were found between the two groups for: (1) the preceding mood, arousal (stress and activation), or cortisol levels (Mann-Whitney U test); (2) the mood and the arousal responses to TSD as well as the cortisol excretion and peak shift response (Table 3); and (3) the severity of depression (according to the 7 a.m. AMS score) on the day of dexamethasone administration.
Discussion Evidence that the mood response to TSD is mediated by dimensions of arousal can be seen in the direct relationships between mood response and responses of
156 Fig. Stress levels to total sleep + cortisolexcretion
patients with (TSD) resp. to TSD
l
o -
cortisoi
excretion
resp. toTSD
cortisol
excretion
1”:;; n
stress
35
:... 30
I-
? :
‘%
9
h
‘\d’
d'
25
:
'b
20
15
.1 7
13
22
7
13
22
7
13
time Asterisks indicate significant excretion response to TSD.
Spearman correlations
2214
7
13
22
713
22
7
(hours)
between stress levels at different time points and the cortisol
* p < 0.05. ** p < 0.01.
subjective stress and activation to TSD. Little additional evidence was found. Neither subjective arousal nor cortisol excretion before TSD predicted the mood response to TSD. Furthermore, this mood response was not related to either the level or the pattern of cortisol response. Cortisol has been shown to be reactive to psychological stress (Lundberg and Forsman, 1979; Davies et al., 1981; Forsman and Lundberg, 1982; Vaernes et al., 1982; Sinyor et al., 1983) and may therefore be considered as an indicator of arousal. TSD may have an arousal-increasing effect in depressives as demonstrated by an increased 24-hour urinary secretion of cortisol during and after TSD. However, this effect is not paralleled by changes in the two self-rated measures of arousal, i.e., stress and activation. This might suggest that subjective stress, activation, and cortisol excretion responses could be interpreted as different aspects of arousal. The TSD-induced increase in cortisol excretion levels is mainly due to the increase during the periods 10 p.m.-4 a.m., 4 a.m.-7 a.m., and 4 p.m.-IO p.m. (Fig. 2). These results are in agreement with those of other TSD experiments in depressed patients. Yamaguchi et al. (1978) found an increase of plasma cortisol in depressed patients at 8 a.m. and 4 p.m. and, in addition, comparison of depressed patients with normal controls revealed an increase at 4 a.m. Comparable observations were reported by Goetze and Tiille (1987), who found an increase in amplitude of the urinary cortisol production after TSD, though the total 24-hour production of cortisol after TSD was not significantly increased. Thus, depressed patients seem to react differently to TSD in comparison with controls. In normal subjects, TSD does not increase cortisol excretion even after 48 or 72
157 hours of sleep deprivation (Akerstedt et al., 1980; Kant et al., 1984). Yamaguchi et al. (1978) and Gerner et al. (1979) found some evidence that the increased levels of cortisol as a result of TSD were confined to clinical responders to TSD. In contrast, we measured increased cortisol levels in both responders and nonresponders to TSD. This disagreement might be due to differences in response definition of clinical change or in pharmacological conditions. Antidepressants are of crucial importance for the mood responses to TSD (Loosen et al., 1976; Elsenga and Van den Hoofdakker, 1983) and in the study of Yamaguchi et al. (1978), patients received tricyclic antidepressants. Probably the TSD-induced increase of cortisol in the depressed patients of the present study reflects an enhanced sensitivity to environmental factors (e.g., social contacts, attention). One would have expected this enhanced sensitivity to have been reflected in the self-reports on experienced arousal, but this was not the case. No direct relationships were found between the cortisol excretion response to TSD and the subjective arousal response.
Table 3. Mean and standard deviation of self-rated arousal, mood, and cortisol responses to TSD (after minus before) in depressed patients classified as DST nonsuppressors and suppressors Nonsuppressors Mean 1. Mood response response
2. Activation 3. Stress 4. Cortisol
response excretion
response’
5. Peak shift2
Suppressors
SD
Mean
-7.4
14.1 (8)
-1.6
7.5 (7)
0.0
4.1 (8)
0.5
4.3 (7)
-4.1
3.5 (8)
-3.0
1.9 (7)
0.2
6.7 (8)
-0.5
1.7 (7)
2.5
2.3 (61
1.5
Note. The n’s are shown in parentheses. TSD = total sleep deprivation. DST = dexamethasone
