Acta psychiat. scand. (1981) 63,277-289

University Psychiatric Hospital (Head: Prof. Dr. H. Heimann), Tiibingen, West Ger- many, and Institute of Physics, NLHT, University of Trondheim, Norway

Manic-depressive states and daily temperature SOME CIRCADIAN STUDIES

B. PPLUG, A. JOHNSSON AND A. TVEITO EKSE

Proceeding from the hypothesis of disturbed circadian rhythms in endogenous depression, we observed the oral temperature of four patients in a long-term study. The results showed the following: 1) Depression is linked to higher mean daily temperatures com- pared with normal states. In manic states, the mean daily tem- perature is even higher than in depressive stata. Sleep deprivation as effective treatment causes a decrease in mean daily temperature. 2) The daily temperature maximum changes its position in depres- sive states. This is interpreted as indicating a disturbed circadian system. 3) A period shorter or longer than 24 h c m o t be observed in depressive states.

Key words: Depression - mania - oral temperature - circadian rhythms - sleep deprivation.

In a previously reported long-term study of a manic-depressive patient (Pflug et al. (1976)), it was found that the daily temperature pattern was different on the depressive days compared with normal days. During the depressive periods, the daily maximum temperature often occurred earlier than during periods without complaints. The temperature pattern was often different from day to day and was by no means as stable as during normal periods. Furthermore, the average daily temperature was higher during the depressive period. Al- together, depressive periods were characterized by disturbed body temperature functions. As is well known, many functions in man vary according to a daily pattern. Recordings under constant conditions have also shown that many daily rhythms are circadian, i.e. pertain to a period of about 24 h (Aschoff & Wever (1962), Wever (1969)). Kripke et al. (1978) found disturbances in the circadian system in seven circular manic-depressives. During depression, the circadian rhythm of the oral temperature was free-running and faster than 24 h. It has been hypothesized that not only the daily temperature rhythm, but the whole system of circadian rhythms in man might be disturbed during the depressive state in manic-depressive patients. In one case, Kripke et al. (1978) found similar disturbances in the circadian system of urine variables (water and free hydro- cortisone) and activity. The hypothesis that disturbed circadian rhythms play an important role in the pathogenesis of manic-depressive disorders is furthermore supported by investigations on excretion of electrolytes (Lobban et al. (1963),

0001-690x/81/030277-13 $02.50/0 @ 1981 Munksgaard, Copenhagen

278

Lithium

Moody & AZZsopp (1969)), neurohumoral metabolites (Riederer et al. (1974)), biogenic amines in blood plasma (Birkmayer & Linauer (1970), Klempel (1972), Niskaunen et al. (1976)), magnesium (PfIug (1976)), hormones in blood plasma (Halberg (1968), Sachur et al. (1973, 1976)) and sleep parameters (Hawkins & Mendels (1966), Hajnsek et al. (1973), Kupfer (1976)). In the report by Pflug et at. (1976) mentimed above, the Occurrence of a

period at variance with the normal 24-h rhythm in the oral temperature curves of one patient was also interpreted as indicating a disorganized circadian system (desynchronization).

The present report includes new data from the same patient in addition to measurements on new patients. The report concentrates on the following problems: 1) Is there a relationship between the daily mean temperature and the depres-

2) Are there differences in the daily temperature pattern of the patients during

3) Is the frequency content of the temperature data different during depressive

sive state of the patient?

depressive and normal periods?

and normal states?

0 Lithium

CASE HISTORIES Care history No. 1 The case history of the manic-depressive patient H.F., born in 1942, has been previ- ously described (Pflug et al. (1976)). U p to January 1975, the patient had had eight depressive episodes and one manic (1970). From mid-January 1975 until mid-March 1975, she felt well (Fig. 1). After a few slightly euphoric days (March 8-13), she felt imtable, sometimes aggressive and unbalanced, but there were also days when she felt well. Until March 1 she was treated with lithium carbonate (plasma level 0.65- 1.12 mEq). During a journey, she stopped taking lithium carbonate until April 25, but continued the medication afterwards. From April 26 to May 23, she felt well, then she complained of sleep disturbances, inner restlessness, fatigue, despair and heart trouble. This state continued until July 2 and could be interrupted by therapeutic sleep deprivation for 1 or 2 days. From July 3 mward, she was without camplaints after another sleep deprivation. Except for lithium carbonate, she took no drugs. In

I I. I. M. I . I I Sleep deprivations Sleep deprivations

I I 1 lllu 1 111-

Fig. 1. History for the investigated period, Patient 1. The following abbreviations are used: Imipramine = I; Medazepam = M . Black areas denote depression; arrows denote

sleep deprivation; Q = no medication.

279

I I I I I I I I Map! Apr I May I June 1 July 1 Aug 1 Sept I Oct 1

1975

Fig. 2. History for the investigation period, Patient 2. Black areas denote either manic or depressive state, as indicated.

mid-October, the temperature patterns showed irregularities as during times of de- pression, although she did not complain. Preventive imipramine treatment led to nausea and reduced concentration, and was therefore discontinued. The patient felt well until October 31, after this she felt depressed and tired, complained of a sore throat, perspiration and anxiety. This state lasted until the beginning of January 1976. Then she slowly improved. From January 16 onward, she had no complaints. Sleep deprivation led only to short improvements in this patient, and thymoleptics did not improve the depression. A second imipramine treatment was stopped on December 27, and the depression disappeared without thymoleptic drugs.

