93
Journal of Aff..ctioe Disorders, 20 (1990) 93-99 Elsevier
JAD 00744
The influence of physical activity and posture on the antidepressant effect of sleep deprivation in depressed patients Andreas Psychiatrische
Klinik und Poliklinik
Baumgartner
of the Klinikum
and Nikolaus
Rudolf-Virchow
(Charlottenburg),
Sucher Freie Uniuersitiit Berlin, Berlin, Germany
(Received 7 February 1990) (Revision received 5 May 1990) (Accepted 21 May 1990)
Summary A possible role of the factors ‘physical activity’ and ‘posture’ in the antidepressant effect of a total night’s sleep deprivation (TSD) was investigated in 30 patients with major depressive disorder. Fifteen patients underwent TSD under ‘conventional’ conditions, while the other 15 were kept in bed during TSD but were not permitted to sleep. There was no significant difference between the antidepressant effects of TSD in the two groups. This result suggests that it is wakefulness itself rather than changes in physical activity or posture that is involved in the mechanism of the antidepressant action of TSD.
Key words: Sleep deprivation;
Posture; Physical activity; Depression
Introduction The antidepressant effect of a total night’s sleep deprivation (TSD) was first described by Fir&e and Schulte (1970) and later systematically investigated by Pflug and Tijlle (1971). Since then numerous studies have attempted to elucidate the biological mechanisms responsible for the antidepressant action of TSD. These include biochemical (e.g., Matussek et al., 1974; Post et al., 1976; Gerner et al., 1979) and electrophysiological (e.g.,
Address for correspondence: Dr. A. Baumgartner, Psychiatrische Klinik und Poliklinik, Eschenallee 3, D-1000 Berlin 19, Germany. 0165-0327/90/$03.50
Buchsbaum et al., 1981) studies, investigations of chronobiological hypotheses (e.g., Wehr et al., 1979; Wehr and Wirz-Justice, 1981), a possible role of light (Wehr et al., 1985) and the interaction between sleep parameters and response to sleep deprivation (e.g., Reynolds et al., 1987) and many others. Nonetheless, as yet no convincing and consistent explanation of the mechanisms that could be responsible for the effect of TSD has been advanced (for reviews see, for example, Gillin et al., 1983; Kuhs and Tijlle, 1986). The first systematic study of the antidepressant effect of TSD by Pflug and Tiille (1971) was inspired by some clinical observations by Schulte. Schulte described a severely melancholic patient whose condition improved considerably after having ridden a bicycle for a whole night and concluded that the
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
94
effect of muscular effort may also have contributed to the antidepressant effect. Another example refers to a depressed physician who was only able to carry out his professional duties after having stayed awake for one night ‘not just reading a book but doing real work’ (Finke and Schulte, 1970). These examples raise the question whether wakefulness in itself is the sole factor responsible for the antidepressant effect of TSD, or whether other factors such as ‘physical activity’ or ‘upright posture’ during TSD might also play some role. The latter idea is also supported by the fact that physical activity affects some physiological variables which may have some importance for theories of mechanisms of antidepressant therapies. Physical activity enhances serum norepinephrine levels (e.g., Kozlowski et al., 1973; Dimsdale and Moss, 1980; Davidson et al., 1984). This is also true of upright posture in comparison with the prone position (e.g., Cryer et al., 1974; Lake et al., 1976; Saar and Gordon, 1979). As regards deductions of central norepinephrine (NE) activity from serum NE levels, it is now well known that although NE does not easily cross the blood-brain barrier there are highly significant correlations between concentrations of NE in the CSF and plasma in healthy subjects, and also in patients in, for example, Alzheimer’s disease (e.g., Ziegler et al., 1977; Raskind et al., 1984). On the other hand, we have recently reported that the secretory profiles of many hormones change during sleep deprivation in depressed patients (Baumgartner et al., 1990a, b). It was shown that this ‘pattern’ of changes in secretory profiles is probably due to enhanced central NE activity. On the basis of these findings we hypothesized that enhanced activity of the locus coeruleus during sleep deprivation influences central NE receptor function, thereby leading to the antidepressant action of TSD. We were therefore interested to investigate whether the factors ‘physical activity’ and ‘upright posture’, which both lead to enhanced peripheral and possibly also central NE activity, are involved in the mechanism of the antidepressant action of TSD. We thus compared the effect of a TSD spent in bed with that of a conventionally conducted TSD and hypothesized that the latter would have a significantly higher antidepressant efficacy.