SD
2.5 (61 suppression test
1. Difference score in nmolihour. 2. Difference score in hours.
As to the excretion pattern, TSD was found to shift the maximum excretion from 858 a.m. to 6:53 a.m. (Fig. 2). Because our data were collected at 3-hour intervals and large differences between individual shifts were found (mean shift 2.1 hours + 2.3 hours [SD]), results on maxima should be considered with caution. Nevertheless, the baseline location of the maximum is in line with other observations (Yamaguchi et al., 1978; Linkowski et al., 1985; von Zerssen et al., 1987). The shift of the acrophase under TSD conditions was not found by Yamaguchi et al. (1978). This discrepancy may be explained by different sampling techniques used. While in the present study the mean 3-hour urinary cortisol excretion was measured, in the study of Yamaguchi et al. (1978), blood samples were taken at 4-hour intervals, giving no integrated measure of the cortisol production. By this procedure, shifts during the intervals between the samples can remain unobserved (see Sachar et al., 1973). Much emphasis is currently being placed on the possibility that changes in circadian organization of biochemical and behavioral processess may be of causal importance in depression (Halaris, 1987). One hypothesis states that in depressives circadian processes show a phase-advance in comparison to the phase in controls
158 (Doig et al., 1966; Wehr and Goodwin, 1981). Our results do not support such a phase-advance for the following reasons: (1) Severity of depression was not found to be related to the baseline location of excretion maxima. (2) The shift in peak position was not related to the mood response to TSD. (3) In the mood responders to TSD, one would expect to find a delay of the excretion peak. The responders and the nonresponders, however, showed an advance. The lack of support is not without precedent (von Zerssen et al., 1987; Souetre et al., 1988). The occurrence of high baseline cortisol levels and an advanced position of the nadir in depressives in comparison with controls and with themselves when in remission (Carroll et al., 1976; Berger et al., 1982; Linkowski et al., 1985; Holsboer et al., 1988) may be considered to be a reaction to the clinical condition and may be indicative of an as yet unspecified instability of the hypothalamic-pituitary-adrenocortical (HPA) system. Our data suggest an increase in this instability, and therefore the clinical improvement induced by TSD (accompanied by increased levels of cortisol) may be of another quality than that obtained with other therapeutic treatments (accompanied by normalized levels of cortisol). The transient character of the clinical response to TSD may also support this suggestion. The cortisol response to TSD was found to be related to stress levels on each of the days receding TSD, strongly suggesting that this relationship is not a chance finding. The patients who showed less subjective stress also showed stronger cortisol responses to TSD. While these relations were consistently found for each of the 3 baseline days, only incidental relations were found between activation on baseline days and the cortisol excretion response to TSD (Table 2). The finding that preceding subjective stress levels covary with the cortisol excretion response to TSD is not easy to understand and needs confirmation. One possibility might be that highly stressed patients produce high cortisol levels before TSD and have little capacity for a further increase of cortisol production during and after TSD. The finding that the pre-TSD cortisol levels were not related to the cortisol excretion response to TSD does not support this possibility. Another possibility might be that low levels of stress in the morning are a result of cortisol-suppressing processes during sleep (Weitzman et al., 1983). Sleep deprivation might then interfere with these processes, leading to an increased response of cortisol excretion to TSD. Asnis et al. (1981) found positive correlations between age and cortisol secretion in major depressed patients during the depressive phase. Jacobs et al. (1984) reported that elderly normal persons under stress excreted larger amounts of urinary cortisol than did middle-aged persons, especially those persons with depressive symptoms. In contrast, Hunt et al. (1989) did not find a relationship between cortisol levels and age in a group of 139 major depressed patients. We were also unable to establish a relationship between cortisol excretion before TSD and age. Likewise no significant relationships were found between age and the cortisol responses to TSD (cortisol excretion reaction: r = 0.125, n = 16; cortisol peak shift: I = 0.463, n = 13). In our study, the DST response was not related to the mood response to TSD. This finding is in agreement with Kuhs (1985) and Holsboer-Trachsler and Ernst (1986) but in contrast with Nasrallah and Coryell(l982) and Kasper et al. (1983). Although the nonsuppressors in the current study improved more than the suppressors (see
159 Table 3), this difference did not reach significance (Mann-Whitney U test,p < 0.42). Also, statistical procedures used by the aforementioned authors did not reveal significant effects h2 = 5.2, p < 0.12, n = 15; or Fisher exact probability test, p < 0.10). The absence of a relationship between the DST and the mood response to TSD cannot be explained on diagnostic grounds. Our patients belonged to the same diagnostic categories as those in the other studies and the proportion of responders, as well as the degree of the response to TSD, also did not differ from those found in the majority of TSD studies in the same depressive class (see Fig. 1) (Pflug and Tolle, 1971; Gerner et al., 1979; Gillin, 1983; Roy-Byrne et al., 1984). In contrast to the aforementioned authors, we administered the DST 3 days after TSD, but we do not think that this has affected our results. On the day of DST administration, the patients were as depressed as during the 3 days before TSD. The mean depression (AMS) group scores at 7 a.m. were 40.4 and, respectively, 41.5, 40.3, and 40.1. In addition, the urinary cortisol levels on the days after TSD (days 4 and 5) did not differ from the baseline levels. This finding is in line with the results of Goetze and Tolle (1987). In conclusion, indications that the mood response to TSD may be mediated by dimensions of arousal are the significant relationships between this response and the response of subjective stress and activation to TSD. TSD has a considerable number of endocrinological effects in depressives in comparison to the effects in healthy subjects, but these effects are not related to changes in depressed mood. The increased level of cortisol excretion itself could be predicted by the averaged baseline levels of subjective stress: the lower the stress levels before TSD, the larger the cortisol response to TSD. Acknowledgments. The authors are indebted to Mrs. R. Medema for expert technical assistance, and to Mrs. L.C. W. Dols and the nursing staff for their assistance in data collection.
