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Effects of light treatment on core body temperature in seasonal affective disorder
BIOl. PSYCHIATRY 1990;2"h~k-50
39
Effects of Light Treatment on Core Body Temperature in Seasonal Affective Disorder Norman E. Rosenthal, Alytia A. Levendosky, Robert G. Skwerer, Jean R. Joseph-Vanderpool, Karen A. Kelly, Todd Hardin, Siegfried Kasper, Peter DellaBella, Thomas A. Wehr
Abnormalities in circcuitan rhyfhms of core body temperature have been reported previously in depressed patients. In this study, we competed the temperature rhythms of 10 depressed seasonal affective disorder (SAD) patients with winter depression with those of 12 normal controls and evaluated the effects of bright light on temperature in SAD. Unlike previous studies of depressed patients, the temperature curves of the patients and normal controls during the off-ligFytcondition were nearly identical. We found a significant difference in amplitude between the patients in the untreated and light-treatea conditions. Although there was no systematic difference in circadian phase across groups or treatment conditions, we present preliminary .,vidence that suggests that phase-typed subgroups may be present in the population distinguished by their treatment responses.
Introduction Abnormalities in the daily rhythm of body temperarare have long been known to be present .~n affective disorders (Clouston 1868). In the past 20 years, extensive studies of this rhythm have been conducted in depressed patients, and the resulting observations have been conceptualized in different ways. First, several studies have suggested that some depressed patients have phase-advanced circadian rhythms, including that of temperature (Htug et al. 1976; Wehr et al. 1983). These studies have shown that the acrophase of the temperature curve occurs earlier in patients when they are depressed than when they are in remission. In contrast to this, Lewy et al. (1987a, 1987b) have reported that some depressed patients with seasonal affective disorder (SAD) have phase-delayed circadian rhythms. These workers have proposed a circadian typology of depression in which certain depressed patients can be separated according to the phase position of their circadian rhythms into phase-advanced and phase-delayed categories. They have further suggested that such a typology might have treatment implications insofar as the former group might benefit i~rom having their rhySams phase-advanced (as occurs wit1" morning light), whereas the latter group might benefit from having their rhythms phase-delayed (as occurs with evening light).
From the Clinical Psychobiology Branch of the National Institutes of Health, Bethesda, MD. Address reprint requests to Norman E. Rosenthal, M.D., Clinical Psychobiology Branch National Institutes of Health, Bldg. 10/4S-239 9000 RockviUe Pike, Bethesda, MD 20892 Received November 17, 1988; revised February 28, 1989. This article is in ~e Public Domain.
0006-3223/90/$00.00
40
BIOL PSYCHIATRY 1990;27:39--50
N.E. Rosenthal et
al.
Another circadian parameter considered to be abnormal in depression is amplituae; some studies have shown that the amplitude of several circadian rhythms, that of temperature included, is abnormally low in depression (Avery et al. 1982, 1986; Souetre et al. in press). The reduction in amplitude is largely a function of increased nocturnal temperatures in depressed patients as compared with recovered patients or normal controls. These different categories can overlap in certain instances. For example, Pttug et al. (1981) described a combination of phase-advance and reduced amplitude of temperature rhythms in 4 bipolar patients. Some researchers have emphasized that there is an inconsistency in the timing of circadian temperature rhythms from night to night and that this, rather than any consistent deviation in timing, is a cardinal abnormality in depressed patients. Thus, Nikitopoulou and Crammer (1976) studied a group of 6 manic depressives and found that although the daily temperature curves were not abnormal in mania, they were very variable from day to day within each subject during depression. Likewise, Pflug et ai. (1981) and Wehr et al. (1982) found that the timing of daily temperature maxima in depression shifts markedly from day to day. The study of body temperature in SAD is of particular interest because seasonal variations in body temperature have been described in animals (Pengelley and Asmundson 1974; Gwinner 1981). In addition, the behavioral abnormalities seen in depression have been compared with the changes in energy balance seen in hibernation and other seasonal rhythms in animals (Lange 1928; Kripke et al. 1978; Rosenthal 1983). The purpose of this study was to investigate the 24-hr profile of core body temperature in patients with seasonal affective disorder, both untreated and treated with bright environmental light, as compared with normal controls during Lhe winter. Bright light (at least 2500 lux) has been established as an effective treatment for SAD (Lewy et al. 1982; Rosenthal et al. 1984, 1985, 1987). We discuss our findings in terms of current circadian theories of how light might exert its antider~ressant effects. Methods In order to be included in this study, all patients were required to (1) meet lifetime criteria for SAD (Rosenthal et al. 1984); (2) score a total of at least 14 on the 21-item Hamilton Depression Rating Scale (HDRS) (Hamilton i967) during the untreated condition of the study (although we recognized that between the time of admission and the time of temperature measurement, the HDRS score could rise or fall to some degree, accounting for those few subjects whose HDR$ total scores fell below 14; see Table 1); (3) be drug free (in most cases) for at least 1 month prior to admission. The few exceptions, such as patients on maintenance thyroid or antipyretic drugs, are noted in Table 1. The normal controls were recruited through an advertisement in the Washington Post. They were sc~ened and evaluated by means of the Structured Clinical Interview for DSM-III-R diagnoses (SCID-R), and those with personal or family histories (first-degree relatives only) of psychiatric illness or any significant medical illness were excluded. The HDRS supplementary questionnaire (Rosenthal and Heffernan 1986), which inquires about several symptoms that specifically trouble patients with SAD (including appetite increase, overeating, carbohydrate craving, weight gain, social withdrawal, hypersonmia, and increased fatigability), was also administered with each Hamilton Rating. Patients were studied under two conditions: treated (on-light) and untreated (off-ligh0o
Light and Core Body Temperature in SAD
BIOL PSYCHIATRY 1990;27:39-50
4I
Table 1. Demographic Features of SAD Patients and Normal Controls Patients
Age
Gender
Drugs
HDRS Off
HDRS On
1 2 3 4 5 6 7 8 9 10
45 35 36 53 56 21 51 28 37 54
M M M F F F M M F M
None None None Synthroid, Nalfon daily Aspirin daily None None None None None
23 28 26 26 15 20 13 11 13 10
8 23 2 ! 5 8 7 6 9 12
Normals
Age
Gender
Drugs
1 2 3 4 5 6 7 8 9 10 l! 12
40 37 30 48 49 27 51 28 43 56 29 45
M M M F F F M M F M F F
RDC Diagnosis Unipolar Bipolar H Bipolar I Bipolar H Bipolar H Bipolar H Bipolar II Bipolar H Bipolar H Bipolar II
None None None None None None Tylenol daily None None None None None
The on-light condition consisted of 5 hr of 2500 lux full-spectrum fluorescent light (Sunbox fixtures; Vim!ire lamps), administered for 2 1/2 hi" between 6:00 and 9:00 AM and 2 1/2 hr between 6"00 and 9:00 PM each day, for at least 9 days prior to the temperature study. The light ~eatment procedure is described in more detail elsewhere (Rosenthal et al. 1985). In the off-light condition, patients stayed in ordinary room light (about 300 lux) between 6:00 and 9:00 AM and 6:00 and 9:00 PM for at least 9 days before the temperature study. The order of m~ two conditions was ~ou,~t~Lb~anceu to prevent an ordering effect. Normal controls were studied only in the off-light condition. All subjects remained on an inpatient research unit in the Intramural program of the NIMH during the temperature study and engaged in ordinary sedentary pursuits. Beyond that, we did not specifically control their activity. The population, as shown in Table 1, consisted of 10 patients (6 men, 4 women, aged 20-65), and 12 normal controls (6 men, 6 women, aged 20--65). Two of the 4 female patients and one of the 6 female controls were post menopausal. All subjects were studied during the winters of 1985 through i988. Their sleep schedules were set at 11:00 P M - 7 : 0 0 AM. Patients were admitted to the hospital after 9 days of treatment with either the on-light or off-light condition. The temperature recording always began on the first evening at 7 PM, and the first 24-hr period of ;emperature recording was used for analysis. On the day of the temperature study, during the on-light condition on the inpatient unit, lights were administered between 7 and 9 AM and 7 and 9 PM (this minor deviation from their normal light schedule permitted standard sleep studies to be performed between 11 PM and 7 AM). Core body temperature was measured %
42
tool PSYCHIATRY
N.E. Rosenthal et al.