Methods Thirty inpatients fulfilling Research Diagnostic Criteria (RDC, Spitzer et al., 1978) for major depressive disorder (probable or definite) were included in the study. The patients were divided into two groups of 15, one of which underwent TSD in a conventional form (TSD-conv.) while the other was kept in bed during TSD (TSD-bed). All patients had endogenous depression (RDC). The TSD-conv. group comprised 10 unipolar and five bipolar patients, whereas the TSD-bed group was made up of 12 unipolar and three bipolar patients. In the TSD-conv. group there were 11 women and four men, and the mean age of the group as a whole was 45.4 + 15.5 years (range 19-70). The TSD-bed group comprised 13 women and two men and the mean age was 57.7 + 14.7 years (range 25-77 years). The TSD-conv. group was part of a larger sample (n = 50) in whom different hormones were measured at 8 a.m. both before and after TSD (Baumgartner and Meinhold, 1986; Baumgartner et al., 1990a). In order to compare the clinical effect of TSD-conv. with that of TSD-bed the first 15 patients of the whole TSD-conv. group (n = 50) were selected for comparison with the TSD-bed group. Criteria for exclusion were a history of alcoholism or drug abuse, serious somatic illness, a history of or acute thyroid disorder and acute suicidal tendencies. Eight of the TSD-conv. patients and seven of the TSD-bed patients had not received psychotropic drugs for at least 3 months prior to hospital admission. These patients underwent their first TSD within the first week, but not sooner than 3 days after admission, at which time they were not receiving any psychotropic medication. The remaining seven TSD-conv. and eight TSD-bed patients underwent TSD at various times during their hospital stay, sometimes even 1 or 2 months after admission when antidepressant medication had proved unsuccessful. All 15 of these patients antidepressants (clomipramine, were receiving amitriptyline or maprotiline). The doses ranged from 100 to 150 mg/day. No other psychotropic medication, such as minor or major tranquilizers, was permitted. All of the patients who were receiv-
95
ing drugs at the time of the TSD had started taking them at least 14 days beforehand. As we recently found (Baumgartner et al., 1990a) that concomitant antidepressant medication has no influence on the outcome of a TSD and as, furthermore, the patients who were taking drugs and those who were not were almost equally distributed in both groups, we did not believe that the uninterrupted medication of some of the patients at the time of TSD would interfere with the investigation of the specific issues we wished to examine in this study. On the mornings before and after TSD all patients were rated on the 21-item Hamilton Rating Scale for Depression (HRSD, Hamilton, 1960). The mean score for the TSDconv. group was 24.8 + 5.3 (range 15-37) and that for the TSD-bed group 25.2 t_ 4.8 (range 17-37) indicating that our sample consisted mostly of moderately and severely ill patients. To evaluate the response to TSD we used a modified, six-item version of the HRSD. These six items had been taken from the original 21-item HRSD scale as follows: 1 (depressed mood), 2 (feelings of guilt), 7 (work and activities), 8 (retardation), 10 (anxiety, psychic) and 13 (somatic symptoms, general). In addition, all the patients completed the visual Analogue Mood Scale (VAS, Aitken, 1969) at 8 a.m. (VASM, morning score) and 8 p.m. (VASE, evening score) on both the day before and the day after TSD. (The VAS is a self-rating scale consisting of five items, in which the patient marks his condition on a line 10 cm in length with the best condition at the left hand end and the poorest condition at the right hand end.) For our calculations we used the mean scores of the five VAS items. In order to evaluate the degree of the patient’s responses the following calculations were performed: the mean ‘day’ score (VASD) was calculated as follows: (VASM + VASE)/2. These calculations were done separately for days 1 (VASDl) and 2 (VASDZ). The difference (VASD2-VASDl) was designated AVASD and represents the response to TSD. The method of evaluating the response to TSD has been suggested previously, for example, by Rudolf and Tolle (1978). The morning (AVASM) and evening (AVASE) responses were calculated separately. We also divided the patients into one group
with an improvement of over 30% on the HRSD and VASMD (responders) and another comprising those with a less than 30% improvement on the HRSD and VASMD (non-responders). We used this criterion for distinguishing between responders and non-responders as a basis for comparing our results with those of several other study groups (Matussek et al., 1974; Kuhs et al., 1985; Wiegand et al., 1987; Kasper et al., 1988) who employed the same criterion. During the investigation all the patients stayed awake for at least 36 h between 8 a.m. on day 1 and 8 p.m. on day 2. No naps were permitted during this time. Meals were served at 8 a.m., noon and 6 p.m. During TSD an additional meal was served at around midnight. Neither smoking nor lighting conditions were controlled. The light in all our sitting rooms is somewhat subdued at night, that is, slightly dimmer than in the evening, but sufficient to permit reading. During the night of TSD the TSD-conv. patients were not allowed to stay in their bedrooms or lie down elsewhere. They spent their time in the sitting room of their ward. A nurse was constantly present in order to ensure that they did not fall asleep and also to help them stay awake by playing games, talking to them or permitting them to watch television. Occasionally walks in the clinic garden were allowed if the weather and the patient’s condition permitted. The TSD-bed patients went to bed at 10 p.m. and were kept in bed until 8 a.m. They were only allowed to get up to go to the toilet. The mean frequency of visits to the bathroom was 2.4 t- 1.7 (range O-7) times. None of these visits lasted longer than 5 min. An additional nurse was present throughout the night for the sole purpose of ensuring that the patients stayed awake and remained in bed. The TSD was not conducted in the patients’ own rooms but in a special room in which only the patients and the nurse were present, at least after midnight. Until midnight the patients were permitted to watch television in a semi-reclining position (half sitting up). The nurse was instructed to try to keep them awake by talking alone and only to play games with them while they remained sitting in bed if this failed. At 8 a.m. the TSD-bed patients were allowed to get up and follow the same regime as the TSD-conv. patients until the evening (see above).
96
A single blood sample was taken from all patients at 8 a.m. before TSD and after TSD for measurement of different hormones. The endocrine results for the TSD-conv. patients have already been reported (Baumgartner and Meinhold, 1986; Baumgartner et al., 1990a) and those of the TSD-bed patients will be presented in a separate report (Baumgartner et al., submitted). The TSD-conv. patients were informed that TSD is an effective but possibly short-acting antidepressant treatment which has been used in psychiatry for many years. The TSD-bed patients were given the additional information that they were taking part in a study the purpose of which was to establish whether this form of therapy is also effective if patients spend the night lying down. A statistical analysis was performed using l-tests (two-tailed) for dependent and independent variables. For small sample sizes (< 10) we used the Mann-Whitney U-test. To correlate the response to TSD with other variables such as age, we used Pearson’s coefficient of correlation. The x2 test was used for dichotomous variables (the FisherYates correlation was not necessary for this sample) (Camilli and Hopkins, 1979). Means and standard deviations (SD) were used throughout and P values of less than 0.05 were regarded as significant. Results The mean HRSD score (six-item version) before TSD was 12.7 + 3.1 for the TSD-bed patients and 11.9 _t 3.9 for the TSD-conv. group. This difference was not significant (t = 0.43). The VASD
VAS D Iday’s score)
Sleep depr,vat,on before SD
I” bed a‘ter SD
10 1
Fig. 1. Comparison of the antidepressant effects of TSD-bed and TSD-cow.
scores before sleep deprivation were 6.52 & 1.81 for the TSD-bed group and 6.55 k 2.46 for the TSD-conv. patients. This difference was also not indicating that the two significant (t = 0.12) groups were comparable with respect to self-rated initial severity of illness (see also Fig. 1). The same applies for the comparison of the morning values alone (VASMl = 6.90 + 1.97 for the TSD-bed patients and 6.84 k 2.19 for the TSD-conv. group) and for the evening values alone (VASE1 = 6.15 + 2.07 for the TSD-bed group and 6.26 f 2.90 for the TSD-conv. group (Table 1).