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160
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162 Vaernes, R.; Ursin, H.; Darragh, A.; and Lambe, R. Endocrine response patterns and psychological correlates. Journal of Psychosomatic Research, 26: 123-13 1, 1982. Van den Burg, W., and Van den Hoofdakker, R.H. Total sleep deprivation on endogenous depression. Archives of General Psychiatry, 32:1121-l 125, 1975. Van den Hoofdakker, R.H.; Bouhuys, A.L.; and Beersma, D.G.M. The effects of sleep deprivation on depressive mood and subjective arousal. Biological Psychiatry, 26:733-736, 1989. Wehr, T.A., and Goodwin, F.K. Biological rhythms in psychiatry. In: Arieti, A., and Brodie, K., eds. American Handbook of Psychiatry. Vol. 7. New York: Basic Books, 1981. pp. 46-74. Weitzman, E.D.; Zimmerman, J.C.; Czeisler, CA.; and Ronda, J. Cortisol secretion is inhibited during sleep in normal men. Journal of Clinical Endocrinology and Metabolism, 56:352-358, 1983. Yamaguchi, N.; Maeda, K.; and Kuromaru, S. The effects of sleep deprivation on the circadian rhythm of plasma cortisol levels in depressive patients. Folia Psychiatrica et Neurologica, 32:479-487, 1978. Zerssen, D. von. Die Befindlichkeitsskala, Manual. Weinheim: Beltz Test Verlag, 1976. Zerssen, D. von. Clinical self-rating scales (CSRS) of the Munich Psychiatric Information System (PSYCHIS Miinchen). In: Sartorius, N., and Ban, T.A., eds. Assessment of Depression. Berlin: Springer-Verlag, 1986. pp. 270-303. Zerssen, D. von.; Doerr, P.; Emrich, H.M.; Lund, R.; and Pirke, K.M. Diurnal variation of mood and the cortisol rhythm in depression and normal states of mind. European Archives of Psychiatric and Neurological Sciences, 237:36-45, 1987.
149
Effects of Total Sleep Deprivation on Urinary Cortisol, Self-rated Arousal, and Mood in Depressed Patients Antoinette Received 1990.
L. Bouhuys,
Frans Flentge, and Rutger H. Van den Hoofdakker
June 26, 1989; revised version received November
21, 1989; accepted February
10,
Abstract. The possibility that the clinical response to total sleep deprivation (TSD) is mediated by dimensions of arousal was investigated in a group of 16 depressed patients. Self-reports of activation, stress, and mood were assessed 3 days before, during, and 2 days after TSD. Urinary cortisol excretion and responses to the dexamethasone suppression test (DST) were also measured. TSD increased cortisol excretion in depressed patients and advanced the time of the maximal excretion of cortisol. No such changes have been reported for normal subjects. Neither the increased excretion nor the time shift was related to the mood response to TSD. The DST results were also unrelated to this response. Indications that the mood response to TSD may be mediated by dimensions of arousal are the significant relationships between this response and the responses of subjective stress and activation to TSD. The TSD-induced cortisol increase was not related to the subjective arousal response to TSD. The increased cortisol excretion itself could be predicted by the averaged baseline levels of subjective stress: the lower the stress levels before TSD, the larger the cortisol response to TSD. Key Words. Sleep deprivation,
depressives,
cortisol,
arousal.
About 50% of patients with endogenous depression respond to total sleep deprivation (TSD) with clinical improvement (Gerner et al., 1979; Gillin, 1983; Elsenga and Van den Hoofdakker, 1987). The mechanisms underlying these mood changes are unknown. One hypothesis is that the response to TSD might be related to TSDinduced changes in arousal (Van den Burg and Van den Hoofdakker, 1975). A number of factors support the plausibility of this explanation. The presence or absence of sleep is related to the course of arousal (Horne, 1978). Moreover, the relationships between primary dimensions of emotions (depressed mood) and arousal (activation and stress or anxiety) are widely recognized (Thayer, 1978b; relationships Tellegen, 1985; Van den Hoofdakker et al., 1989). Consequently, between mood, sleep, and wakefulness might be explained by the interaction of sleep and wakefulness with dimensions of arousal. This explanation can be pursued in
Antoinette L. Bouhuys, Ph.D., is Senior Behavior Researcher; Frans Flentge is Senior Lecturer; and Rutger H. Van den Hoofdakker, M.D., Ph.D., is Professor of Psychiatry and Head, Department of Biological Psychiatry, Academic Hospital, University of Groningen, The Netherlands. (Reprint requests to Dr. A.L. Bouhuys, Dept. of Biological Psychiatry, Psychiatric University Clinic, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.) 01651781/90/
$03.50 @ 1990 Elsevier Scientific
Publishers
Ireland
Ltd.