1990;27:39-50
via an indwelling rectal thermistor probe by a portable solid-state recording device (Vitalog) which sampled temperature at 5-rain intervals; data were stored in solid-state memory, and retrieved after the study. Because so many variables had to be accommodated in conducting this study--timing of depression, treatment, season of year, and bed availability--we were not able to control for phase of menstrual cycle as well. There were, however, similar menstrual profiles for patients and normals, and for patients on and off lights. Data were analyzed by two analyses of variance (ANOVAs), one with two repeated measures (time and treatment condition) and one grouping factor (order of condition) comparing patients on and off lights, and one with one repeated measure (time) and one grouping factor (patient versus normal) comparing patientz off lights with normals off lights. The same analyses were repeated for sleep-time (11:00 PM-7:00 AM) and waketime (7:00 AM-11:00 PM) temperatures, as some researchers have suggested that the former measurement is a better index of circadian phase (Wever 1985) because the circadian temperature rhythm is "mlmasked" by sleep and not subject to the perturbations of daytime activity. Tb_e ~m.Jng of miv3ma was identified by ~.~sual inspection by a rater blind to the subject's diagnosis and treatment status, and these values were compared in patients on and off treatment by means of paired t-tests and in patients and normal controls off treatment by means of group t-tests. When 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 24hr temperature values. Twenty-four hr cosine functions were fitted by the method of least squares (Brown and Czeisler 1985) to the individual temperature rhythms, and the three parameters of the cosine curves (mesor, amplitude, and acrophase) were computed and compared across populations and conditions.
Results There was a significant antidepressant effect of bright light in the patient population as measured by the HDRS (t = 3.80, df = 9, p ~< 0.01; see Table 1). When all time points were considered, there was a significant difference between circadian temperatm~e profiler, in patients on and off light treatment (F = 4.29; df = i; p ~< 0.05; see Figure ib). There was a significant ordering effect whereby the difference between the on- and offlight conditions was greater in patients who received the on-light condition second than in those who received it first (F = 4.65, df = 1, p ~< 0.G5). This difference was due to lower nocturnal temperature in the off-light condition when this followed the on-light condition. The overall difference between the two conditions was due mostly to a significant lowering of nocturnal temperature (11 PM-7 AM) (F = 6.54; df = 31; p ~< 0.001) rather than to wake-related temperature (7 AM-II PM), which did not differ significantly across conditions (F = 1.10; df = 31; p = 0.33). The mean daily values for patients in the on-light condition were significantly lower than those measured during the off-light condition (paired t value = - 2.37; p ~< 0.05). The peak-to-trough intervals (amplitudes) of patients in the on-light condition were significantly higher than those in the off-light condition (paired t value = - 2 . 1 4 ; p ~< 0.05). There was no significant difference between patients and normals in the off-light condition (F = 0.40; df = 287; p = 1.00; see Figure la). Neither was there a difference between the amplitudes in patients in the off-light condition and normal controls.
39.5 13.58
56 21 45 36 51 28
# Age
2:30 2:33 1 : 5 5 i:45
5:08 1"13
Means SD
4 9 I0 2
Patient
44.75 10.14
53 37 54 35
# Age 0:10 6:25 4:20 2:25 3:20 2:40
23:25 4:00 0:30 0:55 l:15 1:55
F F M M
On
Off
Gender
2:07 1:20
0:45 2:25 3:50 !;30 36.37 0,06
36.42 36.42 36.29 36.36
Change Off
36.25 0.20
36.42 36.07 36.42 36.07
On
-0.13 0.23
0.00 -0.35 0,13 - 0.29
Cbange
Treatment
-O.31 0.32
-0.06 -0.70 -0.48 0.00 --0.60 0.00
Treatment
36.13 0.19
36.36 36.23 36.29 36.00 35.88 36.00
Change
Temperature Minima
36.43 0.38
36.42 36.93 36.77 36.00 36.48 36.00
On
Timing of Minima
3:45 5:00 0:30 2:55 2:20 0:35
0:20 1:40 5:15 2:35 1:00 4:25
4:05 6:40 5:45 5:40 3:20 5:00
Change Off
F F M M M M
On
Off
Gender
Treatment
Treatment
Patients Phase-Delayed by Light
Means SD
5 6 1 2 7 8
Patient
Temperature Minima
Timing of Minima
Table 2. Patients Phase-Advanced by Light
1 9 12 23
On
1 9 , 2 5 11.25 9,07 9. l I
26 13 10 28
Off
8 11.75
25 4 - 2 5
0.33 0.82
0 2 0 0 0 0
Early
Inc. or dec. Increase Decrease Increase
1.25 0.96
1 2 0 2
Early
Seasonal Screening Questionnaire
Increase increase Increase Increase Increase Increase
Change Winter Sleep
i2 6.9
10 12 15 24 6 5
Change Winter Sleep
Total H D R S
6 2.3
5 8 8 2 7 6
On
Treatment
18 5.9
15 20 23 26 13 1!
Off
Treatment
Total H D R S
3easonal Screening Questionnaire
0.33 0.52
0 1 1 0 0 0
Late
Middle
0,75 0.96
0.75 0.96
1 0 0 2
Late
Insomnia
1 0 0 2
1.17 1.47
1 0 0 4 1 1
Hypersomnia
0,25 0.50
0 0 1 0
Hypersomnia
Supplementary HDRS
0.83 0,75
1 1 1 2 0 0
Middle
Insomnia
Supplementary HDRS
~.
tin.
t-
4~
-t .¢
>
O~
*..6*
O ,,¢
O
e,4
0,a ~r
44
BIOL PSYCHIATRY
3e1
i!i i i!i i !i!i i i!i!i ~i~~ii i!i i!i i !i !i!i!i i !i!!
37.6
37.6
g.I
N.E. Rosenthal et al.
1990;27:39-50
1
37.4 t 37.2
Iz IJJ
iiiii~ii~iiiii!iliiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii! 36.6
i,~ii:i:ii,ii,,i,i,i,i,i;i,,i!il;il,ii,~;,!il;i!~ii:/!i i:ii~;ii~iii!iiiiiil
_
C O N T R O L S (N=12)
i~i~i!i !i!i~!iii,!:!i i!i!i ii!i~.' ~ _PATIE.rs .=,o)7:~o~.
36.4
36,2
36 7:00pm
11:( TIME
Figure la.
With regard to the 3 subjects (2 patients, 1 normal control) who were on medications, the circadian temperature rhythm of all 3 subjects in the off-light condition appeared to be similar to the other subjects in minima, maxima, and timing. However, the increased amplitude seen in the other patients in the on-light condition was not found in the 2 patients on antipyretics. Therefore, it is possible that the antipyretic drugs prevented a 36'
37.6
!~ii ~i i ~i !i ~i i ~i i i i ~i~i~i ~!ii ~i ~i~i i i ~!i~i i i i ~i i i ~i~i ~i i~i~i i i i i i i i !
i!ii'~iiiiiiiiii!=,ii!~,ili'i',i~i~~=~iiii !i'!!!!i!i i ~i i i : : :::::::::::::::::::::::::::::::::
:: :,
.:..- : .:.:+:,;.:.;+:.:.:.:.:.:,: :+.,:.:.:.:.:.:.
