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Core Body Temperature in Patients with Seasonal Affective Disorder and Normal Controls in Summer and Winter Alytia A. Leven.dosky, Jean R. Joseph-Vanderpool, Todd Hardin, Elizabeth Sorek, and Norman E. Rosenthal
The rationale for phototherapy in seasonal affective disorder (SAD) was originally based on the notion that SAD patients were light deprived during the wintertime and needed more light. We previously found normal temperature profiles of untreated SAD patients during the winter, and that phototherapy significantly enhanced the amplitude of the circadian temperature profile in SAD patients during the winter (Rosenthal et al 1990). We hypothesized that summer would act similarly on the temperature rhythm of these patients. In this study we examined the temperature data from SAD patients and r,ormal controls during the summer and compared it to the results of our previous study. We found identical profiles for SAD patients and normal controls during the summer and that summer significantly lowered the overall temperature profiles of both groups and did not alter the amplitudes. These results raise questions about the validity of the current theories of the mechanism of light therapy.
Introduction Seasonal affective disorder (SAD) has been hypothesized to be caused by an abnormality in the circadian pacemaker, either in its timing (Lewy et al 1987) or its amplitude (Czeisler et al 1987). Lewy hypothesized that winter depressives have abnormally delayed circadian rnyt_hms (Lewy e~ al 1984). Since then, several studies have found supporting evidence for the phase-delay hypothesis of SAD (Lewy et al 1987; Avery et al 1989; Depue 1989). Information about the behavior of the circadian pacemaker can be inferred from measurements of various circadian rhythms, of which core body temperature is one of the most frequently studied. A newer theory, with as yet less data to support it, is the hypothesis of reduced circadian mnplitude in SAD patients which has been suggested by Kronauer (1987) and Czeisler et al (1987). Information about the timing and amplitude of the oscillation of the circadian pacemaker can be inferred from corresponding features of the circadian temperature rhythm.
From the Clinical Psychobiology Branch, NIMH (AAL, ~RJ-V, TH, NER), and the Clinical Center Nursing Department, Nil-', (ES), Bethesda, MD. Address reprint requests to Alytia A. Levendosky, Clinical Psychobiology Branch, Bldg. 10/4S-239, 9000 Rockville Pike, Bethesda, MD 20892. Received June 2.', 1990; revised August 29, 1990. © 1991 Society of Biological Psychiatry
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Several investigators have found abnormally high nocturnal temperatures and consequently reduced amplitudes of circadian rhythms in depressed patients. Such temperature abnormalities have been thought to reflect disturbed re.gulation of energy balance in depressed patients (Souetre et al 1988). Energy metabolism dysregulation has also been postulated to exist in SAD (Rosenthal et al 1990; Arhisi et al 1989; Gaist et al, u n p u b l i s ~ data). Some investigators have hypothesized that an increase in amplitude of circadian rhythms is responsible for the antidepressant effects of medication and bright light because amplitude has been found to increase to normal levels when depressed patients become euthymic (Smallwood et al 1983; Avery et al 1982, 1986; Czeisler et al 1987; Souetre et al 1988). Other investigators have found that the timing of circadian phase is altered in depression. Wehr et al (1983) found that some depressed patients have advanced circadian rhythms which return to a ncrmal phase position during remission. Lev,T et al (19.87) have observed phase-delayed circadian rhythms in most SAD patients and suggest that the correction of this delay is responsible for the antidepressant effect of bright light treatment in the morning. Seasonal variation in phase and amplitude of circadian rhythms of core body temperature, plasma hormones, activity cycles, and sleep length have been documented in animals (Daan and Aschoff 1975). Some of these variations seem to be influenced directly by changes in environmental variables, such as ambient temperature and light (Gwirmer 1975). Several researchers have also documented seasonal variations in human physiology, for example, in core body temperature, sleep, thyroid hormones, and basal metabolic rate (as reviewed by Lacoste and Wirz-Justice 1989). In contrast to reports on nonseasonal depressives, we have previously found that the temperature profiles of 10 depressed SAD patients, measured during the winter, were not different from those of normal controls (Rosenthal et al !990). Nonetheless, effective treatment with bright (2500 lux) light in both morning and evening enhanced the amplitude of the circadian rhythms in patients significantly beyond normal levels. Thus, paradoxically, the profiles of the depressed patients were normal and those of the treated patients were abnormal. In an attempt to understand this paradox, we have followed up our previous study by comparing the circadian temperature profiles of remitted SAD patients and matched normal controls during the summer months with those obtained in our earlier winter study. This comparison is the basis of the present repo_rt.