150 various ways. We previously reported on the covariation of mood and self-reported arousal measures before, during, and after TSD (Van den Hoofdakker et al., 1989) and on the predictive value of arousal-related observed behavior and the subsequent response to TSD (Bouhuys et al., 1985, 1988, 1989). These studies support the suggestion that the clinical response to TSD is mediated by dimensions of arousal. This suggestion is further examined in the present report. Cortisol excretion in response to psychological stress is often considered to be an indicator of arousal (Lundberg and Forsman, 1979; Davies et al., 1981; Forsman and Lundberg, 1982; Vaemes et al., 1982; Sinyor et al., 1983). Depressive patients excrete more cortisol than controls and depressive patients in remission (Stokes et al., 1984; Souetre et al., 1988; Goetze and Tolle, 1987; Linkowski et al., 1987; Holsboer, 1988), suggesting that they are in a relatively high state of arousal or show an increased sensitivity of the adrenals to stimulation by adrenocorticotropic hormone (ACTH) (Amsterdam et al., 1983; Mendlewicz and Linkowski, 1987). In addition, the diurnal pattern of cortisol secretion in depressed patients has been reported to show an early timing in the acute phase of the illness in comparison with the remitted state (Linkowski et al., 1985; Goetze and Tblle, 1987). The phase-advance hypothesis of depression (Wehr and Goodwin, 1981) has been used to interpret these findings. There is evidence suggesting that the suppression of cortisol excretion after dexamethasone is negatively related to the clinical response to TSD (Nasrallah and Coryell, 1982; Kasper et al., 1983; Kuhs, 1985) and to the severity of depression (Klein et al., 1984; Sangal et al., 1984; Arana et al., 1985; Miller and Nelson, 1987). The aim of the current study is to report on relationships between biochemical and psychological measures of arousal and mood in relation to TSD. The first question concerns the effect of TSD on the various arousal measures, i.e., self-reported stress and activation, overall cortisol excretion, and phase position of the cortisol distribution pattern. The second question deals with the interrelationships of these measures. The third question examines the ability of arousal measures to predict the mood response to TSD. Finally, dexamethasone suppression test (DST) results are related to mood and arousal responses to TSD.
Methods Sixteen drug-free depressed patients (major depression and bipolar disorder; D&WZZZ, American Psychiatric Association, 1980) (12 females and 4 males, mean + SD age = 45.1 f 13.7 years) participated in an extensive study on circadian rhythms in depression. The interval between admission and the start of the experiment was at least 10 days. Once the experimental period began, measurements were taken over a period of 6 days (called days l-6). Only assessments of self-reported arousal and mood, and urinary cortisol measurements are presented here. At the start of the experimental period, the patients had been free of medication for at least 7 days. At that moment the severity of depression was assessed (Hamilton Rating Scale for Depression, HRSD; Hamilton, 1967) by two independent raters (mean zb SD of the 2 scores = 26.0 f 4.6). The patients underwent TSD after 3 baseline days (days l-3). Except during planned sleeping time, naps were not allowed. Self-reported arousal (i.e., stress and activation; Activation-Deactivation Checklist; AD-ACL; Thayer, 1967, 1978a) was assessed at 3-hour intervals, from 7 a.m. until 10 p.m. During TSD, additional scores were collected at 1 a.m. and 4 a.m. Mood (Adjective Mood Scale; AMS; Von Zerssen, 1976, 1986) was assessed thrice daily at 7 a.m., 1 p.m., and 10 p.m. Urine samples were collected at 3-hour intervals from 7 a.m. until 10 p.m. Additional
151 samples were collected during the night preceding the experimental period of 6 days, from 10 p.m. until 4 a.m. and from 4 a.m. until 7 a.m. During TSD two 3-hour samples at 1 a.m. and 4 a.m. were obtained. In order not to interfere with biochemical and behavioral data collection, a DST was performed on day 6. Blood samples were taken before the administration of 1 mg dexamethasone at 11 p.m. To measure the cortisol response, blood samples were collected at 4 p.m. and 11 p.m. on the next day. A patient was defined as a nonsuppressor if one of the cortisol levels at these time points exceeded 140 nmol/l. Patients were under dietary control to ascertain adequate daily food intake. Cortisol was measured by radioimmunoassay with locally prepared rabbit antiserum. Urinary cortisol was first purified on Sep-pack Cl8 columns and isolated on Sephadex LH-20 columns. Plasma cortisol was measured without purification. For technical reasons, some samples were pooled (see Results). Mood and activation scores underwent a trend correction based on the scores of the 3 baseline days, by means of a regression analysis. The effect of TSD on depression, activation, or stress was defined as the difference of the averaged trend corrected scores on the day before and the day after TSD (7 a.m. until 10 p.m.; after minus before). Mood responders to TSD showed a decrease of more than 5 points on the AMS (i- mood response; n = 7). The remaining group showed a 5-point change or less (- mood response; n = 9) (Elsenga and Van den Hoofdakker, 1987). Two effects of TSD on cortisol were distinguished in the excretion level and the excretion pattern: (1) The effect on the level of excretion was defined as the difference of the averaged hourly excretion during the 24-hour period (10 p.m.-IO p.m.) 2 days before TSD and the corresponding 24-hour period during which TSD took place (scores during and after TSD minus score before TSD). (2) The effect on the excretion pattern was defined as the shift of the acrophase. It was measured by comparing the location of the highest value for cortisol excretion among the 3-hour measurements in the baseline 24-hour period with the location of the highest value in the period during which TSD was applied. A shift was defined as the difference of the corresponding clock times at which these maxima occurred (after minus before). The patients were informed about the nontherapeutic character of the experiment. Nonparametric statistical tests were used to evaluate the results. The Wilcoxon matchedpairs test was used for within-group comparisons. Mann-Whitney U tests were used for
between-group comparisons. Spearman rank correlations were also calculated (Siegel, 1956). The confidence level was set at 5% (two-tailed).