371 .--o--,,j '~!!}ii!~ii~!!:~i~;i~;i~i~i!i~i~i~i~i~!i~!~ii/~i~i!iiii~i!~!i~i~i!i!!!i~ii}~i==i!i~:~/i
tm 7:00pm
1l:~0pm
~
= 1 7:~pm
7:0¢ TIME
F;gure la. Mean core body temperature of patients and normal controls during the off-light condition. Core body temperature was measured every 5 min using a Vitalog temperature monitor and a rectal thermistor, over a 24-hr period, recorded after 9 days of the off-light condition. F = 0.40; df = 287; p = 1.00. (b) Mean 24-hr core body temperature of patients during the off-light condition and the on-light condition, recorded after 9 days of each condition. F = 2.69; df = 287; p < 0.01
Light and Core Body Temperature in SAD
30
BIOL PSYCHIATRY 199o;27:39-5o
45
i!!!!iii!iii!i!]iiiiiiiiiiiiii!i!!!iiiii!ii
37.8 37.6 37.4 I11 e- 37.2
Q.
:E
36.6
---- MEAN OFF LIGHTS (N=6)
36.4
- . - - MEAN ON LIGHTS (N=6) 36.2
:::::::::::::::::::::::::::: :.: ::::::::::::::::::::::::::::
36 7:O0 xn
::'::
.,. :
, •
-.
: ; ::::.
::::::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::::::::::::::::::: !i!!::::!::~i::! ii!ii:::i:i:i:~::i:::::!:i:::!~:i!iii:~!~ii 11:0 3m
7:00; TIME
Figure 2a. Mean 24-hr core body temperature of patients who were phase-advanced by the light treatment, on and off light treatment. (Timing of minima: off lights: 5.08 am ± 1:13; on lights: 2:30 am ± 1:55.) drop in nizhttime temperature in these individuals. These pauents did, however, experience phase shifts. A recent study by Scales et al. (1988) has shown that antipyretic drugs (m a normal dosage) do not alter the circadian temperal~are rhythms in humans. We have included these patients in with the rest for analysis because they are few in number and, they have average temperatures and because of the findings of Scales et all. (1988). Fitting of cosinor functions to the patient did not corroborate the light treatment effect for mean or for amplitude values (patients on lights versus those off lights, mean: t = - 0 . 7 6 , p = 0.45; amplitude: t = 1.37, p = 0.2). The fitted curves did not closely fit the raw data fer many of the individual temperature profiles. For this reason, we believe they are not an accurate model of the rhythm, and therefore we refer only to the raw temperature data in the discussion that follows. For phase comparisons, we have used the timing of the temperature minima derived from the raw data by visual inspection rather than values derived from cosinor analysis. There was no evidence of a circadian phase difference between patients and normal controls off lights, or between patients across treatment conditions. Nor was there a significant correlation between the amount of phase shift and the amount of amplitude enhancement for individual patients across lighting conditions. We subtyped the patients into "phase-advanced" and "phase-delayed" groups in a manner suggested by Lewy et al. (1985, 1987a) and Avery et al. (1982). We assigned to the former group those whose temperature minima were phase-advanced and to the latter, those whose minima were phase-delayed by light treatment. This method of classification was, of course, posthoc but no specific criteria for a priori assignrnent into these categories have as yet been published. By these criteria, 6 patients showed phase advance after light treatment and 4 showed phase delay. The mean temperature profiles for these two subgroups are shown in Figures 2a and b. Those patients advanced by light treatment showed significantly later minima in the untreated condition, as compared to
46
N,E. Rosenthal et al.
BIOL PSYCHIATRY !.o90;27:39-50 38
37.8 37.6 37.4 ~: 37.2
36.8 36.6, 36.4
............. iiii!ii!!i
36.2 36
7:00pro
11:
)rn
7:~ )m
___o, 7:00pm
~ME Figure 2b. Mean 24-hr core body temperature of patients who were phase-delayed by the light treatment, on and off light treatment. Timing of minima: off lights: 1:15 am +__ 1:55; on lights: 3:20 am _ 1:20.
normal controls (patients = 5:08 AM _ 1:13; normal controls = 2.45 AM _+ 2:02; t = 2.52, p < 0.05). Those patients delayed by light treatment had an earlier minimum off treatment compared to the normal controls, though this difference did not reach statistical significance (patients = 1:15 AM ___ 1:55; normal controls = 2.45 AM ----- 2:02; t = -- 1.28, p = 0.22). We recognize that the nt!mbers of these two subgroups are too small for meaningful statistical comparisons, but we have nonetheless compared them for descriptive purposes with respect to several parameters of interest: sleep history in the untreated condition, antidepressant response, and change in amplitude of circadian rhythms (see Table 2). Those whose temperature minL~a were advanced by !'ght treatrnent tended to experience more hypersomnia in the untreated condition (as determined by the supplementary items on the HDRS), greater enhancement of the amplitude of the temperature rhythms on light treatment, and a superior antidepressant response. Cc ~wersely, those whose temperature minima were dek,~yed by light treatment tended to show more early-morning awakening (as determined by the HDRS), less amplitude enhancement, and less marked antidepressant responses on light therapy.
Discussion The results of the present study show that effective light treatment significantly enhances the amplitude of the circadian rhythm of rectal temperature in S/~D patients; this enhancement is largely a function of lowered nighttime tempertures. In the untreated state there are no significant differences between the circadian temperature profiles of patients and ~'~ormals. Several previous studies have similarly found significantly enhanced amplitude of core temperature rhythms in remitted depressive patients (AveD" et al. 1982; Smallwood et al. 1983; Souetre et al. 1988, in press; Czeisler et al. 1987).
Light and Core Body Temperature in SA~__~
BIOL PSYCHIATRY 1990;27:39--50
47
Kro~auer (1987), Kronauer and Frangioni (1987), and Czeisler et al. (1987) have hypothesized that the amplitude of temperature rhythms in depressed SAD patients should increase following successful light treatment. The results of our present study seem to support this hypothesis, as do the results of their one pilot study of two male normal controls (Czeisler et al. 1987). These researchers have hypothesized that the augmented circadian amplitude caused by pkototherapy may account for its antidepressant effect. Unlike the previous studies of temperature La depress~ populations where the augmented circadian amplitude of depressed patients on treatment brought their nighttime temperatures to normal levels [(Avery et al. 1982; Sr~e_llwood eta!. 1983, Souetre et al. 1988 (in press)], in our study, light treatment was f~llowed by a lowering of nocturnal temperature below the levels of the normal con~ois. Patients' temperattrre profiles were normal when their mood was abnormal; and these plofiles became abnormal when they became less depressed. How can we account for these paradoxicfl fir,dings? The differences between our study and those noted above could be explained by a unique pathophysiology in the SAD population, compared to other depressed populations. Perhaps the temperature curves seen in the SAD population in the untreated condition, though similar to those of normal controls, nonetheless reflect abnormally blunted amplitudes for this particular group. This hypothesis could be tested by measuring the temperature rhythms of SAD patients and normal controls during the summer months when patients are well. If this explanation is correct, one would bypo~esize that SAD patients in summer would show abnormally amplified circadian temperavare rhythms. It seems unlikely that the enhanced amplitude of the circadian temperature rhythms following light treatment is specific for SAD. Czeisler et al. (1987) would predict not, and have shown that the amplitude of circadian temperature rhythms can shnilar!y be enhanced by light in normal subjects. This finding does not, however~ detract from the possible mechanistic importance of this amplitude-enhancing effect ha SAD. Indeed, Czeisler et al. (1987) have postulated su:;h circadian amplification as the mechanism of antidepre~zant effects of phototherapyo They have hypothesized low amplitude in depressed (off-light) states which would be increased by light treatment. Therefore, our data are in part consistent with their hypothesis, but are by no means conclusive, especially as there is no difference in circadian rhythm amplitude of core bo~y temperat~ire between untreated patients and normal controls. In addition, the degree of ir~dividual enhancement of circadian temperature amplitude in our patients did not correlate significantly with antidepressant responses. The existence of an ordering effect, _marked by conr.inued lowering of nocturnal temperature even 9 days after light treatment was discontinued, suggests that physiological consequences of light treatment ~e not completely reversed within this period of time. .Although it has been recognized that relapse in mood in SAD patients at 1 week after discontinuing light therapy is only partdal (Rosenthal 1988), it would seem as though physiological relapse, at least wi~ r~,spect to body temperature, is even more delayed. This methodological point needs to be taken into account when i~te~reting all studies of the physiological effects of light where a balanced ordered design is us~. There was no evidence of a phase difference between populat,~ons or treetment conditions. In order to explore the possibility that the SAD population consisted of subgroups whose temperature minLmamight have been shifted in oppG:ate directions by light therapy (thereby yielding no overall shift in the mean), we divided our population il:~:ophaseadvanced and phase-'~elayed sub~pes in a manner suggested by Lewy et al. (1987b) and Avery et ai. (1982). Lewy et al. (1984) have suggested that most SAD patients are phase
48
B~OLPSYCHIATRY
N.E. Rosenthal et al.