TABLE 1 RATING SCORES OF 30 PATIENTS WITH MAJOR DEPRESSIVE DISORDER ON THE VAS AND THE SIX-ITEM HRSD BEFORE AND AFTER SLEEP DEPRIVATION IN BED (n = 15) AND CONVENTIONAL SLEEP DEPRIVATION (n = 15) Before TSD
After TSD
t
P
TSD-bed
VASM VASE VASD HRSD
6.90*1.97 6.15 f 2.07 6.52 + 1.81 12.7 +3.1
5.71+ 2.14 5.74 f 2.60 5.72k2.38 8.5 +3.8
1.94 0.64 1.62 2.24
( > 0.05) NS NS NS < 0.05
TSD-cow.
VASM VASE VASD HRSD
6.84xk2.19 6.26 + 2.90 6.55 f 2.46 11.9 *3.9
6.04zk2.58 5.58 + 2.89 5.80 + 2.57 8.1 *4.0
1.21 0.78 1.08 2.08
NS NS NS < 0.05
97 TABLE
2
COMPARISON OF THE TION
OF
THE
CONVENTIONAL
AND
ANTIDEPRESSANT FORM
SLEEP DEPRIVATION
EFFECTS
OF SLEEP
DEPRIVA-
IN BED
P
TSD-bed
TSD-conv.
t -0.35
NS
AVASM
-1.18i2.33
-0.8Oi2.55
AVASE
- 0.41 k 2.46
- 0.68 f 3.35
&‘ASD
- 0.80 + 2.24
- 0.76 * 2.72
-0.12
NS
dHRSD
-4.2
-3.8
-0.11
NS
*3.4
+3.9
0.28
NS
The changes in mood after TSD are shown for both groups in Table 2 and Fig. 1. It can be seen that TSD induced almost equal decreases in the HSRD and VAS scores for the mornings alone (AVASM), the evenings alone (AVASE) and also for the whole day (AVASD). Thus, there was no significant difference between the responses of the two ‘groups to TSD (Table 2). When the rates of responders and non-responders in each group were calculated, applying the criterion of a 2 30% improvement in the HRSD score, seven of the TSDbed patients were classified as responders and two showed a worsening of mood after TSD. In the TSD-conv. group there were five responders and two patients whose mood deteriorated. The same calculation done for the VASD scale revealed that five of the TSD-bed patients were classified as responders and the conditions of two had worsened. In the TSD-conv. group we obtained three responders and three patients with a deteriorated condition (Fig. 1). These results show a somewhat higher response rate in the TSD-bed group, however, the differences calculated by x2 analysis were not significant for either scale (x2 = 0.04, P = 0.84 for the VAS and x2 = 0.47, P = 0.40 for the HRSD score). Although an influence of antidepressant medication on the response to TSD does not seem likely (see Methods) we compared the response rates of the seven patients in the TSD-bed group who did not receive antidepressants with those of the eight patients who were taking antidepressant drugs. There were no significance differences between the mean AVASD or AHRSD scores of the two groups (Mann-Whitney U-test, P = 0.65 and P = 56 respectively). As our TSD-bed group was somewhat older than the TSD-conv. group we correlated the age of
the TSD-bed group with the outcome of TSD. However, Pearson’s coefficient of correlation between age and AVASD did not show even a trend towards significance (r = 0.15, df= 13, P = 0.58). Although we did not conduct a systematic investigation of the time courses of changes in mood during the TSD spent in bed and the patient’s subjective appraisals of this form of therapy, the nurses kept a record in which they noted the patients’ behavior, verbalizations and their own impressions of how the patients felt hourly. The patients’ assessments of the practicability of a TSD spent in bed varied widely. Several of them complained that they found it very hard to stay awake while others did not have any such difficulties. Of those who had undergone conventional TSD at any time previously, some preferred the conventional form after having experienced TSD in bed but three of them were quite enthusiastic about TSD in bed and suggested that this form of sleep deprivation should be introduced as a routine therapy. Analysis of the nurses’ records also revealed that for most patients it was hard to remain awake before 1, 2 or 3 a.m., but that it became much easier after they had succeeded in staying awake during this period in which drowsiness was strongest. Discussion On the basis of clinical observations and theoretical considerations (see Introduction) we hypothesize that the factors ‘physical activity’ and ‘upright posture’ might be somehow involved in the mechanisms of the antidepressant action of TSD. Our hypothesis was derived from the knowledge that certain physiological changes are induced by physical activity and upright posture and specifically from the findings that plasma NE levels increase in the upright position and during physical activity, and that there are probably some interactions between plasma and central NE activity (for references see Introduction). However, it is evident from the results of the present study that neither of the above factors is involved in the antidepressant effect of TSD. Consequently, factors related to wakefulness itself and associated biochemical and physiological changes are most likely to play the key role in the antidepressant
98
action of TSD. The nature of these changes related to wakefulness that induce the clinical effects of TSD is not yet clear. However, we feel that hypotheses of a possible involvement of the noradrenergic system are supported by at least two facts. First, the increases in thyroid-stimulating hormone, cortisol and growth hormone after TSD that have been reported in many studies point towards an enhancement of noradrenergic activity during TSD (for reviews see Baumgartner et al., 1990b). Second, it has now been shown in three species (the rat, cat and monkey) that the NE activity of the locus coeruleus (LC) is higher during waking than during sleep (Chu and Bloom, 1973; Aston-Jones and Bloom, 1981; for a review see Jacobs, 1986). It could thus be postulated that stimulation of postsynaptic adrenergic receptors is higher during waking than during sleep. Furthermore, the outstanding work of Foote et al. (1980) and Aston-Jones and Bloom (1981) provided evidence that the activity of the locus coeruleus is dependent both on sensory stimulation and on level of arousal. For example, a pip tone caused a much higher rise in LC-NE neuronal discharge activity when the stimulus woke the animal from slow-wave sleep than when it was presented during uninterrupted waking. On the other hand, routine activities such as grooming led to a decrease