Results Effects of TSD on Depressive Mood. Fig. 1 demonstrates the effects of TSD on depressive mood, for responders (n = 7) and nonresponders (n = 9). The results confirm numerous earlier findings that TSD can induce shortlasting moodswings in about 50% of depressive populations (see Gillin, 1983). The suggestion from Fig. 1 that patients who responded well to TSD were those with diurnal variation of mood will be dealt with elsewhere (Reinink et al., 1990). Effects of TSD on Measures of Arousal. The averaged scores of stress and of activation on the day before TSD (17.3 f 3.8 [SD] and 19.3 + 3.8 [SD], respectively) did not differ from the scores on the day following TSD (25.7 + 4.3 [SD] and 18.7 + 4.8 [SD], respectively) (Wilcoxon, n = 16). Fig. 2 depicts the time course of urinary cortisol excretion in the baseline (“before”) and the TSD conditions (“after”). The average secretion of cortisol over the total interval (10 p.m.-10 p.m.) was significantly increased (Wilcoxon: p < 0.001, n = 16). This effect is mainly due to an increase during the 10 p.m.-4 a.m., 4 a.m.7 a.m., and 4 p.m.-IO p.m. intervals (Wilcoxon: p < 0.008, n = 1 I; p < 0.001, n = 15; p < 0.005, n = 16, respectively).
152 Fig. 1. Severity of depressed mood (AK) in patients with different mood responses to total sleep deprivation (TSD) l
+
o -
mood
mood
TSD toTSD
resp. resp.
to
depression 60
36
28
20 7
13
22
7
13
22
7
13
time Responders: n = 7: nonresponders:
22
7
13
22
7
13
22
7
(hours)
n= 9
Fig. 2. Course of the mean (k SEM) excretion of cortisol over 24 hours before and after total sleep deprivation (TSD) in 16 depressed patients PC.001 * L
2 r 2
•I before TSD
24-
Cl after 20-
5 16 -
1Opm
4am
loam Time
Two-tailed Wilcoxon matched pairs test was applied.
4pm
10pm
TSD
153
Average 24-hour cortisol production (7 a.m.-7 a.m.) on baseline days 1 and 2 was compared with the production over the same interval on the day of TSD and the 2 subsequent days. Only on the day during TSD was the cortisol production significantly increased (Wilcoxon: p < 0.002, n = 16). In each patient, the position of the maximum (highest value) of the cortisol excretion curve during the baseline condition was compared with that during the TSD condition. The maximum shifted from 8:58 a.m. + 2:04 (SD) before TSD to 653 a.m. f 1:59 (SD) after TSD (Wilcoxon: p < 0.02, II = 13). Relationships Between Mood and Arousal Responses to TSD. Table 1 shows that only the stress response and the activation response to TSD were significantly related to the mood response to TSD. No relationships were found between the mood response to TSD and the cortisol excretion response to TSD (also see Fig. 3). The cortisol excretion over the interval from 10 p.m. to 10 p.m. before TSD was compared to the same interval starting at 10 p.m. on the night of TSD in patients who improved after TSD and patients who did not. Also a more detailed analysis of the relation between cortisol data (i.e., changes in the 3-hour cortisol excretions after TSD) and the mood response to TSD did not reveal significant results.
Table 1. Correlations between mood and arousal responses to total sleep deprivation (TSD) (n = 16) 1 1. Mood response to TSD
-
2. Activation response
2
3
4
0.5662
-0.76E3
0.318
-0.024
0.336
0.434
-0.057
-
0.068
0.090
-
-0.358 -
-
3. Stress response 4. Cortisol excretion response 5. Peak shift of cortisol maxima
5'
7. n = 13. 2. p < 0.05. 3. p < 0.01.