1990;.~7:39-50
delayed. They found that administration of bright light in the morning phase advanced ,.he SAD patients and alleviated their depressed symptoms, whereas administration of bright light in the evening was less effective and further phase delayed the patients. In our study, 6 of 10 patients showed a phase ady~ce of temperature minima following light treatment and 4 showed a phase d e l a y , ~ e Table 2). It is possible that the phase shift after the light treatment was actually greater than we observed, but that it was masked by the enforced wake-up time. Indeed, it could be argued that the enhanced amplitude of temperature rhythm seen on F.ght treatment might have been due to a net phase advance of the circadian ~ystem. By bringing the lowest temperature minimum earlier into the sleep time, the lowest part of the circadian rhythm might have been unmasked by light treatment. Thus, although no significant shift in timing of the minima following light treatment was observed in the total patient population, our data do not definitely contradict the phase shift theory of Lewy et al. and the amplitude enhancement could actually be construed as supporting it. The validity of classifying our patients into subgroups can be questioned on two counts: (1) the c!z~sification wa~ post hoe; and (2) the night-to-night variability i'~ timing of minima and maxima, which is especially prominent in depression (Nikitopoulou and Crammer 1976; Pttug et al. 1981; V~ehr et al. 1982) could easily have resulted in misclassification as only ot~e night of temperature readings was available for each condition. The value of dividing SAD patients into phase t)laes received some support by our finding of different degrees of response to light treatment among thase advanced by and those delayed by light treatment. For example, it appeared that with the exception of a single patient who did very well when her temperature minimum was markedly delayed, only the patients who were advanced by the fights improved significantly after a combination of morning and evening light (p ~< 0.05, Fischer's exact tes0. The nonsignificant trend for those whose minima were phase advanced bj" !;oht tO show hypersoumia and for those whose minima were phase delayed by light to show decreased winter sleep (p = 0.26, Fischer's Exact Test) appears to lend some further support to the circadian typology of Lewy et al. (1987a) (see Table 2}. The small number of patients in this study, however, did not reveal statistically significant between-group d~fferenees i~.~any parameters other than the defining one. We conclude, therefore, that the phase-advance veKsus phase-delay typology has yet to be validated. The inconsistent phase responses to light treatment in our present study and the absence of any significant cor:eiation between phase-shift and the antidepressant response to light in the group as a whole do not support the phase-advance hypothesis of Lewy et al. (1987b). However, in view of artifacts in the data, for example, the masking effects of the sleep-wake cycle on body temperat~tre, th~.s negative conclusion cannot be regarded as definitive. In addition, just as no causal connection between amplitude change and mood change could be conclusively inferred, the same difficulty in discriminating between con'elation and causation exists in relation to the phase-shift hypothesis.
Conclusion From the present study we conclude that phototherapy administered in the morning plas t~aeevening significantly ei,.l~ancesthe amplitude of the circadi~_nrhythm of the core body tempccamre in SAD patients during winter. Similar amplitude enhancement accompa~:ying effective antidepressant treatment has previously been shown to occur in nonseasoaally depressed populations. The amplitude enhancement seen after successful phototherapy is
Light and Core Body Temperature in SAD
BIOL PSYCHIATRY 1990;27:39--50
49
consistent with the hypothesis of Czeisler et al. (1987), who have suggested that amplitude enhancement is a possible mechanism of action of light. However, contrary to their hypothesis, we did not find abnormally low amplitude in untreated SAD patients compared with normal controls. Amplitude enhancement may also reflect a phase advance and unmasking of the lower portion of the circadian temperature rhythm, an interpretation that would be consistent with the phase-shift theory of the antidepressaat effects of light, advanced by Lewy et al. (1987a, 1987b). It is not clear at this time whether the antidepressant effects of light therapy in SAD patients are mediated by a phase shift, amplitude enhancement, a combination of both, or neither. Though there are interesting ~'ends suggesting that there may be some value to subclassifying SAD patients into groups on the basis of direction of phase shift of their circadian rhytl'ans by light treaw,,cr, L much more data are required before such subgrouping can be regarded as valid. The results of this study clearly demonstrate the value of the investigat'~on of the circadian rhythm of core body temperature because it involves many parameters that are often altered in affective disorders, such as amplitude, phase, regularity, and energy regulation.
References Avery DH, Wildschiodtz G, Rafaelsen OJ (1982): Nocturnal temperature in affective disorder. J Affect Disord 4:61-71. Avery DH, Wildschiodtz G, Smallwood RG, Martin D, Rafaelsen OJ (1986): REM latency and cere temFerature relationships in primary depression. Acta Psychiatr Scand 74:269-280. Brown EN, Czeisler CA (1985): A method for quanti~,,ing phase position of tke deep circadian oscillator =rid determining a confidence interval. Sleep Research 14:290. Clouston TS ¢1868): Observations on the temperature of the body in the insane. J Ment Sc pp 3549. Czeisler CA, Allan JS, Kronauer RE (1987): Rapid manipulation of phase and ampStude of the human circadian pacemaker with light-dark cycles. (Abstracts) 5th Int Congr Sle~. Res, Copenhagen, p 511. Gwinner E (1981) Circamqual systems. In Aschoff J (ed), Handbook of Behavioral Neurobiology, vol. 6. New York: Plenum Press. pp 391-408. HamJ!ton M (!967): Development of a rating scale fer primary depressive illness. Br J Soc Clin Psychoi 6:278-296. Kri~ke DF, Mullaney DJ, AtkJnson ML, Wolf S (1978): Circadian ~ythm disorders in manicclepressives. Biol Psychiatr 13:335-351. Kronauer RE (1987): A model for the effect of light on the human "deep" circadian pacemaker. Sleep Res 16:621. Kronauer RE, Frangioni JV (1987): Modeling laboratory bright light protocols. Sleep Res 16:622. Lange J (1928) Die endogenen und reactive Gemutserkrankugen und die manisch-depressive Kenstitution. In Bumke O. (ed), Handbuch der Gristerkra Geiskheinen, vol. 6. Befl:,n: SpdngerVerlag Lewy AJ, Kern HA, Rosenthal NE, Webr TA (1982): Bright artificial light treatment of a manicdepressive patient with a seasonal mood cycle. Am J P~ychiat 139:1496-1498. Lewy AJ, Sack RL, Singer CM (1984): Assessment and treatment of chronobiolog~c disorders using plasma rnelatonin levels and bright light exposure: The clock-gate model aad the phase response curve. Psychopharmacol Bull 20:561-565. Lewy AJ, Sack RL, Singer CM (1985): Treating pha:,e-typed chronobiologic sleep and mood disorders using approprir~telytimed bright artificial light. Psychopharmacol Buil 21:368-372.
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N.E. Rosenthal et al.