Methods This study was conducted during the summer, when SAD patients are generally euthymic. In order to be lh,.l':2:a in this study, all patients were required to (1) meet lifetime criteria for SAD (Rosenthal et al 1984); (2) be euthymic, as reflected by a score of less than 10 on the 21-item Hamilton Depression Rating Scale (HDRS) (Hamilton 1967); and (3) be drug free for at least 1 month prior to admission. The normal controls were recruited through an .advertisement in the Washington Post. They were screened and evaluated by means of the Structured Clinical Inte~iew for DSM-III-R diagnoses (SCK-~-R) (Spitzer et al 1987), and those with personal or family histories (first-degree relatives only) of psychiatric illness or any significant tiiextical illness were excluded. All subjects were studied on the inpatient research unit in the Intramural program of
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Table 1. Demographic Summary of Subjects in the Summer Study HDRS Score
Patient
Gender
Age
Typical
1 2 3 4
I: F M F M F M F F
36 51 45 35 31 42 38 45 44
5 .5 3 0 3 2 8 7 0
6 7 8 9
Atypical 4 4 0 0 0 2 0 ! 0
High-SAD 0 0 0 ! ! 3 7 0 10
HDRS Score
Control 1 2 3 4 5 6 7 8 9
Gender F F M F M F M F F
Age 38 51 44 34 27 41 44 26 22
Typical 0 2 5 0 0 0 0 ! 0
Atypical O 2 4 O 0 0 0 0 1
High-SAD 0 1 1 0 0 2 0 0 0
Timing of temperatureminima 07:30 07:!5 03:50 03:55 04:!5 06:15 03:20 04:00 06:15 Mean = 05:15 SD = 02:00
Timing of temperatn_re mini_m_~ 03:30 05:10 02:50 07:25 04:45 02:45 04:05 00:05 01:25 Mean = 03:30 2D = 02:10
the NIMH. The subjects were admitted to the hospital at 5 PM and stayed for 26 hr. The HDRS was administered when the patient arrived in the hospital, before temperature monitoring began. The temperature recording began at 7 PM on the first evening and was continued until 7 PM the next evening. Core body temperature was measured via an indwelling rectal thermistor probe by a portable recording device (Vitalog) which sampled temperature at 5-min intervals, data were stored in solid-state memory and retrieved after the study. The sleep schedule of the subjects was set at 11 PM to 7 AM. For the week prior to the study, the patients were requested to maintain their own regular sleep-wake schedule. During the day, all subjects remained on the inpatient unit and engaged in normal sedentary activities. Beyond that, we did not specifically control their activity. The population (Table 1) consisted of 9 patients (6 women, 3 men, aged 31-51) and 9 normal controls (6 women, 3 men, aged 22-51). We attempted to control for phase of menstrual cycle by studying a balanced number of female patients and normal controls in the luteal and the follicular phases. Two women in each group were run through the study during the luteal phase and two in each group during the follicular phase. In addition, two women in each group were postmenopausal. Data from this summer study of SAD patients were analyzed by means of a repeated measure analysis of variance (ANOVA), with one repeated factor (time) and one grouping factor (patient versus normal con~ol). The degrees of freedom were
Core Temperature in SAD Patients
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Table 2. Demographic Summary of Subjects in the Winter Study (Rosenthal et al. 1990) Timing of tcmpcratm~ minima
HDRS Score Patient
Gender
Age
Off-Lights
On-Lights
2 2 3 4 5 ~. 7' 8 9 10
M M F F F F M M F M
45 35 36 53 56 21 52 28 37 54
23 28 ~6 26 25 20 13 Il 23 20
8 23 2 1 5 8 7 6 9 12
Control
Gender
Age
2 2 3 4 5 6 7 8 9 20 22 22
M M M F F F M M F M F F
40 37 30 48 49 27 52 28 43 56 29 45
Off-Lights 05.'¢5 00:55 05:40 23:25 04:05 06:40 03:20 05:00 04:00 00:30 Mean = 03:30 SD = 02:30
On-Liglats 05:15 02:25 02:35 00:10 00:20 O! :40 02 : ~ 04:25 06:25 04:20 02:50
02:10
Timing of temperature 01:05 O1.35 00:45 23:35 03:40 06:05 01:55 02:50 03:20 04:15 02:10 06:25 Mean = 02:45 SD = 02:00
modified according to Greenhouse and Geisser (1959). The timing of minima was identified by visual inspection by a rater blind to the subject's diagnosis and treatmen: states, and these values were compared by means of group t-tests. Wqaen there were two or more clear minima, the times of the minima were averaged and the resulting mean was used for analysis. Similar analyses were performed on temperature amplitudes (peak to trough) and means of 24-hr temperature values. The data were also compared with the results of the winter SAD study of 1985-88 (Rosenthal et al 1990) in a repeated measures ANOVA with one repeated factor (time) and two grouping factors (season: winter or summerwseason was not regarded as a repeated measure as different subjects were studied in summer and winter; and subject type: patient or normal control). The temperature data of patients on light treatment in winter were compared with summer patient data by means of a repeated mc~ures ANOVA (two repeated factors: time, season). Unpaired t-tests were performed on amplitude ~ d timing of minima for patients and controls across seasons. Table 2 summarizes the demographic data of the patients and controls from the winter study.
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BIOLPSYCHIATRY 1991;29:524-534 38
S,.EB=,:nUE
37.8 37.6 37.4 37.2
~
Lg n ~ uJ 36.8 36.6 ,-,-- NORMAL CONTROLS (N=9)
3e.4
---.. PATIENTS (N=9)
36.2 36
7:00pro
11 :OOpm
7:00am
7:0()pm
TIME
Figure I. Mean core body temperature of patients and normal controls during the summer months. Core body temperature was measured every 5 rain using a Vitalog temperature monitor and a zectal thermistor, over a 24-hr period.
Results There was no statistically significant difference between summer temperature profiles of SAD patients and ',hose of normal controls (F = 0.02; df = 1, 16; p = 0.9) (see Figure 1). Although nocturnal temperature was slightly lower in patients than in normal controls, this was also not statistically significant ( F = 0.3; df = 1,16; p = 0.59). Neither were ,*,hetiming of the minima nor the amplitude values significantly different between the two groups (timing: t = 1.27; df = 16; p = 0.22; amplitude: t = 0.01; df = 16; p = 0.99). We compared winter and summer temperature profiles of SAD patients and normal controls, using winter data that had been collected previously (Rosenthal et al 1990). The ANOVA performed on patients and normal controls, during winter and summer, revealed a significant time by season interaction ( F = 2.13; df¢~) = 287,10619; p --< 0.05). In other words, both seasons had the same effect on patients and controls over the 24-hr period, both groups showing significantly lower overall temperatures in summer compared with winter (Figures 2a and b). There was also a significant difference between patient temperature on-lights during winter versus off-lights during the summer (F = 2.92; dff, ll) = 287,5166; p -- 0.01) (Figure 3). In order to determine whether the significant differences found between the seasons across groups were due to amplitude changes or overall profile changes, we compared amplitudes using unpaired t-tests. Amplitudes between subjects across seasons did not differ significantly (patients: t = 0.25, df = 17, p = 0.8; normal controls: t = 0.36, df = 19, p = 0.74). However, there was a trend toward an increase in amplitude during the winter for patients on-lights compared with patients in the summer (amp in summer = 1.17°C; amp in winter on-lights = 1.35°C; t = 1.59, df = 17, p = 0.1).
Core Temperaturein SAD Patients
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38
37.8
SLEEP-TIME
37.6 37.4
tu r;-
~ 37.2 < m 37 IL
~ 36.8 36.6 36.4
36.2
i
t
~
SUMMER(N=g)
36
7:00pro
11:00pm
7:00am
(a)
7:0~m
TIME 38
37.8
SLEEP-rIME
37.6 37.4 ~" 37.2
36.8
36.6 m
36.4
SUMMERIN=9)
36.2 36 7:00pm (b)
..... ii
11:0~] )m
7:00am
7:00pm
TIME
Figure 2. (a) Mean 24-hr core body temperature of patients during the summer and the winter. (b) Mc~m 24-hr core body temperature of normal controls during the summer and the winter.