in LC-NE discharge activity. Although there are problems associated with drawing deductions from these kinds of animal studies and applying them to the situation during sleep deprivation in man, one may speculate that the multiple sensory stimuli which the TSD-bed patients obtained from the nurse could have induced the same or even greater LC-NE activity than is usual during conventional TSD. Finally, psychological stress factors also activate LC neurons and peripheral NE levels (Dimsdale et al., 1987). We can therefore not exclude the possibility that the patients’ fears as to whether they would in fact be able to cope with such a night of sleep deprivation in bed constituted such a stressor that they induced a higher state of arousal, thus on the one hand making it easier for the patients to stay awake, and on the other raising the activity of their central NE neurons. However, it is also clear from our results that the moderate degree of physical activity during the conventional form of
sleep deprivation obviously does not contribute to its antidepressant effect. Whether or not the same is true of more strenuous and therefore unusual physical activity remains to be investigated. References Aitken, D.B. (1969) Measuring of feelings using visual analogue scales. Proc. R. Sot. Med. 62, 989. Aston-Jones, G. and Bloom, F.E. (1981) Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876-886. Baumgartner, A. and Meinhold, H. (1986) Sleep deprivation and thyroid hormone concentrations. Psychiatr. Res. 19, 241-242. Baumgartner, A., Graf, K.J., Klirten, I., Meinhold, H. and Scholz, P. (1990a) Neuroendocrinological investigations during sleep deprivation. I. Concentrations of thyrotropin, thyroid hormones, cortisol, prolactin, luteinizing hormone, follicle stimulating hormone, oestradiol, and testosteron in patients with major depressive disorder at 8 a.m. before and after total sleep deprivation. Biol. Psychiatry (in press). Baumgartner, A., Riemann, D. and Berger, M. (1990b) Neuroendocrinological investigations during sleep deprivation. II. Longitudinal measurement of thyrotropin, thyroid hormones, cortisol, prolactin, growth hormone, and luteinizing hormone during nights of sleep and sleep deprivation in patients with major depressive disorder. Biol. Psychiatry (in press). Buchsbaum, M.S., Gemer, R. and Post, R.M. (1981) The effects of sleep deprivation on average evoked responses in depressed patients and in normals. Biol. Psychiatry 16, 351-363. Camilli, G. and Hopkins, K.D. (1979) Testing for association in 2 X2 contingency tables with very small sample sizes. Psychol. Bull. 85, 1011. Chu, N. and Bloom, F.E. (1973) Norepinephrine-containing neurons: changes in spontaneous discharge patterns during sleeping and waking. Science 179, 908-910. Cryer, P.E., Santiago, J.V. and Shah, S. (1974) Measurement of norepinephrine and epinephrine in small volumes of human plasma by a single isotope derivative method: response to upright posture. J. Clin. Endocrinol. Metab. 39, 1025-1029. Davidson, L., Vandongen, R., Beilin, L.J. and Arkwright, P.D. (1984) Free and sulfate-conjugated catecholamines during exercise in man. J. Clin. Endocrinol. Metab. 58, 415-418. Dimsdale, J.E. and Moss, J. (1988) Plasma catecholamines in stress and exercise. J. Am. Med. Ass. 243, 340-342. Dimsdale, J.E., Young, D., Moore, R. and Strauss, W. (1987) Do plasma norepinephrine levels reflect behavioural stress? Psychosom. Med. 49, 375-382. Finke, J. and Schulte, W. (1970) Schlafstorungen und ihre Behandlung. Thieme, Stuttgart. Foote, S.L., Aston-Jones, G. and Bloom, F.E. (1980) Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc. Natl. Acad. Sci. U.S.A. 77, 3033-3037.
99 Gemer, R.H., Post, R.M., Gillin, C. and Bunney, W.E. (1979) Biological and behavior& effects of one night’s sleep deprivation in depressed patients and in normals. J. Psychiatr. Res. 15, 21-40. Gillin, J.C. (1983) The sleep therapies of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 7, 353-364. Hamilton, M. (1960) A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56. Jacobs, B.L. (1986) Single unit activity of locus coeruleus neurons in behaving animals. Prog. Neurobiol. 27,183-194. Kasper, S., Sack, D.A., Wehr, T.A., Kick, H., Voll, G. and Viera, A. (1988) Nocturnal TSH and prolactin secretion during sleep deprivation and prediction of antidepressant response in patients with major depression. Biol. Psychiatry 24, 631-641. Kozlowski, S., Brzezinska, Z., Nazar, K., Kowalski, W. and Franczyk, M. (1973) Plasma catecholamines during sustained isometric exercise. Clin. Sci. Mol. Med. 45, 723-731. Kuhs, H. (1985) Dexamethasone suppression test and sleep deprivation in endogenous depression. J. Affect. Disord. 9, 121-126. Kuhs, H. and TMle, R. (1986) Schlafentzug (Wachtherapie) als Antidepressivum. Forts&r. Neural. Psychiatric 54,341-355. Lake, CR., Ziegler, M.G. and Kopin, I.J. (1976) Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man. Life Sci. 18, 1315-1326. Matussek, N., Ackenheil, M., Athen, D., Beckmann, H., Benkert. O., Dittmer. T., Hippius, H., Loosen, P., Ruther, E. and Scheller, M. (1974) Catecholamine metabolism under sleep deprivation therapy of improved and not improved depressed patients. Pharmacopsychiatry 7, 108-114. Pflug, B. (1978) The influence of sleep deprivation on the duration of endogenous depressive episodes. Arch. Psychiatrie Nerve&r. 225, 173-177. Pflug, B. and Tolle, R. (1971) Therapie endogener Depressionen durch Schlafentzug. Nervenarzt 42, 117 1124. Post, R.M., Kotin, J. and Goodwin, F.K. (1976) Effects of