Lewy At, Sack RL, Miller S, Hoban TM (1987a): Antidepressant and circadian phase-shifting effects of light. Science 235:352-354. Lewy At, Sack RL, Singer CM, White DM (1987b): The phase shift hypothesis for bright light's therapeutic mechanism of action: Theoretical considerations and experimental evidence. Psychopharmacol Bull 23(3):349-353. Nikitopoulou G, Crammer JL (1976): Change in diurnal temperature rhythm in manic-depressive illness. Br Med J 1:1311-13i4. Pengelle~ ET, Asmundson SJ (1974): Circannual rhythmicity in hibernating mammals. In Pengelley ET (ed), Orcannual Clocks. New York: Academic Press, pp 95-160. Pflug B, Erikson R, Johnsson A (1976): D,~ptession and daily temperature: A long-term study. Acta Psychiatr Scand 54:254-266. Pflug B, Johnssou A, Ekse AT (1981): Manic-depressive states and daily temperature: Some circadian studies. Acta Psychiatr Scand 65:277-289. Rosenthal NE, Heffernan MM (1986): Bulimia, carbohydrate craving, and depression: A central connection? In Whztman IL! Wurtman JJ (eds), Nutrition and the ~rain. New 'fork: Raven Press, pp 139-166. Rosenthal hiE, Kasper S, Schulz PM, Wehr TA (1989) New concepts and developments in seasonal effective disorder. In Thompson C, Silverstone T (eds), Seasonal Affective Disorder. London: CRC Clinical Neuroscience (in press). Rosenthal NE, Lewy At, Wehr TA, Kern HE, Goodwin FK (1983): Seasonal cycling in a bipolar patient. Psychiatr Res 8:25-31. Rosenthal NE, Sack DA, Carpenter CJ, Parry BL, Mendelson WB, Wehr TA (1985): Antidepressant effects of light in seasonal affective disorder. Am J Psychiatry 142:606-608. Rosenthal NE, Sack DA, Gillin JC, Lewy At, Goodwin FK, Davenport Y, Mueller PS, Newsome DA~ Wehr TA (! 984): Seasonal effective Oisorder: A descfiv~o~ c=-f'.hes3n,drome and preliminary timings with light therapy. Arch Gen Psychiatry 41:72-80. Rosenthal NE, Sack DA, Skwerer RG, Jacobsen FM, Wehr TA (1988): Phototherapy for seasonal effective disorder. J Biol Rhythms 3(2):101-120. Rosenthal NE, Skwerer RG, Sack DA, Duncan CC, Jacobsen FM, Tamarkin L, Wehr TA (1987): Biological effects of mÙrning--p•ns-•vening bright ligh" treatment of seasonal effective disorder. Psyc~opharmacol Bull 23(3):364-369. Scales WE, Vander At, Brown MB, Kluger MJ (1988): Human circadian rhythms in temperature, trace metals and blood variables. J Appl Physiol 65:1840-1846. Smallwood RG, Avery DH, Pascualy RA, Prinz PN (1983): Circadian temper.~mre rhythms in primary depression. Sleep Res 12:215. Souetre E, Salvati E, Belugou JL, Pringuey D, Candito M, Ardisson J-L, Datcc~urt G (i989): Circadian rhythras in depn ~sion and recovery: Evidence for blunted amplitu0e as the m~n chronobiological abnormality. Psychiatry Res (in press). Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G (1988): 24-h profiles of body temperature and plasma TSH in bipolar depressed and remitted patients and in normal controls. Am J Psychiat 145:1133-1137. Wehr TA, Goodwin FK, Wirz-Justice A, Breitmaier J, Gray C (1982): 48-Hour sleep-wake cycles in manic-depressive illness: Naturalistic observations and sleep deprivation experiments. Arch Gen Psychiatr 39:559-565. Wehr TA, Sack DA, Rosenthal NE, Duncan WD, Gillin JC (1983): Circadian rhythm disturbances in manic-depressive illness. Fed Proc 42:2809-2814. Wcver RA (1985): Internal interactions within the human circadian system: The masking effect. Experientia 41:332-342.
39
Effects of Light Treatment on Core Body Temperature in Seasonal Affective Disorder Norman E. Rosenthal, Alytia A. Levendosky, Robert G. Skwerer, Jean R. Joseph-Vanderpool, Karen A. Kelly, Todd Hardin, Siegfried Kasper, Peter DellaBella, Thomas A. Wehr
Abnormalities in circcuitan rhyfhms of core body temperature have been reported previously in depressed patients. In this study, we competed the temperature rhythms of 10 depressed seasonal affective disorder (SAD) patients with winter depression with those of 12 normal controls and evaluated the effects of bright light on temperature in SAD. Unlike previous studies of depressed patients, the temperature curves of the patients and normal controls during the off-ligFytcondition were nearly identical. We found a significant difference in amplitude between the patients in the untreated and light-treatea conditions. Although there was no systematic difference in circadian phase across groups or treatment conditions, we present preliminary .,vidence that suggests that phase-typed subgroups may be present in the population distinguished by their treatment responses.
Introduction Abnormalities in the daily rhythm of body temperarare have long been known to be present .~n affective disorders (Clouston 1868). In the past 20 years, extensive studies of this rhythm have been conducted in depressed patients, and the resulting observations have been conceptualized in different ways. First, several studies have suggested that some depressed patients have phase-advanced circadian rhythms, including that of temperature (Htug et al. 1976; Wehr et al. 1983). These studies have shown that the acrophase of the temperature curve occurs earlier in patients when they are depressed than when they are in remission. In contrast to this, Lewy et al. (1987a, 1987b) have reported that some depressed patients with seasonal affective disorder (SAD) have phase-delayed circadian rhythms. These workers have proposed a circadian typology of depression in which certain depressed patients can be separated according to the phase position of their circadian rhythms into phase-advanced and phase-delayed categories. They have further suggested that such a typology might have treatment implications insofar as the former group might benefit i~rom having their rhySams phase-advanced (as occurs wit1" morning light), whereas the latter group might benefit from having their rhythms phase-delayed (as occurs with evening light).
From the Clinical Psychobiology Branch of the National Institutes of Health, Bethesda, MD. Address reprint requests to Norman E. Rosenthal, M.D., Clinical Psychobiology Branch National Institutes of Health, Bldg. 10/4S-239 9000 RockviUe Pike, Bethesda, MD 20892 Received November 17, 1988; revised February 28, 1989. This article is in ~e Public Domain.
0006-3223/90/$00.00
40
BIOL PSYCHIATRY 1990;27:39--50
N.E. Rosenthal et
al.