When we examined the timing of the minima across seasons, we foaad that there was no significant diffc~rence across seasons, although a trend i0r !atcr minima m the summer was seen in both groups. There was a significant difference between the patients during the summer (5:15 AM +_ 2 hr) compared with patients on-lights during the winter (2:50 AM + 2.5 hr) (t -- 2.06, df = 17: p ~ 0.05).
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BIOL PSYCHIATRY 1991;29:524-534
s. i 37.8 ]
SLEEP-TIME i
37.6 ! 37.4 ] IJJ
37.2
37 !--
36.8 36.6
=:,7o
36.4
'
36.2 36 7:00 3111
11 :COpra
7: am
7:001~m
TIME
Figure 3. ~de~,a24-hr core body temperature of patients during the summer and patients on-lights during the winter.
Discussion
We hypothesized that We effects of summer on temperature profiles in patients with SAD would be similar to the effects of bright light treatment. Based on the results of our earlier winter study, we thus predicted that the nocturnal temperature of SAD patients in summer would be lowerwand the circadian temperature amplitudes higher--than the corresponding measures in control subjects and m untreated SAD patients in winter. If enhanced amplitude was responsible for the antidepressant effects of light treatment in the winter study, we argued, then a similar amplitude enhancement should be present in the temperature profiles of SAD patients measured during the summer when they are euthymic. In interpreting the results of this study, some caution must be taken because of the smali sample sizes. Nevertheless, the results are interesting because it is the ~ t study comparing the effects of light treatment in winter versus summer on the circadian temperature rhythms on SAD patients. We did not find a significant difference between the temperature of SAD patients and normal controls measured during the summer, nor was there any enhancement of amplitude of circadian rhythms across the seasons in either group. Instead, we found significantly lower overall temperatures for both patients and controls during the summer as compared with winter. Thus, the effects of light treatment and of summer on temperature profiles in patients with SAD were different, even though both environmental changes result in an improvement of mood. Summer caused lowering of the entire temperature profile, whereas light treatment lowered only nocturnal temperature, thus enhancing circadian amplitude. In a similar fashion, light treatment and summer appeared to have opposite effects on the timing of circadian rhythms in patients with SAD, as determined by comparing the temperature minima across seasons and treatment conditions. The temperature minima
Core Temperature in SAD Patients
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was delayed in both patients and controls in summer compared with winter. Thus, if phase advancing circadian rhythms is instrumental in inducing tl'~ antidepressant effects of bright light, as Lewy et al (1987) have suggested, then one would have to postulate a different mechanism for the antidepressant effects of summer and fight treatment. The nature of phase shifts across seasons in normal individuals varies according to the particular biological variable being measured. In some cases, such as plasma melatonin (which is unaffected by masking except for bright light) and cortisol profiles, the circadian rhythms are advanced in the summer (lllnerova et al 1985; Kennaway and Royles 1986) whereas the rhythms of other plasma hormones, such as growth hormone and prolactin, have not been shown to change phase across se,~sons (Weitzman et al 1975; Van Cauter et al 1981). Studies of core body temperature ~havefound results consistent with ours, namely, that the rhythm of core body temperature is delayed in summer by 1 or 2 hr ~ o m e and Coyne 1975; Mamta et ,_.1 1986). Regarding our findings of phase and amplitude of the temperature rhythm, the biological changes in the summer compared with the winter should be in the same direction and of equal or greater magnitude than the corresponding effect after light treatment during the winter, because patients are usually less depressed (and often euthymic) in summer than when treated during winter. As this was not the case for the results of either amplitude or phase, we should question our current understz-,ding of the mechanism of light therapy. It is possible that the enforced sleep-wake schedule may have masked the true circadian temperature rhythm; the masking may create an artifact in amplitude and/or phase fWever 1985). A constant routine study might circumvent this problem. The results of this study must be interpreted in light of the possibility that the masked temperature minima may not be sufficiently sensitive to detect group phase differences. Insofar as many influences on body temperature were held constant across our winter and summer studies of core body temperature in SAD, notably the timing of sleep, mealtimes, and activities, it seems unlikely that these factors would account for the timing or amplitude differences observed. Two experimental variables that might have contributed to the seasonal effect on temperature in both patients and controls are changes in indoor temperature and relative humidity across seasons. The NIMH Clinical Center, where the studies took place, is air-conditioned in summer and heated in winter. Unfortunately, we do not have any data on indoor temperature or relative humidity in this building across seasons. Nevertheless, some other studies of temperature across seasons have found results similar to ours, namely, overall lowering of temperature (Home and Coyre 1975) and phase delay (Home and Coyne 1975; Maruta et al 1986) in summer, which would suggest that the present findings are not an artifact of ambient temperature under the experimental conditions. The lowest temperatures under any condition occurred in patients at night while they were on light treatment in the winter, when the building is heated and when overall temperature profiles are higher in both normals and untreated patients. This would further argue against ~he temperature profiles being simply an artifact of changes in ambient temperature. Future studies, however. ~hould control for---or at least measuremambient temperature and relative humidity. It is also possible that the natural conditions of summer could cause the lowering of the core body temperature profile in all subjects. Summer, unlike phototherapy, is accompanied not only by increased light but also by increased temperature. Increased ambient temperature may have a different effect on core body temperature than changes in the amount of light. Perhaps the lower body temperature in the summer is a reaction to the hotter ambient temperatures. Indeed, studies of long-term heat adaptation have
532
B!OL PSYCHIATRY 1991;29:524-534
A.A. Levendosky et al
shown that core body tempera~'ure lowers over time exposed to heat (Bass et al 1955; Shvartz et al 1977; Horstman and Christensen 1982). Arbisi et al (1989) found that untreated SAD patients had slower recovery to normal resting temperature after an exercise challenge test. Recovery time was restored to normal levels after successful light treatment and during the summer. Based on these results, these researchers suggested that there is an abnormality in thermoregulation in SAD patients in winter which is corrected by both light treatment and summer. Although we found that SAD patients have normal temperatures at all times of the year, this does not exclude the possibility of abnormalities in the thermoregulatory system. In fact, we have some preliminary results on other biological factors in the thermoregulatory system which may support the hypothesis of energy dysregulation in SAD. In SAD patients during the winter, we found normal TSH levels which were significantly reduced to below normal levels by successful light therapy (Levendosky et al, unpublished data), similar to our core body temperature findings. Our resting metabolic rate (RMR) study, on the other hand, revealed abnormally high RMR values in SAD patients during the off-lights condition, which were normalized on light treatment (Gaist et al, unpublished data). These studies, analyzed together, perhaps indicate an imbalance of the thermoregulatory system. Further studies on thyroid-stimulating hormone secretion and BlVlR of SAD patients in the summer are needed to make these findings clear.