Fig. 3. Urinary cortisol levels in depressed patients with different mood responses to total sleep deprivation (TSD) EZI+ mood resp. to TSD (n ~7) 0
_ mood resp.
to TSD
(n-9)
20 2
18
g
14
$
12 16 i
T
before
TSD
after
TSD
154
Moreover, Table 1 shows that the shift in the cortisol excretion maximum was not correlated with the change in mood after TSD. Fig. 4 illustrates changes in peak position and their relation to the mood response to TSD. The position of the maximum was not significantly correlated with the severity of the depression (averaged day scores): before TSD this correlation was r = 0.289 (n = 13) and after TSD r = 0.466 (n = 13).
Fig. 4. Mean and standard deviations of the cortisol peak position in patients with different mood responses to total sleep deprivation (TSD) EZ3+ mood resp. to TSD O-
llr
Prediction
between response
of Mood
mood resp. to TSD
clock time
T
-I-
before
TSD
Response
to TSD.
h=5) (n=8)
after TSD No significant
any of the stress, activation, or cortisol to TSD (Spearman correlations).
relationships were found scores before TSD and the mood
Prediction of Cortisol Responses to TSD. The finding that patients reacted to TSD with an increase and a peak shift of their cortisol production prompted us to investigate relationships between these reactions and the subjective behavioral measures before TSD (see Table 2). Mood. The negative correlation between the average severity of depression only on day 2 before TSD and the peak advance of cortisol suggests that relatively less severely depressed patients are more likely to show a peak advance in cortisol excretion. No significant relations were detected between the severity of depression before TSD and the magnitude of the cortisol excretion response. Stress and activation. The cortisol excretion response was negatively related to baseline levels of stress on each of the 3 days preceding TSD. Fig. 5 visualizes these correlations. Patients were divided into two groups: patients (n = 8) with the highest cortisol response to TSD (-I- cortisol) and patients (n = 8) with the lowest response (- cortisol). Significant rank correlations between the cortisol excretion response and stress levels are indicated. In addition, Table 2 shows that the average level of activation on the first experimental day was positively related to the cortisol excretion response to TSD. Cortisol. Baseline levels of cortisol excretion were not significantly related to either the excretion response or the peak shift response to TSD (Spearman correlations).
155
Table 2. Correlations between self-rated arousal and mood before total sleep deprivation (TSD) (on days 1, 2, and 3) and cortisol responses to TSD(n=16) Stress Assessment time of self-ratings Day 1
7 a.m. 10 a.m.
Mean
Mean
-0.450
-0.347
0.6263
0.387
-0.7034
-0.051
0.375
0.250
-0.6443
-0.068
0.479
0.241
-0.059
0.5433
0.365
Mood Cortisol excretion
Peak shift
-0.394
-0.419
-0.430
-0.172
7 p.m.
-0.5473
0.008
0.324
0.517
10 p.m.
-0.414
0.163
0.394
-0.108
-0.442
0.051
-0.115
0.5703
0.485
-0.477
-0.308
-0.134
0.023
-0.400
-0.5743
-0.741 4 7 a.m.
-0.5473
-0.085
0.298
0.235
10 a.m.
-0.7434
-0.366
0.332
0.238
1 p.m.
-0.6754
-0.484
0.433
0.535
4 p.m.
-0.55a3
-0.379
0.263
0.516 0.295
7 p.m.
-0.5243
-0.291
0.248
10 p.m.
-0.440
-0.291
0.437
0.61 63
-0.467
-0.5943
-0.6473
-0.395
0.419
0.475
-0.396
-0.5823
-0.7324
-0.139
0.261
-0.125
-0.389
-0.397
-0.61 53
-0.068
0.380
0.438 -0.181
-0.5793
7 a.m.
day 3
Peak shift
-0.6553
10 a.m.
Mean
Cortisol excretion
1 p.m.
day 2
Day 3
Peak shift’
4 p.m.
day 1
Day 2
Cortisol excretion’
Activation
1 p.m.
-0.502
-0.234
0.414
0.453
4 p.m.
-0.465
-0.080
0.151
0.220
7 p.m.
-0.092
0.015
0.292
0.451
10 p.m.
-0.339
-0.285
0.421
0.453
-0.234
-0.385
-0.551 3
-0.130
0.383
0.404
-0.315
-0.514
Note. Results are expressed as Spearman correlation coefficients 1. Urinary cortisol excretion (after TSD minus before). 2. Time position of cortisol excretion maximum (after TSD minus before) (n = 13). 3. p < 0.05. 4. p < 0.01.
DST. Patients were classified as nonsuppressors (n = 8) and suppressors (n = 7). These groups were compared with respect to the various mood, arousal, and cortisol levels. No differences were found between the two groups for: (1) the preceding mood, arousal (stress and activation), or cortisol levels (Mann-Whitney U test); (2) the mood and the arousal responses to TSD as well as the cortisol excretion and peak shift response (Table 3); and (3) the severity of depression (according to the 7 a.m. AMS score) on the day of dexamethasone administration.