sleep deprivation on mood and central amine metabolism in depressed patients. Arch. Gen. Psychiatry 33, 627-632. Raskind, M.A., Peskind, E.R., Halter, J.B. and Jimerson, D.C. (1984) Norepinepbrine and MHPG-levels in CSF and plasma in Alzheimer’s disease. Arch. Gen. Psychiatry 41, 343-346. Reynolds, C.F., Kupfer, D.J., Hoch, C.C., Stack, J.A., Houck, P.A. and Berman, S.R. (1987) Sleep deprivation effects in older endogenous depressed patients. Psychiatr. Res. 21, 95-109. Rudolf, G.A.E. and Tiille, R. (1978) Sleep deprivation and circadian rhythm in depression. Psychiatr. Clin. 11, 198212. Saar, N. and Gordon, R.D. (1979) Variability of plasma catecholamine levels: age, duration of posture and time of day. Br. J. Clin. Pharmacol. 8, 353-358. Spitzer, R.L., Endicott, J. and Robins, E. (1978) Research Diagnostic Criteria: Rationale and reliability. Arch. Gen. Psychiatry 37, 773-781. Wehr, T.A. and Wirz-Justice, A. (1981) Internal coincidence model for sleep deprivation and depression. In: Sleep 1980. Karger, Basel, pp. 26-33. Wehr, T.A., Wirz-Justice, A., Goodwin, F.K., Duncan, W. and Gillin, J.C. (1979) Phase advance of the circadian sleep-wake cycle as an antidepressant. Science 206, 710-713. Wehr, T.A., Rosenthal, N.E., Sack, D.A. and Gillin, J..C. (1985) Antidepressant effects of sleep deprivation in bright and dim light. Acta Psychiatr. Scand. 72, 161-165. Wiegand, M., Berger, M., Zulley, J., Lauer, C. and Von Zerssen, D. (1987) The influence of daytime naps on the therapeutic effect of sleep deprivation. Biol. Psychiatry 22, 386-389. Ziegler, M.G., Lake, C.R., Wood, J.H. and Ebert, M.H. (1976) Circadian rhythm in cerebrospinal fluid noradrenaline of man and monkey. Nature 264, 656-658.
Journal of Aff..ctioe Disorders, 20 (1990) 93-99 Elsevier
JAD 00744
The influence of physical activity and posture on the antidepressant effect of sleep deprivation in depressed patients Andreas Psychiatrische
Klinik und Poliklinik
Baumgartner
of the Klinikum
and Nikolaus
Rudolf-Virchow
(Charlottenburg),
Sucher Freie Uniuersitiit Berlin, Berlin, Germany
(Received 7 February 1990) (Revision received 5 May 1990) (Accepted 21 May 1990)
Summary A possible role of the factors ‘physical activity’ and ‘posture’ in the antidepressant effect of a total night’s sleep deprivation (TSD) was investigated in 30 patients with major depressive disorder. Fifteen patients underwent TSD under ‘conventional’ conditions, while the other 15 were kept in bed during TSD but were not permitted to sleep. There was no significant difference between the antidepressant effects of TSD in the two groups. This result suggests that it is wakefulness itself rather than changes in physical activity or posture that is involved in the mechanism of the antidepressant action of TSD.
Key words: Sleep deprivation;
Posture; Physical activity; Depression
Introduction The antidepressant effect of a total night’s sleep deprivation (TSD) was first described by Fir&e and Schulte (1970) and later systematically investigated by Pflug and Tijlle (1971). Since then numerous studies have attempted to elucidate the biological mechanisms responsible for the antidepressant action of TSD. These include biochemical (e.g., Matussek et al., 1974; Post et al., 1976; Gerner et al., 1979) and electrophysiological (e.g.,
Address for correspondence: Dr. A. Baumgartner, Psychiatrische Klinik und Poliklinik, Eschenallee 3, D-1000 Berlin 19, Germany. 0165-0327/90/$03.50
Buchsbaum et al., 1981) studies, investigations of chronobiological hypotheses (e.g., Wehr et al., 1979; Wehr and Wirz-Justice, 1981), a possible role of light (Wehr et al., 1985) and the interaction between sleep parameters and response to sleep deprivation (e.g., Reynolds et al., 1987) and many others. Nonetheless, as yet no convincing and consistent explanation of the mechanisms that could be responsible for the effect of TSD has been advanced (for reviews see, for example, Gillin et al., 1983; Kuhs and Tijlle, 1986). The first systematic study of the antidepressant effect of TSD by Pflug and Tiille (1971) was inspired by some clinical observations by Schulte. Schulte described a severely melancholic patient whose condition improved considerably after having ridden a bicycle for a whole night and concluded that the
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
94
effect of muscular effort may also have contributed to the antidepressant effect. Another example refers to a depressed physician who was only able to carry out his professional duties after having stayed awake for one night ‘not just reading a book but doing real work’ (Finke and Schulte, 1970). These examples raise the question whether wakefulness in itself is the sole factor responsible for the antidepressant effect of TSD, or whether other factors such as ‘physical activity’ or ‘upright posture’ during TSD might also play some role. The latter idea is also supported by the fact that physical activity affects some physiological variables which may have some importance for theories of mechanisms of antidepressant therapies. Physical activity enhances serum norepinephrine levels (e.g., Kozlowski et al., 1973; Dimsdale and Moss, 1980; Davidson et al., 1984). This is also true of upright posture in comparison with the prone position (e.g., Cryer et al., 1974; Lake et al., 1976; Saar and Gordon, 1979). As regards deductions of central norepinephrine (NE) activity from serum NE levels, it is now well known that although NE does not easily cross the blood-brain barrier there are highly significant correlations between concentrations of NE in the CSF and plasma in healthy subjects, and also in patients in, for example, Alzheimer’s disease (e.g., Ziegler et al., 1977; Raskind et al., 1984). On the other hand, we have recently reported that the secretory profiles of many hormones change during sleep deprivation in depressed patients (Baumgartner et al., 1990a, b). It was shown that this ‘pattern’ of changes in secretory profiles is probably due to enhanced central NE activity. On the basis of these findings we hypothesized that enhanced activity of the locus coeruleus during sleep deprivation influences central NE receptor function, thereby leading to the antidepressant action of TSD. We were therefore interested to investigate whether the factors ‘physical activity’ and ‘upright posture’, which both lead to enhanced peripheral and possibly also central NE activity, are involved in the mechanism of the antidepressant action of TSD. We thus compared the effect of a TSD spent in bed with that of a conventionally conducted TSD and hypothesized that the latter would have a significantly higher antidepressant efficacy.