Conclusion Our initial use of light therapy was inspired to some degree by the observation that patients recovered in summer and light levels are highest in summer. In this study, however, we found that the effects of summer and bright light treatment on body temperature profiles are different. Although our study is limited by a small sample size and the possibility of masking effects, the results s ~ raise questions about the validity of two current theories of mechanism of light therapy: (1) that it is mediated by changing circadian phase in a specific way (Lewy et al 1987); and (2) that it acts by enhancing circadian amplitude (Czeisler et al 1987). On the basis of the present study, one must conclude that either light and summer are acting in different ways to produce recovery in SAD patients, or else that effects on amplitude and timing of temperature rhythms do not reflect the common mechanism of action of phototherapy and change of season. In summer, there is also a rise in ambient temperature, which could perhaps account for the difference in the effects of phototherapy and summer on core body temperature. Though the role of body temperature in the pathogenesis of SAD and the mechanism of action of light treatment remains obscure, there is considerable evidence that therrnoregulation is altered across seasons in SAD patients compared with normals and by effective light treatment. For these reasons, it appears to be a highly worthwhile direction for further study.
References Arbisi PA, Depue RA, Spoont MR, Leon A, Ainsworth B (1989): Thermoregulatory response to thermal challenge in seasonal affective disorder: A preliminary report. Psychiatry Res 28:323334. Avery DH, Wildschiodtz G, Rafaelsen OJ (1982): Nocturnal temperature in affective disorder. J Affective Disord 4:61-71.
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Avery DH, Wildschiodtz G, Smallwood RG, Martin D, Rafaelsen OJ (1986): REM latency core temperature relationships in primary depression. Acta Psychiatr Scand 74:269-280. Avery D, Dahl K, Savage M, et al (1989): The temperature rhythm is phase~layed in winter depression (Abstract). Biol Psychiatry (Suppl) 27(9A): 129. Bass DE, Kleeman CR, Quinn M, Henschel A, Hegnauer All (1955): Mechanisms of acclimatization to heat in man. Medicine 34:323-380. Czeisler CA, Allan JS, Kronauer RE (1987): Rapid manipulation of phase and amplitude of human circadian pacemaker with light-dark cycles (Abstract). 5th Int Congr Sleep Res, Copenhagen, p 51 I. Daan S, Aschoff J (1975): Circadian rhythms of locomotor activity in captive birds and mammals: Their variations with season and latitude. Oecologia 18:269-316. Depue RA (1989): Effects of light on the biology of seasonal affective disorder (Abstract). ~ u a l Meeting of the Socie~~for Light Treatment and Biological Rhythms, NIH, Bethesda, Maryland, June 21, 1989. Greenhouse SW, Geisser S (1959): On methods in the analysis of profile data. Psychometrika 25:127-152. Gwinner E (1975): Effects of season and external testosterone on the freerunning circadian activity rhythm of European starlings. Y Comp Physiol 103:315-328. Hamilton M (1967): Development of a rating scale for primary depressive illn¢,=. Br Y Soc Clin Psychol 6:278-296. Home JA, Coyne I (1975): Seasonal changes in the circadian variation of temperature during wakefulness. Experientia 31(11): 1296-1298. Horstman DH, Christensen E (1982): Acclimatization to dry heat: Active men versus active women. Y Appl Physiol 52:825-831. mnerova H, Zvolsky P, Vanecek J (1985): The circadian rhythm in plasma melatonin concentration f the urbanized man: The effect of winter and summer. Brain Res 328:186-189. Kennaway DJ, Royles P (1986): Circadian rhythms of 6-sulphtoxy melatonin, cortisol and electrolyte excretion at summer and winter solstices in normal men and women. Acta Endocrinol 113:450456. Kronauer RE (1987): A model for the effect of light on the human "deep" circadian pacemaker. Sleep Res 16:621. Lacoste V, Wirz-Justice A (1989): Seasonal variation in normal subjects: An update of variables current in depression research. In Rosenthal hE, Blehar MC (eds), Seasonal Affective Disorders and Phototherapy. New York: Guildford Press, pp 167-229. Lewy AJ, Sack RL, Singer CM (1984): Assessment and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: The clock-gate model and the phase response curve. Psychopharmacol Bull 20:561-565. Lewy AJ, Sack RL, Singer CM, White DM (1987): The phase shift hypothesis for bright fight's therapeutic mechanism: Theoretica~ considerations and experimental evidence. P~chopharmacol Bull 23(3):349-353. Mamta N, Natsume K, Tokura H, Kawakami K, Isoda N (1986): Seasonality of circadian rhythm patterns in human rectal temperature rhythm under semi-natural conditions. Experientia 43:294-296. Rosenthal NE, Sack DA, Gillin JC, et al (1984): Seasonal affective disorder: A description of the syndrome and pre!im~--m,-yfindings with light therapy. Arch Gen Psychiatry 41:72-80. Rosenthal NE, Levendosky AA, Skwerer RG, et al (1990) Effects of light treatment on core ~cl)' temperature in seasonal affective disorder. Biol Psychiatry 27:39-50. Shvartz E, Shapiro Y, Magazanik A, et al (1977): Heat acclimation, physical fitness, and response to exercise in temperate and hot environments. J Appl Physiol 43:678-683. Smallwood RG, Avery DI-I, Pascualy RA, prinz PN (1983): Circadian temperature rhythms in primary depression. Sleep Res 12:215. Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G (1988): Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 145:1133-1137.
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Spitzer RL, Williams JBW, Gibbon M (1987): Structured Clinical Imer,iew for :he DSM-lil-RPatient Version. Biome~cs Research Department, New York State Psychiatric Institute, New York. Van Cauter E, L'Hermite M, Copinschi G, Refetoff S, Desir D, Robyn C (1981): Quantitative analysis of spontaneous variations of plasma prolactin in normal man. Am J Physiol 241:355363. Wehr TA, Sack DA, Rosenthal NE, Duncan WD, Gillin JC (1983): Circadian rhythm disturbances in manic-depressive illness. Fed Proc 42:2809-2814. Weitzman ED, de Graaf AS, Sassin JF, et al (t975): Seasonal patterns of sleep stages and secretion of cortisol, and growth hormone during 24 hour periods in Northern Norway. Acta Endocrinol 78:65-:6. Wever RA (1985): Internal interactions within the human circadian system: The masking effect. Experientia 41:332-342.