Discussion Evidence that the mood response to TSD is mediated by dimensions of arousal can be seen in the direct relationships between mood response and responses of
156 Fig. Stress levels to total sleep + cortisolexcretion
patients with (TSD) resp. to TSD
l
o -
cortisoi
excretion
resp. toTSD
cortisol
excretion
1”:;; n
stress
35
:... 30
I-
? :
‘%
9
h
‘\d’
d'
25
:
'b
20
15
.1 7
13
22
7
13
22
7
13
time Asterisks indicate significant excretion response to TSD.
Spearman correlations
2214
7
13
22
713
22
7
(hours)
between stress levels at different time points and the cortisol
* p < 0.05. ** p < 0.01.
subjective stress and activation to TSD. Little additional evidence was found. Neither subjective arousal nor cortisol excretion before TSD predicted the mood response to TSD. Furthermore, this mood response was not related to either the level or the pattern of cortisol response. Cortisol has been shown to be reactive to psychological stress (Lundberg and Forsman, 1979; Davies et al., 1981; Forsman and Lundberg, 1982; Vaernes et al., 1982; Sinyor et al., 1983) and may therefore be considered as an indicator of arousal. TSD may have an arousal-increasing effect in depressives as demonstrated by an increased 24-hour urinary secretion of cortisol during and after TSD. However, this effect is not paralleled by changes in the two self-rated measures of arousal, i.e., stress and activation. This might suggest that subjective stress, activation, and cortisol excretion responses could be interpreted as different aspects of arousal. The TSD-induced increase in cortisol excretion levels is mainly due to the increase during the periods 10 p.m.-4 a.m., 4 a.m.-7 a.m., and 4 p.m.-IO p.m. (Fig. 2). These results are in agreement with those of other TSD experiments in depressed patients. Yamaguchi et al. (1978) found an increase of plasma cortisol in depressed patients at 8 a.m. and 4 p.m. and, in addition, comparison of depressed patients with normal controls revealed an increase at 4 a.m. Comparable observations were reported by Goetze and Tiille (1987), who found an increase in amplitude of the urinary cortisol production after TSD, though the total 24-hour production of cortisol after TSD was not significantly increased. Thus, depressed patients seem to react differently to TSD in comparison with controls. In normal subjects, TSD does not increase cortisol excretion even after 48 or 72
157 hours of sleep deprivation (Akerstedt et al., 1980; Kant et al., 1984). Yamaguchi et al. (1978) and Gerner et al. (1979) found some evidence that the increased levels of cortisol as a result of TSD were confined to clinical responders to TSD. In contrast, we measured increased cortisol levels in both responders and nonresponders to TSD. This disagreement might be due to differences in response definition of clinical change or in pharmacological conditions. Antidepressants are of crucial importance for the mood responses to TSD (Loosen et al., 1976; Elsenga and Van den Hoofdakker, 1983) and in the study of Yamaguchi et al. (1978), patients received tricyclic antidepressants. Probably the TSD-induced increase of cortisol in the depressed patients of the present study reflects an enhanced sensitivity to environmental factors (e.g., social contacts, attention). One would have expected this enhanced sensitivity to have been reflected in the self-reports on experienced arousal, but this was not the case. No direct relationships were found between the cortisol excretion response to TSD and the subjective arousal response.
Table 3. Mean and standard deviation of self-rated arousal, mood, and cortisol responses to TSD (after minus before) in depressed patients classified as DST nonsuppressors and suppressors Nonsuppressors Mean 1. Mood response response
2. Activation 3. Stress 4. Cortisol
response excretion
response’
5. Peak shift2
Suppressors
SD
Mean
-7.4
14.1 (8)
-1.6
7.5 (7)
0.0
4.1 (8)
0.5
4.3 (7)
-4.1
3.5 (8)
-3.0
1.9 (7)
0.2
6.7 (8)
-0.5
1.7 (7)
2.5
2.3 (61
1.5
Note. The n’s are shown in parentheses. TSD = total sleep deprivation. DST = dexamethasone