Methods Thirty inpatients fulfilling Research Diagnostic Criteria (RDC, Spitzer et al., 1978) for major depressive disorder (probable or definite) were included in the study. The patients were divided into two groups of 15, one of which underwent TSD in a conventional form (TSD-conv.) while the other was kept in bed during TSD (TSD-bed). All patients had endogenous depression (RDC). The TSD-conv. group comprised 10 unipolar and five bipolar patients, whereas the TSD-bed group was made up of 12 unipolar and three bipolar patients. In the TSD-conv. group there were 11 women and four men, and the mean age of the group as a whole was 45.4 + 15.5 years (range 19-70). The TSD-bed group comprised 13 women and two men and the mean age was 57.7 + 14.7 years (range 25-77 years). The TSD-conv. group was part of a larger sample (n = 50) in whom different hormones were measured at 8 a.m. both before and after TSD (Baumgartner and Meinhold, 1986; Baumgartner et al., 1990a). In order to compare the clinical effect of TSD-conv. with that of TSD-bed the first 15 patients of the whole TSD-conv. group (n = 50) were selected for comparison with the TSD-bed group. Criteria for exclusion were a history of alcoholism or drug abuse, serious somatic illness, a history of or acute thyroid disorder and acute suicidal tendencies. Eight of the TSD-conv. patients and seven of the TSD-bed patients had not received psychotropic drugs for at least 3 months prior to hospital admission. These patients underwent their first TSD within the first week, but not sooner than 3 days after admission, at which time they were not receiving any psychotropic medication. The remaining seven TSD-conv. and eight TSD-bed patients underwent TSD at various times during their hospital stay, sometimes even 1 or 2 months after admission when antidepressant medication had proved unsuccessful. All 15 of these patients antidepressants (clomipramine, were receiving amitriptyline or maprotiline). The doses ranged from 100 to 150 mg/day. No other psychotropic medication, such as minor or major tranquilizers, was permitted. All of the patients who were receiv-
95
ing drugs at the time of the TSD had started taking them at least 14 days beforehand. As we recently found (Baumgartner et al., 1990a) that concomitant antidepressant medication has no influence on the outcome of a TSD and as, furthermore, the patients who were taking drugs and those who were not were almost equally distributed in both groups, we did not believe that the uninterrupted medication of some of the patients at the time of TSD would interfere with the investigation of the specific issues we wished to examine in this study. On the mornings before and after TSD all patients were rated on the 21-item Hamilton Rating Scale for Depression (HRSD, Hamilton, 1960). The mean score for the TSDconv. group was 24.8 + 5.3 (range 15-37) and that for the TSD-bed group 25.2 t_ 4.8 (range 17-37) indicating that our sample consisted mostly of moderately and severely ill patients. To evaluate the response to TSD we used a modified, six-item version of the HRSD. These six items had been taken from the original 21-item HRSD scale as follows: 1 (depressed mood), 2 (feelings of guilt), 7 (work and activities), 8 (retardation), 10 (anxiety, psychic) and 13 (somatic symptoms, general). In addition, all the patients completed the visual Analogue Mood Scale (VAS, Aitken, 1969) at 8 a.m. (VASM, morning score) and 8 p.m. (VASE, evening score) on both the day before and the day after TSD. (The VAS is a self-rating scale consisting of five items, in which the patient marks his condition on a line 10 cm in length with the best condition at the left hand end and the poorest condition at the right hand end.) For our calculations we used the mean scores of the five VAS items. In order to evaluate the degree of the patient’s responses the following calculations were performed: the mean ‘day’ score (VASD) was calculated as follows: (VASM + VASE)/2. These calculations were done separately for days 1 (VASDl) and 2 (VASDZ). The difference (VASD2-VASDl) was designated AVASD and represents the response to TSD. The method of evaluating the response to TSD has been suggested previously, for example, by Rudolf and Tolle (1978). The morning (AVASM) and evening (AVASE) responses were calculated separately. We also divided the patients into one group
with an improvement of over 30% on the HRSD and VASMD (responders) and another comprising those with a less than 30% improvement on the HRSD and VASMD (non-responders). We used this criterion for distinguishing between responders and non-responders as a basis for comparing our results with those of several other study groups (Matussek et al., 1974; Kuhs et al., 1985; Wiegand et al., 1987; Kasper et al., 1988) who employed the same criterion. During the investigation all the patients stayed awake for at least 36 h between 8 a.m. on day 1 and 8 p.m. on day 2. No naps were permitted during this time. Meals were served at 8 a.m., noon and 6 p.m. During TSD an additional meal was served at around midnight. Neither smoking nor lighting conditions were controlled. The light in all our sitting rooms is somewhat subdued at night, that is, slightly dimmer than in the evening, but sufficient to permit reading. During the night of TSD the TSD-conv. patients were not allowed to stay in their bedrooms or lie down elsewhere. They spent their time in the sitting room of their ward. A nurse was constantly present in order to ensure that they did not fall asleep and also to help them stay awake by playing games, talking to them or permitting them to watch television. Occasionally walks in the clinic garden were allowed if the weather and the patient’s condition permitted. The TSD-bed patients went to bed at 10 p.m. and were kept in bed until 8 a.m. They were only allowed to get up to go to the toilet. The mean frequency of visits to the bathroom was 2.4 t- 1.7 (range O-7) times. None of these visits lasted longer than 5 min. An additional nurse was present throughout the night for the sole purpose of ensuring that the patients stayed awake and remained in bed. The TSD was not conducted in the patients’ own rooms but in a special room in which only the patients and the nurse were present, at least after midnight. Until midnight the patients were permitted to watch television in a semi-reclining position (half sitting up). The nurse was instructed to try to keep them awake by talking alone and only to play games with them while they remained sitting in bed if this failed. At 8 a.m. the TSD-bed patients were allowed to get up and follow the same regime as the TSD-conv. patients until the evening (see above).