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Core Body Temperature in Patients with Seasonal Affective Disorder and Normal Controls in Summer and Winter Alytia A. Leven.dosky, Jean R. Joseph-Vanderpool, Todd Hardin, Elizabeth Sorek, and Norman E. Rosenthal
The rationale for phototherapy in seasonal affective disorder (SAD) was originally based on the notion that SAD patients were light deprived during the wintertime and needed more light. We previously found normal temperature profiles of untreated SAD patients during the winter, and that phototherapy significantly enhanced the amplitude of the circadian temperature profile in SAD patients during the winter (Rosenthal et al 1990). We hypothesized that summer would act similarly on the temperature rhythm of these patients. In this study we examined the temperature data from SAD patients and r,ormal controls during the summer and compared it to the results of our previous study. We found identical profiles for SAD patients and normal controls during the summer and that summer significantly lowered the overall temperature profiles of both groups and did not alter the amplitudes. These results raise questions about the validity of the current theories of the mechanism of light therapy.
Introduction Seasonal affective disorder (SAD) has been hypothesized to be caused by an abnormality in the circadian pacemaker, either in its timing (Lewy et al 1987) or its amplitude (Czeisler et al 1987). Lewy hypothesized that winter depressives have abnormally delayed circadian rnyt_hms (Lewy e~ al 1984). Since then, several studies have found supporting evidence for the phase-delay hypothesis of SAD (Lewy et al 1987; Avery et al 1989; Depue 1989). Information about the behavior of the circadian pacemaker can be inferred from measurements of various circadian rhythms, of which core body temperature is one of the most frequently studied. A newer theory, with as yet less data to support it, is the hypothesis of reduced circadian mnplitude in SAD patients which has been suggested by Kronauer (1987) and Czeisler et al (1987). Information about the timing and amplitude of the oscillation of the circadian pacemaker can be inferred from corresponding features of the circadian temperature rhythm.
From the Clinical Psychobiology Branch, NIMH (AAL, ~RJ-V, TH, NER), and the Clinical Center Nursing Department, Nil-', (ES), Bethesda, MD. Address reprint requests to Alytia A. Levendosky, Clinical Psychobiology Branch, Bldg. 10/4S-239, 9000 Rockville Pike, Bethesda, MD 20892. Received June 2.', 1990; revised August 29, 1990. © 1991 Society of Biological Psychiatry
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Several investigators have found abnormally high nocturnal temperatures and consequently reduced amplitudes of circadian rhythms in depressed patients. Such temperature abnormalities have been thought to reflect disturbed re.gulation of energy balance in depressed patients (Souetre et al 1988). Energy metabolism dysregulation has also been postulated to exist in SAD (Rosenthal et al 1990; Arhisi et al 1989; Gaist et al, u n p u b l i s ~ data). Some investigators have hypothesized that an increase in amplitude of circadian rhythms is responsible for the antidepressant effects of medication and bright light because amplitude has been found to increase to normal levels when depressed patients become euthymic (Smallwood et al 1983; Avery et al 1982, 1986; Czeisler et al 1987; Souetre et al 1988). Other investigators have found that the timing of circadian phase is altered in depression. Wehr et al (1983) found that some depressed patients have advanced circadian rhythms which return to a ncrmal phase position during remission. Lev,T et al (19.87) have observed phase-delayed circadian rhythms in most SAD patients and suggest that the correction of this delay is responsible for the antidepressant effect of bright light treatment in the morning. Seasonal variation in phase and amplitude of circadian rhythms of core body temperature, plasma hormones, activity cycles, and sleep length have been documented in animals (Daan and Aschoff 1975). Some of these variations seem to be influenced directly by changes in environmental variables, such as ambient temperature and light (Gwirmer 1975). Several researchers have also documented seasonal variations in human physiology, for example, in core body temperature, sleep, thyroid hormones, and basal metabolic rate (as reviewed by Lacoste and Wirz-Justice 1989). In contrast to reports on nonseasonal depressives, we have previously found that the temperature profiles of 10 depressed SAD patients, measured during the winter, were not different from those of normal controls (Rosenthal et al !990). Nonetheless, effective treatment with bright (2500 lux) light in both morning and evening enhanced the amplitude of the circadian rhythms in patients significantly beyond normal levels. Thus, paradoxically, the profiles of the depressed patients were normal and those of the treated patients were abnormal. In an attempt to understand this paradox, we have followed up our previous study by comparing the circadian temperature profiles of remitted SAD patients and matched normal controls during the summer months with those obtained in our earlier winter study. This comparison is the basis of the present repo_rt.