Another circadian parameter considered to be abnormal in depression is amplituae; some studies have shown that the amplitude of several circadian rhythms, that of temperature included, is abnormally low in depression (Avery et al. 1982, 1986; Souetre et al. in press). The reduction in amplitude is largely a function of increased nocturnal temperatures in depressed patients as compared with recovered patients or normal controls. These different categories can overlap in certain instances. For example, Pttug et al. (1981) described a combination of phase-advance and reduced amplitude of temperature rhythms in 4 bipolar patients. Some researchers have emphasized that there is an inconsistency in the timing of circadian temperature rhythms from night to night and that this, rather than any consistent deviation in timing, is a cardinal abnormality in depressed patients. Thus, Nikitopoulou and Crammer (1976) studied a group of 6 manic depressives and found that although the daily temperature curves were not abnormal in mania, they were very variable from day to day within each subject during depression. Likewise, Pflug et ai. (1981) and Wehr et al. (1982) found that the timing of daily temperature maxima in depression shifts markedly from day to day. The study of body temperature in SAD is of particular interest because seasonal variations in body temperature have been described in animals (Pengelley and Asmundson 1974; Gwinner 1981). In addition, the behavioral abnormalities seen in depression have been compared with the changes in energy balance seen in hibernation and other seasonal rhythms in animals (Lange 1928; Kripke et al. 1978; Rosenthal 1983). The purpose of this study was to investigate the 24-hr profile of core body temperature in patients with seasonal affective disorder, both untreated and treated with bright environmental light, as compared with normal controls during Lhe winter. Bright light (at least 2500 lux) has been established as an effective treatment for SAD (Lewy et al. 1982; Rosenthal et al. 1984, 1985, 1987). We discuss our findings in terms of current circadian theories of how light might exert its antider~ressant effects. Methods In order to be included in this study, all patients were required to (1) meet lifetime criteria for SAD (Rosenthal et al. 1984); (2) score a total of at least 14 on the 21-item Hamilton Depression Rating Scale (HDRS) (Hamilton i967) during the untreated condition of the study (although we recognized that between the time of admission and the time of temperature measurement, the HDRS score could rise or fall to some degree, accounting for those few subjects whose HDR$ total scores fell below 14; see Table 1); (3) be drug free (in most cases) for at least 1 month prior to admission. The few exceptions, such as patients on maintenance thyroid or antipyretic drugs, are noted in Table 1. The normal controls were recruited through an advertisement in the Washington Post. They were sc~ened and evaluated by means of the Structured Clinical Interview for DSM-III-R diagnoses (SCID-R), and those with personal or family histories (first-degree relatives only) of psychiatric illness or any significant medical illness were excluded. The HDRS supplementary questionnaire (Rosenthal and Heffernan 1986), which inquires about several symptoms that specifically trouble patients with SAD (including appetite increase, overeating, carbohydrate craving, weight gain, social withdrawal, hypersonmia, and increased fatigability), was also administered with each Hamilton Rating. Patients were studied under two conditions: treated (on-light) and untreated (off-ligh0o
Light and Core Body Temperature in SAD
BIOL PSYCHIATRY 1990;27:39-50
4I
Table 1. Demographic Features of SAD Patients and Normal Controls Patients
Age
Gender
Drugs
HDRS Off
HDRS On
1 2 3 4 5 6 7 8 9 10
45 35 36 53 56 21 51 28 37 54
M M M F F F M M F M
None None None Synthroid, Nalfon daily Aspirin daily None None None None None
23 28 26 26 15 20 13 11 13 10
8 23 2 ! 5 8 7 6 9 12
Normals
Age
Gender
Drugs
1 2 3 4 5 6 7 8 9 10 l! 12
40 37 30 48 49 27 51 28 43 56 29 45
M M M F F F M M F M F F
RDC Diagnosis Unipolar Bipolar H Bipolar I Bipolar H Bipolar H Bipolar H Bipolar II Bipolar H Bipolar H Bipolar II
None None None None None None Tylenol daily None None None None None
The on-light condition consisted of 5 hr of 2500 lux full-spectrum fluorescent light (Sunbox fixtures; Vim!ire lamps), administered for 2 1/2 hi" between 6:00 and 9:00 AM and 2 1/2 hr between 6"00 and 9:00 PM each day, for at least 9 days prior to the temperature study. The light ~eatment procedure is described in more detail elsewhere (Rosenthal et al. 1985). In the off-light condition, patients stayed in ordinary room light (about 300 lux) between 6:00 and 9:00 AM and 6:00 and 9:00 PM for at least 9 days before the temperature study. The order of m~ two conditions was ~ou,~t~Lb~anceu to prevent an ordering effect. Normal controls were studied only in the off-light condition. All subjects remained on an inpatient research unit in the Intramural program of the NIMH during the temperature study and engaged in ordinary sedentary pursuits. Beyond that, we did not specifically control their activity. The population, as shown in Table 1, consisted of 10 patients (6 men, 4 women, aged 20-65), and 12 normal controls (6 men, 6 women, aged 20--65). Two of the 4 female patients and one of the 6 female controls were post menopausal. All subjects were studied during the winters of 1985 through i988. Their sleep schedules were set at 11:00 P M - 7 : 0 0 AM. Patients were admitted to the hospital after 9 days of treatment with either the on-light or off-light condition. The temperature recording always began on the first evening at 7 PM, and the first 24-hr period of ;emperature recording was used for analysis. On the day of the temperature study, during the on-light condition on the inpatient unit, lights were administered between 7 and 9 AM and 7 and 9 PM (this minor deviation from their normal light schedule permitted standard sleep studies to be performed between 11 PM and 7 AM). Core body temperature was measured %
42
tool PSYCHIATRY
N.E. Rosenthal et al.
1990;27:39-50
via an indwelling rectal thermistor probe by a portable solid-state recording device (Vitalog) which sampled temperature at 5-rain intervals; data were stored in solid-state memory, and retrieved after the study. Because so many variables had to be accommodated in conducting this study--timing of depression, treatment, season of year, and bed availability--we were not able to control for phase of menstrual cycle as well. There were, however, similar menstrual profiles for patients and normals, and for patients on and off lights. Data were analyzed by two analyses of variance (ANOVAs), one with two repeated measures (time and treatment condition) and one grouping factor (order of condition) comparing patients on and off lights, and one with one repeated measure (time) and one grouping factor (patient versus normal) comparing patientz off lights with normals off lights. The same analyses were repeated for sleep-time (11:00 PM-7:00 AM) and waketime (7:00 AM-11:00 PM) temperatures, as some researchers have suggested that the former measurement is a better index of circadian phase (Wever 1985) because the circadian temperature rhythm is "mlmasked" by sleep and not subject to the perturbations of daytime activity. Tb_e ~m.Jng of miv3ma was identified by ~.~sual inspection by a rater blind to the subject's diagnosis and treatment status, and these values were compared in patients on and off treatment by means of paired t-tests and in patients and normal controls off treatment by means of group t-tests. When 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 24hr temperature values. Twenty-four hr cosine functions were fitted by the method of least squares (Brown and Czeisler 1985) to the individual temperature rhythms, and the three parameters of the cosine curves (mesor, amplitude, and acrophase) were computed and compared across populations and conditions.
Results There was a significant antidepressant effect of bright light in the patient population as measured by the HDRS (t = 3.80, df = 9, p ~< 0.01; see Table 1). When all time points were considered, there was a significant difference between circadian temperatm~e profiler, in patients on and off light treatment (F = 4.29; df = i; p ~< 0.05; see Figure ib). There was a significant ordering effect whereby the difference between the on- and offlight conditions was greater in patients who received the on-light condition second than in those who received it first (F = 4.65, df = 1, p ~< 0.G5). This difference was due to lower nocturnal temperature in the off-light condition when this followed the on-light condition. The overall difference between the two conditions was due mostly to a significant lowering of nocturnal temperature (11 PM-7 AM) (F = 6.54; df = 31; p ~< 0.001) rather than to wake-related temperature (7 AM-II PM), which did not differ significantly across conditions (F = 1.10; df = 31; p = 0.33). The mean daily values for patients in the on-light condition were significantly lower than those measured during the off-light condition (paired t value = - 2.37; p ~< 0.05). The peak-to-trough intervals (amplitudes) of patients in the on-light condition were significantly higher than those in the off-light condition (paired t value = - 2 . 1 4 ; p ~< 0.05). There was no significant difference between patients and normals in the off-light condition (F = 0.40; df = 287; p = 1.00; see Figure la). Neither was there a difference between the amplitudes in patients in the off-light condition and normal controls.
39.5 13.58
56 21 45 36 51 28
# Age
2:30 2:33 1 : 5 5 i:45
5:08 1"13
Means SD
4 9 I0 2
Patient
44.75 10.14
53 37 54 35
# Age 0:10 6:25 4:20 2:25 3:20 2:40
23:25 4:00 0:30 0:55 l:15 1:55
F F M M
On
Off
Gender
2:07 1:20
0:45 2:25 3:50 !;30 36.37 0,06
36.42 36.42 36.29 36.36
Change Off
36.25 0.20
36.42 36.07 36.42 36.07
On
-0.13 0.23
0.00 -0.35 0,13 - 0.29
Cbange
Treatment
-O.31 0.32
-0.06 -0.70 -0.48 0.00 --0.60 0.00
Treatment
36.13 0.19
36.36 36.23 36.29 36.00 35.88 36.00
Change
Temperature Minima
36.43 0.38
36.42 36.93 36.77 36.00 36.48 36.00
On
Timing of Minima
3:45 5:00 0:30 2:55 2:20 0:35
0:20 1:40 5:15 2:35 1:00 4:25
4:05 6:40 5:45 5:40 3:20 5:00
Change Off
F F M M M M
On
Off
Gender
Treatment
Treatment
Patients Phase-Delayed by Light
Means SD
5 6 1 2 7 8
Patient
Temperature Minima
Timing of Minima
Table 2. Patients Phase-Advanced by Light
1 9 12 23
On
1 9 , 2 5 11.25 9,07 9. l I
26 13 10 28
Off
8 11.75
25 4 - 2 5
0.33 0.82
0 2 0 0 0 0
Early
Inc. or dec. Increase Decrease Increase
1.25 0.96
1 2 0 2
Early
Seasonal Screening Questionnaire
Increase increase Increase Increase Increase Increase
Change Winter Sleep
i2 6.9
10 12 15 24 6 5
Change Winter Sleep
Total H D R S
6 2.3
5 8 8 2 7 6
On
Treatment
18 5.9
15 20 23 26 13 1!