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A single blood sample was taken from all patients at 8 a.m. before TSD and after TSD for measurement of different hormones. The endocrine results for the TSD-conv. patients have already been reported (Baumgartner and Meinhold, 1986; Baumgartner et al., 1990a) and those of the TSD-bed patients will be presented in a separate report (Baumgartner et al., submitted). The TSD-conv. patients were informed that TSD is an effective but possibly short-acting antidepressant treatment which has been used in psychiatry for many years. The TSD-bed patients were given the additional information that they were taking part in a study the purpose of which was to establish whether this form of therapy is also effective if patients spend the night lying down. A statistical analysis was performed using l-tests (two-tailed) for dependent and independent variables. For small sample sizes (< 10) we used the Mann-Whitney U-test. To correlate the response to TSD with other variables such as age, we used Pearson’s coefficient of correlation. The x2 test was used for dichotomous variables (the FisherYates correlation was not necessary for this sample) (Camilli and Hopkins, 1979). Means and standard deviations (SD) were used throughout and P values of less than 0.05 were regarded as significant. Results The mean HRSD score (six-item version) before TSD was 12.7 + 3.1 for the TSD-bed patients and 11.9 _t 3.9 for the TSD-conv. group. This difference was not significant (t = 0.43). The VASD
VAS D Iday’s score)
Sleep depr,vat,on before SD
I” bed a‘ter SD
10 1
Fig. 1. Comparison of the antidepressant effects of TSD-bed and TSD-cow.
scores before sleep deprivation were 6.52 & 1.81 for the TSD-bed group and 6.55 k 2.46 for the TSD-conv. patients. This difference was also not indicating that the two significant (t = 0.12) groups were comparable with respect to self-rated initial severity of illness (see also Fig. 1). The same applies for the comparison of the morning values alone (VASMl = 6.90 + 1.97 for the TSD-bed patients and 6.84 k 2.19 for the TSD-conv. group) and for the evening values alone (VASE1 = 6.15 + 2.07 for the TSD-bed group and 6.26 f 2.90 for the TSD-conv. group (Table 1).
TABLE 1 RATING SCORES OF 30 PATIENTS WITH MAJOR DEPRESSIVE DISORDER ON THE VAS AND THE SIX-ITEM HRSD BEFORE AND AFTER SLEEP DEPRIVATION IN BED (n = 15) AND CONVENTIONAL SLEEP DEPRIVATION (n = 15) Before TSD
After TSD
t
P
TSD-bed
VASM VASE VASD HRSD
6.90*1.97 6.15 f 2.07 6.52 + 1.81 12.7 +3.1
5.71+ 2.14 5.74 f 2.60 5.72k2.38 8.5 +3.8
1.94 0.64 1.62 2.24
( > 0.05) NS NS NS < 0.05
TSD-cow.
VASM VASE VASD HRSD
6.84xk2.19 6.26 + 2.90 6.55 f 2.46 11.9 *3.9
6.04zk2.58 5.58 + 2.89 5.80 + 2.57 8.1 *4.0
1.21 0.78 1.08 2.08
NS NS NS < 0.05
97 TABLE
2
COMPARISON OF THE TION
OF
THE
CONVENTIONAL
AND
ANTIDEPRESSANT FORM
SLEEP DEPRIVATION
EFFECTS
OF SLEEP
DEPRIVA-
IN BED
P
TSD-bed
TSD-conv.
t -0.35
NS
AVASM
-1.18i2.33
-0.8Oi2.55
AVASE
- 0.41 k 2.46
- 0.68 f 3.35
&‘ASD
- 0.80 + 2.24
- 0.76 * 2.72
-0.12
NS
dHRSD
-4.2
-3.8
-0.11
NS
*3.4
+3.9
0.28
NS
The changes in mood after TSD are shown for both groups in Table 2 and Fig. 1. It can be seen that TSD induced almost equal decreases in the HSRD and VAS scores for the mornings alone (AVASM), the evenings alone (AVASE) and also for the whole day (AVASD). Thus, there was no significant difference between the responses of the two ‘groups to TSD (Table 2). When the rates of responders and non-responders in each group were calculated, applying the criterion of a 2 30% improvement in the HRSD score, seven of the TSDbed patients were classified as responders and two showed a worsening of mood after TSD. In the TSD-conv. group there were five responders and two patients whose mood deteriorated. The same calculation done for the VASD scale revealed that five of the TSD-bed patients were classified as responders and the conditions of two had worsened. In the TSD-conv. group we obtained three responders and three patients with a deteriorated condition (Fig. 1). These results show a somewhat higher response rate in the TSD-bed group, however, the differences calculated by x2 analysis were not significant for either scale (x2 = 0.04, P = 0.84 for the VAS and x2 = 0.47, P = 0.40 for the HRSD score). Although an influence of antidepressant medication on the response to TSD does not seem likely (see Methods) we compared the response rates of the seven patients in the TSD-bed group who did not receive antidepressants with those of the eight patients who were taking antidepressant drugs. There were no significance differences between the mean AVASD or AHRSD scores of the two groups (Mann-Whitney U-test, P = 0.65 and P = 56 respectively). As our TSD-bed group was somewhat older than the TSD-conv. group we correlated the age of
the TSD-bed group with the outcome of TSD. However, Pearson’s coefficient of correlation between age and AVASD did not show even a trend towards significance (r = 0.15, df= 13, P = 0.58). Although we did not conduct a systematic investigation of the time courses of changes in mood during the TSD spent in bed and the patient’s subjective appraisals of this form of therapy, the nurses kept a record in which they noted the patients’ behavior, verbalizations and their own impressions of how the patients felt hourly. The patients’ assessments of the practicability of a TSD spent in bed varied widely. Several of them complained that they found it very hard to stay awake while others did not have any such difficulties. Of those who had undergone conventional TSD at any time previously, some preferred the conventional form after having experienced TSD in bed but three of them were quite enthusiastic about TSD in bed and suggested that this form of sleep deprivation should be introduced as a routine therapy. Analysis of the nurses’ records also revealed that for most patients it was hard to remain awake before 1, 2 or 3 a.m., but that it became much easier after they had succeeded in staying awake during this period in which