Methods This study was conducted during the summer, when SAD patients are generally euthymic. In order to be lh,.l':2:a in this study, all patients were required to (1) meet lifetime criteria for SAD (Rosenthal et al 1984); (2) be euthymic, as reflected by a score of less than 10 on the 21-item Hamilton Depression Rating Scale (HDRS) (Hamilton 1967); and (3) be drug free for at least 1 month prior to admission. The normal controls were recruited through an .advertisement in the Washington Post. They were screened and evaluated by means of the Structured Clinical Inte~iew for DSM-III-R diagnoses (SCK-~-R) (Spitzer et al 1987), and those with personal or family histories (first-degree relatives only) of psychiatric illness or any significant tiiextical illness were excluded. All subjects were studied on the inpatient research unit in the Intramural program of
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Table 1. Demographic Summary of Subjects in the Summer Study HDRS Score
Patient
Gender
Age
Typical
1 2 3 4
I: F M F M F M F F
36 51 45 35 31 42 38 45 44
5 .5 3 0 3 2 8 7 0
6 7 8 9
Atypical 4 4 0 0 0 2 0 ! 0
High-SAD 0 0 0 ! ! 3 7 0 10
HDRS Score
Control 1 2 3 4 5 6 7 8 9
Gender F F M F M F M F F
Age 38 51 44 34 27 41 44 26 22
Typical 0 2 5 0 0 0 0 ! 0
Atypical O 2 4 O 0 0 0 0 1
High-SAD 0 1 1 0 0 2 0 0 0
Timing of temperatureminima 07:30 07:!5 03:50 03:55 04:!5 06:15 03:20 04:00 06:15 Mean = 05:15 SD = 02:00
Timing of temperatn_re mini_m_~ 03:30 05:10 02:50 07:25 04:45 02:45 04:05 00:05 01:25 Mean = 03:30 2D = 02:10
the NIMH. The subjects were admitted to the hospital at 5 PM and stayed for 26 hr. The HDRS was administered when the patient arrived in the hospital, before temperature monitoring began. The temperature recording began at 7 PM on the first evening and was continued until 7 PM the next evening. Core body temperature was measured via an indwelling rectal thermistor probe by a portable recording device (Vitalog) which sampled temperature at 5-min intervals, data were stored in solid-state memory and retrieved after the study. The sleep schedule of the subjects was set at 11 PM to 7 AM. For the week prior to the study, the patients were requested to maintain their own regular sleep-wake schedule. During the day, all subjects remained on the inpatient unit and engaged in normal sedentary activities. Beyond that, we did not specifically control their activity. The population (Table 1) consisted of 9 patients (6 women, 3 men, aged 31-51) and 9 normal controls (6 women, 3 men, aged 22-51). We attempted to control for phase of menstrual cycle by studying a balanced number of female patients and normal controls in the luteal and the follicular phases. Two women in each group were run through the study during the luteal phase and two in each group during the follicular phase. In addition, two women in each group were postmenopausal. Data from this summer study of SAD patients were analyzed by means of a repeated measure analysis of variance (ANOVA), with one repeated factor (time) and one grouping factor (patient versus normal con~ol). The degrees of freedom were
Core Temperature in SAD Patients
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Table 2. Demographic Summary of Subjects in the Winter Study (Rosenthal et al. 1990) Timing of tcmpcratm~ minima
HDRS Score Patient
Gender
Age
Off-Lights
On-Lights
2 2 3 4 5 ~. 7' 8 9 10
M M F F F F M M F M
45 35 36 53 56 21 52 28 37 54
23 28 ~6 26 25 20 13 Il 23 20
8 23 2 1 5 8 7 6 9 12
Control
Gender
Age
2 2 3 4 5 6 7 8 9 20 22 22
M M M F F F M M F M F F
40 37 30 48 49 27 52 28 43 56 29 45
Off-Lights 05.'¢5 00:55 05:40 23:25 04:05 06:40 03:20 05:00 04:00 00:30 Mean = 03:30 SD = 02:30
On-Liglats 05:15 02:25 02:35 00:10 00:20 O! :40 02 : ~ 04:25 06:25 04:20 02:50
02:10
Timing of temperature 01:05 O1.35 00:45 23:35 03:40 06:05 01:55 02:50 03:20 04:15 02:10 06:25 Mean = 02:45 SD = 02:00
modified according to Greenhouse and Geisser (1959). The timing of minima was identified by visual inspection by a rater blind to the subject's diagnosis and treatmen: states, and these values were compared by means of group t-tests. Wqaen there were two or more clear minima, the times of the minima were averaged and the resulting mean was used for analysis. Similar analyses were performed on temperature amplitudes (peak to trough) and means of 24-hr temperature values. The data were also compared with the results of the winter SAD study of 1985-88 (Rosenthal et al 1990) in a repeated measures ANOVA with one repeated factor (time) and two grouping factors (season: winter or summerwseason was not regarded as a repeated measure as different subjects were studied in summer and winter; and subject type: patient or normal control). The temperature data of patients on light treatment in winter were compared with summer patient data by means of a repeated mc~ures ANOVA (two repeated factors: time, season). Unpaired t-tests were performed on amplitude ~ d timing of minima for patients and controls across seasons. Table 2 summarizes the demographic data of the patients and controls from the winter study.
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BIOLPSYCHIATRY 1991;29:524-534 38
S,.EB=,:nUE
37.8 37.6 37.4 37.2
~
Lg n ~ uJ 36.8 36.6 ,-,-- NORMAL CONTROLS (N=9)
3e.4
---.. PATIENTS (N=9)
36.2 36
7:00pro
11 :OOpm
7:00am
7:0()pm
TIME
Figure I. Mean core body temperature of patients and normal controls during the summer months. Core body temperature was measured every 5 rain using a Vitalog temperature monitor and a zectal thermistor, over a 24-hr period.
Results There was no statistically significant difference between summer temperature profiles of SAD patients and ',hose of normal controls (F = 0.02; df = 1, 16; p = 0.9) (see Figure 1). Although nocturnal temperature was slightly lower in patients than in normal controls, this was also not statistically significant ( F = 0.3; df = 1,16; p = 0.59). Neither were ,*,hetiming of the minima nor the amplitude values significantly different between the two groups (timing: t = 1.27; df = 16; p = 0.22; amplitude: t = 0.01; df = 16; p = 0.99). We compared winter and summer temperature profiles of SAD patients and normal controls, using winter data that had been collected previously (Rosenthal et al 1990). The ANOVA performed on patients and normal controls, during winter and summer, revealed a significant time by season interaction ( F = 2.13; df¢~) = 287,10619; p --< 0.05). In other words, both seasons had the same effect on patients and controls over the 24-hr period, both groups showing significantly lower overall temperatures in summer compared with winter (Figures 2a and b). There was also a significant difference between patient temperature on-lights during winter versus off-lights during the summer (F = 2.92; dff, ll) = 287,5166; p -- 0.01) (Figure 3). In order to determine whether the significant differences found between the seasons across groups were due to amplitude changes or overall profile changes, we compared amplitudes using unpaired t-tests. Amplitudes between subjects across seasons did not differ significantly (patients: t = 0.25, df = 17, p = 0.8; normal controls: t = 0.36, df = 19, p = 0.74). However, there was a trend toward an increase in amplitude during the winter for patients on-lights compared with patients in the summer (amp in summer = 1.17°C; amp in winter on-lights = 1.35°C; t = 1.59, df = 17, p = 0.1).
Core Temperaturein SAD Patients
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38
37.8
SLEEP-TIME
37.6 37.4
tu r;-
~ 37.2 < m 37 IL
~ 36.8 36.6 36.4
36.2
i
t
~
SUMMER(N=g)
36
7:00pro
11:00pm
7:00am
(a)
7:0~m
TIME 38
37.8
SLEEP-rIME
37.6 37.4 ~" 37.2
36.8
36.6 m
36.4
SUMMERIN=9)
36.2 36 7:00pm (b)
..... ii
11:0~] )m
7:00am
7:00pm
TIME
Figure 2. (a) Mean 24-hr core body temperature of patients during the summer and the winter. (b) Mc~m 24-hr core body temperature of normal controls during the summer and the winter.