Off
Treatment
Total H D R S
3easonal Screening Questionnaire
0.33 0.52
0 1 1 0 0 0
Late
Middle
0,75 0.96
0.75 0.96
1 0 0 2
Late
Insomnia
1 0 0 2
1.17 1.47
1 0 0 4 1 1
Hypersomnia
0,25 0.50
0 0 1 0
Hypersomnia
Supplementary HDRS
0.83 0,75
1 1 1 2 0 0
Middle
Insomnia
Supplementary HDRS
~.
tin.
t-
4~
-t .¢
>
O~
*..6*
O ,,¢
O
e,4
0,a ~r
44
BIOL PSYCHIATRY
3e1
i!i i i!i i !i!i i i!i!i ~i~~ii i!i i!i i !i !i!i!i i !i!!
37.6
37.6
g.I
N.E. Rosenthal et al.
1990;27:39-50
1
37.4 t 37.2
Iz IJJ
iiiii~ii~iiiii!iliiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii! 36.6
i,~ii:i:ii,ii,,i,i,i,i,i;i,,i!il;il,ii,~;,!il;i!~ii:/!i i:ii~;ii~iii!iiiiiil
_
C O N T R O L S (N=12)
i~i~i!i !i!i~!iii,!:!i i!i!i ii!i~.' ~ _PATIE.rs .=,o)7:~o~.
36.4
36,2
36 7:00pm
11:( TIME
Figure la.
With regard to the 3 subjects (2 patients, 1 normal control) who were on medications, the circadian temperature rhythm of all 3 subjects in the off-light condition appeared to be similar to the other subjects in minima, maxima, and timing. However, the increased amplitude seen in the other patients in the on-light condition was not found in the 2 patients on antipyretics. Therefore, it is possible that the antipyretic drugs prevented a 36'
37.6
!~ii ~i i ~i !i ~i i ~i i i i ~i~i~i ~!ii ~i ~i~i i i ~!i~i i i i ~i i i ~i~i ~i i~i~i i i i i i i i !
i!ii'~iiiiiiiiii!=,ii!~,ili'i',i~i~~=~iiii !i'!!!!i!i i ~i i i : : :::::::::::::::::::::::::::::::::
:: :,
.:..- : .:.:+:,;.:.;+:.:.:.:.:.:,: :+.,:.:.:.:.:.:.
371 .--o--,,j '~!!}ii!~ii~!!:~i~;i~;i~i~i!i~i~i~i~i~!i~!~ii/~i~i!iiii~i!~!i~i~i!i!!!i~ii}~i==i!i~:~/i
tm 7:00pm
1l:~0pm
~
= 1 7:~pm
7:0¢ TIME
F;gure la. Mean core body temperature of patients and normal controls during the off-light condition. Core body temperature was measured every 5 min using a Vitalog temperature monitor and a rectal thermistor, over a 24-hr period, recorded after 9 days of the off-light condition. F = 0.40; df = 287; p = 1.00. (b) Mean 24-hr core body temperature of patients during the off-light condition and the on-light condition, recorded after 9 days of each condition. F = 2.69; df = 287; p < 0.01
Light and Core Body Temperature in SAD
30
BIOL PSYCHIATRY 199o;27:39-5o
45
i!!!!iii!iii!i!]iiiiiiiiiiiiii!i!!!iiiii!ii
37.8 37.6 37.4 I11 e- 37.2
Q.
:E
36.6
---- MEAN OFF LIGHTS (N=6)
36.4
- . - - MEAN ON LIGHTS (N=6) 36.2
:::::::::::::::::::::::::::: :.: ::::::::::::::::::::::::::::
36 7:O0 xn
::'::
.,. :
, •
-.
: ; ::::.
::::::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::::::::::::::::::: !i!!::::!::~i::! ii!ii:::i:i:i:~::i:::::!:i:::!~:i!iii:~!~ii 11:0 3m
7:00; TIME
Figure 2a. Mean 24-hr core body temperature of patients who were phase-advanced by the light treatment, on and off light treatment. (Timing of minima: off lights: 5.08 am ± 1:13; on lights: 2:30 am ± 1:55.) drop in nizhttime temperature in these individuals. These pauents did, however, experience phase shifts. A recent study by Scales et al. (1988) has shown that antipyretic drugs (m a normal dosage) do not alter the circadian temperal~are rhythms in humans. We have included these patients in with the rest for analysis because they are few in number and, they have average temperatures and because of the findings of Scales et all. (1988). Fitting of cosinor functions to the patient did not corroborate the light treatment effect for mean or for amplitude values (patients on lights versus those off lights, mean: t = - 0 . 7 6 , p = 0.45; amplitude: t = 1.37, p = 0.2). The fitted curves did not closely fit the raw data fer many of the individual temperature profiles. For this reason, we believe they are not an accurate model of the rhythm, and therefore we refer only to the raw temperature data in the discussion that follows. For phase comparisons, we have used the timing of the temperature minima derived from the raw data by visual inspection rather than values derived from cosinor analysis. There was no evidence of a circadian phase difference between patients and normal controls off lights, or between patients across treatment conditions. Nor was there a significant correlation between the amount of phase shift and the amount of amplitude enhancement for individual patients across lighting conditions. We subtyped the patients into "phase-advanced" and "phase-delayed" groups in a manner suggested by Lewy et al. (1985, 1987a) and Avery et al. (1982). We assigned to the former group those whose temperature minima were phase-advanced and to the latter, those whose minima were phase-delayed by light treatment. This method of classification was, of course, posthoc but no specific criteria for a priori assignrnent into these categories have as yet been published. By these criteria, 6 patients showed phase advance after light treatment and 4 showed phase delay. The mean temperature profiles for these two subgroups are shown in Figures 2a and b. Those patients advanced by light treatment showed significantly later minima in the untreated condition, as compared to
46
N,E. Rosenthal et al.
BIOL PSYCHIATRY !.o90;27:39-50 38
37.8 37.6 37.4 ~: 37.2
36.8 36.6, 36.4
............. iiii!ii!!i
36.2 36
7:00pro
11:
)rn
7:~ )m
___o, 7:00pm
~ME Figure 2b. Mean 24-hr core body temperature of patients who were phase-delayed by the light treatment, on and off light treatment. Timing of minima: off lights: 1:15 am +__ 1:55; on lights: 3:20 am _ 1:20.
normal controls (patients = 5:08 AM _ 1:13; normal controls = 2.45 AM _+ 2:02; t = 2.52, p < 0.05). Those patients delayed by light treatment had an earlier minimum off treatment compared to the normal controls, though this difference did not reach statistical significance (patients = 1:15 AM ___ 1:55; normal controls = 2.45 AM ----- 2:02; t = -- 1.28, p = 0.22). We recognize that the nt!mbers of these two subgroups are too small for meaningful statistical comparisons, but we have nonetheless compared them for descriptive purposes with respect to several parameters of interest: sleep history in the untreated condition, antidepressant response, and change in amplitude of circadian rhythms (see Table 2). Those whose temperature minL~a were advanced by !'ght treatrnent tended to experience more hypersomnia in the untreated condition (as determined by the supplementary items on the HDRS), greater enhancement of the amplitude of the temperature rhythms on light treatment, and a superior antidepressant response. Cc ~wersely, those whose temperature minima were dek,~yed by light treatment tended to show more early-morning awakening (as determined by the HDRS), less amplitude enhancement, and less marked antidepressant responses on light therapy.