drowsiness was strongest. Discussion On the basis of clinical observations and theoretical considerations (see Introduction) we hypothesize that the factors ‘physical activity’ and ‘upright posture’ might be somehow involved in the mechanisms of the antidepressant action of TSD. Our hypothesis was derived from the knowledge that certain physiological changes are induced by physical activity and upright posture and specifically from the findings that plasma NE levels increase in the upright position and during physical activity, and that there are probably some interactions between plasma and central NE activity (for references see Introduction). However, it is evident from the results of the present study that neither of the above factors is involved in the antidepressant effect of TSD. Consequently, factors related to wakefulness itself and associated biochemical and physiological changes are most likely to play the key role in the antidepressant
98
action of TSD. The nature of these changes related to wakefulness that induce the clinical effects of TSD is not yet clear. However, we feel that hypotheses of a possible involvement of the noradrenergic system are supported by at least two facts. First, the increases in thyroid-stimulating hormone, cortisol and growth hormone after TSD that have been reported in many studies point towards an enhancement of noradrenergic activity during TSD (for reviews see Baumgartner et al., 1990b). Second, it has now been shown in three species (the rat, cat and monkey) that the NE activity of the locus coeruleus (LC) is higher during waking than during sleep (Chu and Bloom, 1973; Aston-Jones and Bloom, 1981; for a review see Jacobs, 1986). It could thus be postulated that stimulation of postsynaptic adrenergic receptors is higher during waking than during sleep. Furthermore, the outstanding work of Foote et al. (1980) and Aston-Jones and Bloom (1981) provided evidence that the activity of the locus coeruleus is dependent both on sensory stimulation and on level of arousal. For example, a pip tone caused a much higher rise in LC-NE neuronal discharge activity when the stimulus woke the animal from slow-wave sleep than when it was presented during uninterrupted waking. On the other hand, routine activities such as grooming led to a decrease in LC-NE discharge activity. Although there are problems associated with drawing deductions from these kinds of animal studies and applying them to the situation during sleep deprivation in man, one may speculate that the multiple sensory stimuli which the TSD-bed patients obtained from the nurse could have induced the same or even greater LC-NE activity than is usual during conventional TSD. Finally, psychological stress factors also activate LC neurons and peripheral NE levels (Dimsdale et al., 1987). We can therefore not exclude the possibility that the patients’ fears as to whether they would in fact be able to cope with such a night of sleep deprivation in bed constituted such a stressor that they induced a higher state of arousal, thus on the one hand making it easier for the patients to stay awake, and on the other raising the activity of their central NE neurons. However, it is also clear from our results that the moderate degree of physical activity during the conventional form of
sleep deprivation obviously does not contribute to its antidepressant effect. Whether or not the same is true of more strenuous and therefore unusual physical activity remains to be investigated. References Aitken, D.B. (1969) Measuring of feelings using visual analogue scales. Proc. R. Sot. Med. 62, 989. Aston-Jones, G. and Bloom, F.E. (1981) Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876-886. Baumgartner, A. and Meinhold, H. (1986) Sleep deprivation and thyroid hormone concentrations. Psychiatr. Res. 19, 241-242. Baumgartner, A., Graf, K.J., Klirten, I., Meinhold, H. and Scholz, P. (1990a) Neuroendocrinological investigations during sleep deprivation. I. Concentrations of thyrotropin, thyroid hormones, cortisol, prolactin, luteinizing hormone, follicle stimulating hormone, oestradiol, and testosteron in patients with major depressive disorder at 8 a.m. before and after total sleep deprivation. Biol. Psychiatry (in press). Baumgartner, A., Riemann, D. and Berger, M. (1990b) Neuroendocrinological investigations during sleep deprivation. II. Longitudinal measurement of thyrotropin, thyroid hormones, cortisol, prolactin, growth hormone, and luteinizing hormone during nights of sleep and sleep deprivation in patients with major depressive disorder. Biol. Psychiatry (in press). Buchsbaum, M.S., Gemer, R. and Post, R.M. (1981) The effects of sleep deprivation on average evoked responses in depressed patients and in normals. Biol. Psychiatry 16, 351-363. Camilli, G. and Hopkins, K.D. (1979) Testing for association in 2 X2 contingency tables with very small sample sizes. Psychol. Bull. 85, 1011. Chu, N. and Bloom, F.E. (1973) Norepinephrine-containing neurons: changes in spontaneous discharge patterns during sleeping and waking. Science 179, 908-910. Cryer, P.E., Santiago, J.V. and Shah, S. (1974) Measurement of norepinephrine and epinephrine in small volumes of human plasma by a single isotope derivative method: response to upright posture. J. Clin. Endocrinol. Metab. 39, 1025-1029. Davidson, L., Vandongen, R., Beilin, L.J. and Arkwright, P.D. (1984) Free and sulfate-conjugated catecholamines during exercise in man. J. Clin. Endocrinol. Metab. 58, 415-418. Dimsdale, J.E. and Moss, J. (1988) Plasma catecholamines in stress and exercise. J. Am. Med. Ass. 243, 340-342. Dimsdale, J.E., Young, D., Moore, R. and Strauss, W. (1987) Do plasma norepinephrine levels reflect behavioural stress? Psychosom. Med. 49, 375-382. Finke, J. and Schulte, W. (1970) Schlafstorungen und ihre Behandlung. Thieme, Stuttgart. Foote, S.L., Aston-Jones, G. and Bloom, F.E. (1980) Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc. Natl. Acad. Sci. U.S.A. 77, 3033-3037.
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