When we examined the timing of the minima across seasons, we foaad that there was no significant diffc~rence across seasons, although a trend i0r !atcr minima m the summer was seen in both groups. There was a significant difference between the patients during the summer (5:15 AM +_ 2 hr) compared with patients on-lights during the winter (2:50 AM + 2.5 hr) (t -- 2.06, df = 17: p ~ 0.05).
530
A.A. Levendosky et al
BIOL PSYCHIATRY 1991;29:524-534
s. i 37.8 ]
SLEEP-TIME i
37.6 ! 37.4 ] IJJ
37.2
37 !--
36.8 36.6
=:,7o
36.4
'
36.2 36 7:00 3111
11 :COpra
7: am
7:001~m
TIME
Figure 3. ~de~,a24-hr core body temperature of patients during the summer and patients on-lights during the winter.
Discussion
We hypothesized that We effects of summer on temperature profiles in patients with SAD would be similar to the effects of bright light treatment. Based on the results of our earlier winter study, we thus predicted that the nocturnal temperature of SAD patients in summer would be lowerwand the circadian temperature amplitudes higher--than the corresponding measures in control subjects and m untreated SAD patients in winter. If enhanced amplitude was responsible for the antidepressant effects of light treatment in the winter study, we argued, then a similar amplitude enhancement should be present in the temperature profiles of SAD patients measured during the summer when they are euthymic. In interpreting the results of this study, some caution must be taken because of the smali sample sizes. Nevertheless, the results are interesting because it is the ~ t study comparing the effects of light treatment in winter versus summer on the circadian temperature rhythms on SAD patients. We did not find a significant difference between the temperature of SAD patients and normal controls measured during the summer, nor was there any enhancement of amplitude of circadian rhythms across the seasons in either group. Instead, we found significantly lower overall temperatures for both patients and controls during the summer as compared with winter. Thus, the effects of light treatment and of summer on temperature profiles in patients with SAD were different, even though both environmental changes result in an improvement of mood. Summer caused lowering of the entire temperature profile, whereas light treatment lowered only nocturnal temperature, thus enhancing circadian amplitude. In a similar fashion, light treatment and summer appeared to have opposite effects on the timing of circadian rhythms in patients with SAD, as determined by comparing the temperature minima across seasons and treatment conditions. The temperature minima
Core Temperature in SAD Patients
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was delayed in both patients and controls in summer compared with winter. Thus, if phase advancing circadian rhythms is instrumental in inducing tl'~ antidepressant effects of bright light, as Lewy et al (1987) have suggested, then one would have to postulate a different mechanism for the antidepressant effects of summer and fight treatment. The nature of phase shifts across seasons in normal individuals varies according to the particular biological variable being measured. In some cases, such as plasma melatonin (which is unaffected by masking except for bright light) and cortisol profiles, the circadian rhythms are advanced in the summer (lllnerova et al 1985; Kennaway and Royles 1986) whereas the rhythms of other plasma hormones, such as growth hormone and prolactin, have not been shown to change phase across se,~sons (Weitzman et al 1975; Van Cauter et al 1981). Studies of core body temperature ~havefound results consistent with ours, namely, that the rhythm of core body temperature is delayed in summer by 1 or 2 hr ~ o m e and Coyne 1975; Mamta et ,_.1 1986). Regarding our findings of phase and amplitude of the temperature rhythm, the biological changes in the summer compared with the winter should be in the same direction and of equal or greater magnitude than the corresponding effect after light treatment during the winter, because patients are usually less depressed (and often euthymic) in summer than when treated during winter. As this was not the case for the results of either amplitude or phase, we should question our current understz-,ding of the mechanism of light therapy. It is possible that the enforced sleep-wake schedule may have masked the true circadian temperature rhythm; the masking may create an artifact in amplitude and/or phase fWever 1985). A constant routine study might circumvent this problem. The results of this study must be interpreted in light of the possibility that the masked temperature minima may not be sufficiently sensitive to detect group phase differences. Insofar as many influences on body temperature were held constant across our winter and summer studies of core body temperature in SAD, notably the timing of sleep, mealtimes, and activities, it seems unlikely that these factors would account for the timing or amplitude differences observed. Two experimental variables that might have contributed to the seasonal effect on temperature in both patients and controls are changes in indoor temperature and relative humidity across seasons. The NIMH Clinical Center, where the studies took place, is air-conditioned in summer and heated in winter. Unfortunately, we do not have any data on indoor temperature or relative humidity in this building across seasons. Nevertheless, some other studies of temperature across seasons have found results similar to ours, namely, overall lowering of temperature (Home and Coyre 1975) and phase delay (Home and Coyne 1975; Maruta et al 1986) in summer, which would suggest that the present findings are not an artifact of ambient temperature under the experimental conditions. The lowest temperatures under any condition occurred in patients at night while they were on light treatment in the winter, when the building is heated and when overall temperature profiles are higher in both normals and untreated patients. This would further argue against ~he temperature profiles being simply an artifact of changes in ambient temperature. Future studies, however. ~hould control for---or at least measuremambient temperature and relative humidity. It is also possible that the natural conditions of summer could cause the lowering of the core body temperature profile in all subjects. Summer, unlike phototherapy, is accompanied not only by increased light but also by increased temperature. Increased ambient temperature may have a different effect on core body temperature than changes in the amount of light. Perhaps the lower body temperature in the summer is a reaction to the hotter ambient temperatures. Indeed, studies of long-term heat adaptation have
532
B!OL PSYCHIATRY 1991;29:524-534
A.A. Levendosky et al
shown that core body tempera~'ure lowers over time exposed to heat (Bass et al 1955; Shvartz et al 1977; Horstman and Christensen 1982). Arbisi et al (1989) found that untreated SAD patients had slower recovery to normal resting temperature after an exercise challenge test. Recovery time was restored to normal levels after successful light treatment and during the summer. Based on these results, these researchers suggested that there is an abnormality in thermoregulation in SAD patients in winter which is corrected by both light treatment and summer. Although we found that SAD patients have normal temperatures at all times of the year, this does not exclude the possibility of abnormalities in the thermoregulatory system. In fact, we have some preliminary results on other biological factors in the thermoregulatory system which may support the hypothesis of energy dysregulation in SAD. In SAD patients during the winter, we found normal TSH levels which were significantly reduced to below normal levels by successful light therapy (Levendosky et al, unpublished data), similar to our core body temperature findings. Our resting metabolic rate (RMR) study, on the other hand, revealed abnormally high RMR values in SAD patients during the off-lights condition, which were normalized on light treatment (Gaist et al, unpublished data). These studies, analyzed together, perhaps indicate an imbalance of the thermoregulatory system. Further studies on thyroid-stimulating hormone secretion and BlVlR of SAD patients in the summer are needed to make these findings clear.