Discussion The results of the present study show that effective light treatment significantly enhances the amplitude of the circadian rhythm of rectal temperature in S/~D patients; this enhancement is largely a function of lowered nighttime tempertures. In the untreated state there are no significant differences between the circadian temperature profiles of patients and ~'~ormals. Several previous studies have similarly found significantly enhanced amplitude of core temperature rhythms in remitted depressive patients (AveD" et al. 1982; Smallwood et al. 1983; Souetre et al. 1988, in press; Czeisler et al. 1987).
Light and Core Body Temperature in SA~__~
BIOL PSYCHIATRY 1990;27:39--50
47
Kro~auer (1987), Kronauer and Frangioni (1987), and Czeisler et al. (1987) have hypothesized that the amplitude of temperature rhythms in depressed SAD patients should increase following successful light treatment. The results of our present study seem to support this hypothesis, as do the results of their one pilot study of two male normal controls (Czeisler et al. 1987). These researchers have hypothesized that the augmented circadian amplitude caused by pkototherapy may account for its antidepressant effect. Unlike the previous studies of temperature La depress~ populations where the augmented circadian amplitude of depressed patients on treatment brought their nighttime temperatures to normal levels [(Avery et al. 1982; Sr~e_llwood eta!. 1983, Souetre et al. 1988 (in press)], in our study, light treatment was f~llowed by a lowering of nocturnal temperature below the levels of the normal con~ois. Patients' temperattrre profiles were normal when their mood was abnormal; and these plofiles became abnormal when they became less depressed. How can we account for these paradoxicfl fir,dings? The differences between our study and those noted above could be explained by a unique pathophysiology in the SAD population, compared to other depressed populations. Perhaps the temperature curves seen in the SAD population in the untreated condition, though similar to those of normal controls, nonetheless reflect abnormally blunted amplitudes for this particular group. This hypothesis could be tested by measuring the temperature rhythms of SAD patients and normal controls during the summer months when patients are well. If this explanation is correct, one would bypo~esize that SAD patients in summer would show abnormally amplified circadian temperavare rhythms. It seems unlikely that the enhanced amplitude of the circadian temperature rhythms following light treatment is specific for SAD. Czeisler et al. (1987) would predict not, and have shown that the amplitude of circadian temperature rhythms can shnilar!y be enhanced by light in normal subjects. This finding does not, however~ detract from the possible mechanistic importance of this amplitude-enhancing effect ha SAD. Indeed, Czeisler et al. (1987) have postulated su:;h circadian amplification as the mechanism of antidepre~zant effects of phototherapyo They have hypothesized low amplitude in depressed (off-light) states which would be increased by light treatment. Therefore, our data are in part consistent with their hypothesis, but are by no means conclusive, especially as there is no difference in circadian rhythm amplitude of core bo~y temperat~ire between untreated patients and normal controls. In addition, the degree of ir~dividual enhancement of circadian temperature amplitude in our patients did not correlate significantly with antidepressant responses. The existence of an ordering effect, _marked by conr.inued lowering of nocturnal temperature even 9 days after light treatment was discontinued, suggests that physiological consequences of light treatment ~e not completely reversed within this period of time. .Although it has been recognized that relapse in mood in SAD patients at 1 week after discontinuing light therapy is only partdal (Rosenthal 1988), it would seem as though physiological relapse, at least wi~ r~,spect to body temperature, is even more delayed. This methodological point needs to be taken into account when i~te~reting all studies of the physiological effects of light where a balanced ordered design is us~. There was no evidence of a phase difference between populat,~ons or treetment conditions. In order to explore the possibility that the SAD population consisted of subgroups whose temperature minLmamight have been shifted in oppG:ate directions by light therapy (thereby yielding no overall shift in the mean), we divided our population il:~:ophaseadvanced and phase-'~elayed sub~pes in a manner suggested by Lewy et al. (1987b) and Avery et ai. (1982). Lewy et al. (1984) have suggested that most SAD patients are phase
48
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1990;.~7:39-50
delayed. They found that administration of bright light in the morning phase advanced ,.he SAD patients and alleviated their depressed symptoms, whereas administration of bright light in the evening was less effective and further phase delayed the patients. In our study, 6 of 10 patients showed a phase ady~ce of temperature minima following light treatment and 4 showed a phase d e l a y , ~ e Table 2). It is possible that the phase shift after the light treatment was actually greater than we observed, but that it was masked by the enforced wake-up time. Indeed, it could be argued that the enhanced amplitude of temperature rhythm seen on F.ght treatment might have been due to a net phase advance of the circadian ~ystem. By bringing the lowest temperature minimum earlier into the sleep time, the lowest part of the circadian rhythm might have been unmasked by light treatment. Thus, although no significant shift in timing of the minima following light treatment was observed in the total patient population, our data do not definitely contradict the phase shift theory of Lewy et al. and the amplitude enhancement could actually be construed as supporting it. The validity of classifying our patients into subgroups can be questioned on two counts: (1) the c!z~sification wa~ post hoe; and (2) the night-to-night variability i'~ timing of minima and maxima, which is especially prominent in depression (Nikitopoulou and Crammer 1976; Pttug et al. 1981; V~ehr et al. 1982) could easily have resulted in misclassification as only ot~e night of temperature readings was available for each condition. The value of dividing SAD patients into phase t)laes received some support by our finding of different degrees of response to light treatment among thase advanced by and those delayed by light treatment. For example, it appeared that with the exception of a single patient who did very well when her temperature minimum was markedly delayed, only the patients who were advanced by the fights improved significantly after a combination of morning and evening light (p ~< 0.05, Fischer's exact tes0. The nonsignificant trend for those whose minima were phase advanced bj" !;oht tO show hypersoumia and for those whose minima were phase delayed by light to show decreased winter sleep (p = 0.26, Fischer's Exact Test) appears to lend some further support to the circadian typology of Lewy et al. (1987a) (see Table 2}. The small number of patients in this study, however, did not reveal statistically significant between-group d~fferenees i~.~any parameters other than the defining one. We conclude, therefore, that the phase-advance veKsus phase-delay typology has yet to be validated. The inconsistent phase responses to light treatment in our present study and the absence of any significant cor:eiation between phase-shift and the antidepressant response to light in the group as a whole do not support the phase-advance hypothesis of Lewy et al. (1987b). However, in view of artifacts in the data, for example, the masking effects of the sleep-wake cycle on body temperat~tre, th~.s negative conclusion cannot be regarded as definitive. In addition, just as no causal connection between amplitude change and mood change could be conclusively inferred, the same difficulty in discriminating between con'elation and causation exists in relation to the phase-shift hypothesis.
Conclusion From the present study we conclude that phototherapy administered in the morning plas t~aeevening significantly ei,.l~ancesthe amplitude of the circadi~_nrhythm of the core body tempccamre in SAD patients during winter. Similar amplitude enhancement accompa~:ying effective antidepressant treatment has previously been shown to occur in nonseasoaally depressed populations. The amplitude enhancement seen after successful phototherapy is
Light and Core Body Temperature in SAD
BIOL PSYCHIATRY 1990;27:39--50
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consistent with the hypothesis of Czeisler et al. (1987), who have suggested that amplitude enhancement is a possible mechanism of action of light. However, contrary to their hypothesis, we did not find abnormally low amplitude in untreated SAD patients compared with normal controls. Amplitude enhancement may also reflect a phase advance and unmasking of the lower portion of the circadian temperature rhythm, an interpretation that would be consistent with the phase-shift theory of the antidepressaat effects of light, advanced by Lewy et al. (1987a, 1987b). It is not clear at this time whether the antidepressant effects of light therapy in SAD patients are mediated by a phase shift, amplitude enhancement, a combination of both, or neither. Though there are interesting ~'ends suggesting that there may be some value to subclassifying SAD patients into groups on the basis of direction of phase shift of their circadian rhytl'ans by light treaw,,cr, L much more data are required before such subgrouping can be regarded as valid. The results of this study clearly demonstrate the value of the investigat'~on of the circadian rhythm of core body temperature because it involves many parameters that are often altered in affective disorders, such as amplitude, phase, regularity, and energy regulation.
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