SD
2.5 (61 suppression test
1. Difference score in nmolihour. 2. Difference score in hours.
As to the excretion pattern, TSD was found to shift the maximum excretion from 858 a.m. to 6:53 a.m. (Fig. 2). Because our data were collected at 3-hour intervals and large differences between individual shifts were found (mean shift 2.1 hours + 2.3 hours [SD]), results on maxima should be considered with caution. Nevertheless, the baseline location of the maximum is in line with other observations (Yamaguchi et al., 1978; Linkowski et al., 1985; von Zerssen et al., 1987). The shift of the acrophase under TSD conditions was not found by Yamaguchi et al. (1978). This discrepancy may be explained by different sampling techniques used. While in the present study the mean 3-hour urinary cortisol excretion was measured, in the study of Yamaguchi et al. (1978), blood samples were taken at 4-hour intervals, giving no integrated measure of the cortisol production. By this procedure, shifts during the intervals between the samples can remain unobserved (see Sachar et al., 1973). Much emphasis is currently being placed on the possibility that changes in circadian organization of biochemical and behavioral processess may be of causal importance in depression (Halaris, 1987). One hypothesis states that in depressives circadian processes show a phase-advance in comparison to the phase in controls
158 (Doig et al., 1966; Wehr and Goodwin, 1981). Our results do not support such a phase-advance for the following reasons: (1) Severity of depression was not found to be related to the baseline location of excretion maxima. (2) The shift in peak position was not related to the mood response to TSD. (3) In the mood responders to TSD, one would expect to find a delay of the excretion peak. The responders and the nonresponders, however, showed an advance. The lack of support is not without precedent (von Zerssen et al., 1987; Souetre et al., 1988). The occurrence of high baseline cortisol levels and an advanced position of the nadir in depressives in comparison with controls and with themselves when in remission (Carroll et al., 1976; Berger et al., 1982; Linkowski et al., 1985; Holsboer et al., 1988) may be considered to be a reaction to the clinical condition and may be indicative of an as yet unspecified instability of the hypothalamic-pituitary-adrenocortical (HPA) system. Our data suggest an increase in this instability, and therefore the clinical improvement induced by TSD (accompanied by increased levels of cortisol) may be of another quality than that obtained with other therapeutic treatments (accompanied by normalized levels of cortisol). The transient character of the clinical response to TSD may also support this suggestion. The cortisol response to TSD was found to be related to stress levels on each of the days receding TSD, strongly suggesting that this relationship is not a chance finding. The patients who showed less subjective stress also showed stronger cortisol responses to TSD. While these relations were consistently found for each of the 3 baseline days, only incidental relations were found between activation on baseline days and the cortisol excretion response to TSD (Table 2). The finding that preceding subjective stress levels covary with the cortisol excretion response to TSD is not easy to understand and needs confirmation. One possibility might be that highly stressed patients produce high cortisol levels before TSD and have little capacity for a further increase of cortisol production during and after TSD. The finding that the pre-TSD cortisol levels were not related to the cortisol excretion response to TSD does not support this possibility. Another possibility might be that low levels of stress in the morning are a result of cortisol-suppressing processes during sleep (Weitzman et al., 1983). Sleep deprivation might then interfere with these processes, leading to an increased response of cortisol excretion to TSD. Asnis et al. (1981) found positive correlations between age and cortisol secretion in major depressed patients during the depressive phase. Jacobs et al. (1984) reported that elderly normal persons under stress excreted larger amounts of urinary cortisol than did middle-aged persons, especially those persons with depressive symptoms. In contrast, Hunt et al. (1989) did not find a relationship between cortisol levels and age in a group of 139 major depressed patients. We were also unable to establish a relationship between cortisol excretion before TSD and age. Likewise no significant relationships were found between age and the cortisol responses to TSD (cortisol excretion reaction: r = 0.125, n = 16; cortisol peak shift: I = 0.463, n = 13). In our study, the DST response was not related to the mood response to TSD. This finding is in agreement with Kuhs (1985) and Holsboer-Trachsler and Ernst (1986) but in contrast with Nasrallah and Coryell(l982) and Kasper et al. (1983). Although the nonsuppressors in the current study improved more than the suppressors (see
159 Table 3), this difference did not reach significance (Mann-Whitney U test,p < 0.42). Also, statistical procedures used by the aforementioned authors did not reveal significant effects h2 = 5.2, p < 0.12, n = 15; or Fisher exact probability test, p < 0.10). The absence of a relationship between the DST and the mood response to TSD cannot be explained on diagnostic grounds. Our patients belonged to the same diagnostic categories as those in the other studies and the proportion of responders, as well as the degree of the response to TSD, also did not differ from those found in the majority of TSD studies in the same depressive class (see Fig. 1) (Pflug and Tolle, 1971; Gerner et al., 1979; Gillin, 1983; Roy-Byrne et al., 1984). In contrast to the aforementioned authors, we administered the DST 3 days after TSD, but we do not think that this has affected our results. On the day of DST administration, the patients were as depressed as during the 3 days before TSD. The mean depression (AMS) group scores at 7 a.m. were 40.4 and, respectively, 41.5, 40.3, and 40.1. In addition, the urinary cortisol levels on the days after TSD (days 4 and 5) did not differ from the baseline levels. This finding is in line with the results of Goetze and Tolle (1987). In conclusion, indications that the mood response to TSD may be mediated by dimensions of arousal are the significant relationships between this response and the response of subjective stress and activation to TSD. TSD has a considerable number of endocrinological effects in depressives in comparison to the effects in healthy subjects, but these effects are not related to changes in depressed mood. The increased level of cortisol excretion itself could be predicted by the averaged baseline levels of subjective stress: the lower the stress levels before TSD, the larger the cortisol response to TSD. Acknowledgments. The authors are indebted to Mrs. R. Medema for expert technical assistance, and to Mrs. L.C. W. Dols and the nursing staff for their assistance in data collection.
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