Conclusion Our initial use of light therapy was inspired to some degree by the observation that patients recovered in summer and light levels are highest in summer. In this study, however, we found that the effects of summer and bright light treatment on body temperature profiles are different. Although our study is limited by a small sample size and the possibility of masking effects, the results s ~ raise questions about the validity of two current theories of mechanism of light therapy: (1) that it is mediated by changing circadian phase in a specific way (Lewy et al 1987); and (2) that it acts by enhancing circadian amplitude (Czeisler et al 1987). On the basis of the present study, one must conclude that either light and summer are acting in different ways to produce recovery in SAD patients, or else that effects on amplitude and timing of temperature rhythms do not reflect the common mechanism of action of phototherapy and change of season. In summer, there is also a rise in ambient temperature, which could perhaps account for the difference in the effects of phototherapy and summer on core body temperature. Though the role of body temperature in the pathogenesis of SAD and the mechanism of action of light treatment remains obscure, there is considerable evidence that therrnoregulation is altered across seasons in SAD patients compared with normals and by effective light treatment. For these reasons, it appears to be a highly worthwhile direction for further study.
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Avery DH, Wildschiodtz G, Smallwood RG, Martin D, Rafaelsen OJ (1986): REM latency core temperature relationships in primary depression. Acta Psychiatr Scand 74:269-280. Avery D, Dahl K, Savage M, et al (1989): The temperature rhythm is phase~layed in winter depression (Abstract). Biol Psychiatry (Suppl) 27(9A): 129. Bass DE, Kleeman CR, Quinn M, Henschel A, Hegnauer All (1955): Mechanisms of acclimatization to heat in man. Medicine 34:323-380. Czeisler CA, Allan JS, Kronauer RE (1987): Rapid manipulation of phase and amplitude of human circadian pacemaker with light-dark cycles (Abstract). 5th Int Congr Sleep Res, Copenhagen, p 51 I. Daan S, Aschoff J (1975): Circadian rhythms of locomotor activity in captive birds and mammals: Their variations with season and latitude. Oecologia 18:269-316. Depue RA (1989): Effects of light on the biology of seasonal affective disorder (Abstract). ~ u a l Meeting of the Socie~~for Light Treatment and Biological Rhythms, NIH, Bethesda, Maryland, June 21, 1989. Greenhouse SW, Geisser S (1959): On methods in the analysis of profile data. Psychometrika 25:127-152. Gwinner E (1975): Effects of season and external testosterone on the freerunning circadian activity rhythm of European starlings. Y Comp Physiol 103:315-328. Hamilton M (1967): Development of a rating scale for primary depressive illn¢,=. Br Y Soc Clin Psychol 6:278-296. Home JA, Coyne I (1975): Seasonal changes in the circadian variation of temperature during wakefulness. Experientia 31(11): 1296-1298. Horstman DH, Christensen E (1982): Acclimatization to dry heat: Active men versus active women. Y Appl Physiol 52:825-831. mnerova H, Zvolsky P, Vanecek J (1985): The circadian rhythm in plasma melatonin concentration f the urbanized man: The effect of winter and summer. Brain Res 328:186-189. Kennaway DJ, Royles P (1986): Circadian rhythms of 6-sulphtoxy melatonin, cortisol and electrolyte excretion at summer and winter solstices in normal men and women. Acta Endocrinol 113:450456. Kronauer RE (1987): A model for the effect of light on the human "deep" circadian pacemaker. Sleep Res 16:621. Lacoste V, Wirz-Justice A (1989): Seasonal variation in normal subjects: An update of variables current in depression research. In Rosenthal hE, Blehar MC (eds), Seasonal Affective Disorders and Phototherapy. New York: Guildford Press, pp 167-229. Lewy AJ, Sack RL, Singer CM (1984): Assessment and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: The clock-gate model and the phase response curve. Psychopharmacol Bull 20:561-565. Lewy AJ, Sack RL, Singer CM, White DM (1987): The phase shift hypothesis for bright fight's therapeutic mechanism: Theoretica~ considerations and experimental evidence. P~chopharmacol Bull 23(3):349-353. Mamta N, Natsume K, Tokura H, Kawakami K, Isoda N (1986): Seasonality of circadian rhythm patterns in human rectal temperature rhythm under semi-natural conditions. Experientia 43:294-296. Rosenthal NE, Sack DA, Gillin JC, et al (1984): Seasonal affective disorder: A description of the syndrome and pre!im~--m,-yfindings with light therapy. Arch Gen Psychiatry 41:72-80. Rosenthal NE, Levendosky AA, Skwerer RG, et al (1990) Effects of light treatment on core ~cl)' temperature in seasonal affective disorder. Biol Psychiatry 27:39-50. Shvartz E, Shapiro Y, Magazanik A, et al (1977): Heat acclimation, physical fitness, and response to exercise in temperate and hot environments. J Appl Physiol 43:678-683. Smallwood RG, Avery DI-I, Pascualy RA, prinz PN (1983): Circadian temperature rhythms in primary depression. Sleep Res 12:215. Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G (1988): Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 145:1133-1137.
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Spitzer RL, Williams JBW, Gibbon M (1987): Structured Clinical Imer,iew for :he DSM-lil-RPatient Version. Biome~cs Research Department, New York State Psychiatric Institute, New York. Van Cauter E, L'Hermite M, Copinschi G, Refetoff S, Desir D, Robyn C (1981): Quantitative analysis of spontaneous variations of plasma prolactin in normal man. Am J Physiol 241:355363. Wehr TA, Sack DA, Rosenthal NE, Duncan WD, Gillin JC (1983): Circadian rhythm disturbances in manic-depressive illness. Fed Proc 42:2809-2814. Weitzman ED, de Graaf AS, Sassin JF, et al (t975): Seasonal patterns of sleep stages and secretion of cortisol, and growth hormone during 24 hour periods in Northern Norway. Acta Endocrinol 78:65-:6. Wever RA (1985): Internal interactions within the human circadian system: The masking effect. Experientia 41:332-342.