Case history No. 2 Patient No. 2 was a 56-year-old housewife who had suffered from cyclothymia for 13 years. Her mother had once been treated in hospital for a retarded and stuporous syndrome and later for disturbance of mood. The patients first episode was manic. During the one and a half years before examination she had alternating manic and depressive episodes, lasting from 13 to 35 days, with no symptom-free interval. The switch from depression to mania occurred abruptly within a few hours, that fram mania to depression took more than 1 to 2 days. Neither treatment with lithium salts nor sleep deprivation was successful. After many unsuccessful attempts with different drugs, only continuous medication with imipramine and clozapine had some effect on the symptoms. During depression, the dose of imipramine was increased, during mania the dose of clozapine. During mania, the patient was euphoric, hyperactive, sexually uninhibited, showed flights of ideas and overestimated herself excessively. Her relatives could hardly tolerate her during this period. During depression, she was deeply dejected and her psycho-motoric behaviour was inhibited. She complained of inner restlessness, a feeling of heaviness in the chest and very disturbed sleep.

Fig. 2 shows the course of the illness, and the medication during the period of examination.

Case history No. 3 The patient was the 41-year-old wife of a baker and had her first depression when she was 20. Twice, after delivery, she had had depressive episodes lasting 4 to 6 months. In the years before the investigation, she had depressed episodes either in spring or autumn. On each of these occasions, she lost about 20 kg in weight, felt nervous and mentally tense. She lost interest in things and neglected her home. She suffered from constipation, perspiration, sleep disturbances, and diurnal ups and downs in mood and drive. During the intervals, she had no complaints, was a well- balanced, sociable woman, very orderly, reliable and accurate. During the period

280

of her temperature recording, she took neither thymoleptic nor neuroleptic drugs, though occasionally Lorazepam to get to sleep. When the investigation began during a depression she weighed 73 kg. In the interval, in April 1977, she weighed 96 kg. Fig. 3 shows the investigation period.

Case history No. 4 Patient No. 4 was a 56-year-old housewife, working part-time as a seamstress. She had suffered from cyclothymia since she was 34. During intervals, she was well- balanced, calm and very reliable. In depressive episodes, she became agitated, des- paired, wept often, was not capable of doing her housework and could not go to work, she lost all interest and suffered from considerable sleep disturbance. During mania, she was overactive, kept on talking, was euphoric, and in spite of only 2 or 3 hours sleep, she did not get tired. At the beginning of the investigation, she was suffering from the sixth depressive episode, which had started suddenly early in the morning. The patient had thoughts of suicide, was agitated, her arms and legs felt very heavy; she did not get up, and complained about considerable sleep disturbances. After an interval without complaints, which lasted a week, she was first in a hypo- manic and then in a manic state. During the period of investigation, she had a further depressive episode after an interval without complaints (see Fig. 4).

METHODS Self-rating and temperature data The patients were asked to give self-ratings of their mood each day. Only ex- ceptionally did these self-rating estimates deviate from judgements by the doctor or close relatives. Data presented here are given in a scale from 0 to 2: 0 = feeling well, 1 = not feeling well, 2 = depressed. Hypomania and mania states were estimated by the doctor and the relatives.

The recordings of the oral temperature (glass-mercury thermometer) were taken by the patients every 3 h, except during the night.

Time of occurrence of temperature maxima It turned out that the maxima in the temperature rhythms occurred at different times of the day: they varied between patients, but also in the individual pa- tient. During normal periods, the maxima occurred at the same time, but during depression, they fluctuated from day to day. As described earlier (Pflug et al. (1976)) the so-called phase deviation was therefore calculated. The phase devia- tion simply denotes the deviations - in hours - from the actual time of the

I I I I I I I I I I I I Fob I March1 A p I May I June I July I Aug I Sept I Oct I Nw I Dec Jon I Febr I

igm 19n

Fig. 3. History for the investigation period, Patient 3. Black areas denote depressive periods; @ = no medication.

281

,

P. 0 0 M.

M.

F. I) 0 I F. L

Fig. 4. History for the investigation period, Patient 4. The following abbreviations are used: Maprotilin = M; Lorazepam = L; Perazin = P; Flurazepam = F; @ = no medi-

cation. Black areas denote either manic or depressive state, as indicated.

temperature maximum to the time of the day it normally occurred. If a day had two maxima of the same magnitude, the smallest phase deviation was used in the calculations.

Analysis of period content in temperature data The present data were analysed as reported by Ppug et al. (1976) and both autocorrelation and period analysis techniques were used.

RESULTS Daily mean temperature and mood of patient Pflug et al. (1976) found that a depressive state was correlated to a higher tem-

MANIA

HY POMANIA

DEPRESSIVE STATE 2

DEPRESSIVE STATE 1

'NORMAL SELF-RATING

.36.6 36.7 36.8 36.9 37.0 *C Fig. 5. Temperature and rating o f mood. The dairy average temperature is plotted versus rating of mood for the four patients in the investigation. Patient 1 = 0; Pa- tient 2 = +; Patient 3 = n; Patient 4 = x. Typical standard errors of the mean are

indicated for some temperature values.

282

Table 1. Daily average temperature (OC). n = number of days

n =56

36. X !0.03 11.123

x 3671 $001 3675 20023678 $01173691 $00 depress/vo depresswe bypomanra

self- rating 0 f 2

1

36.98 $003

- I 3699 -7 $003

mama I 2 values are given as SEM 2AZ

n (n - 1) perature: days with self-rating 2 were found to have a higher mean temperature, whereas days with a slight depressive state (1 on the present scale) and normal days (days with self-rating 0) had a lower mean temperature. New data sup- porting this conclusion (see Table 1) are plotted in Fig. 5 .

Circles represent data of Patient 1, who had no manic period during the time these data were collected. The circles represent mean values of all record- ings on this patient, from November 1, 1973, to March 22, 1976, and thus include mean values already presented in Pfrug et al. (1976) (Fig. 4). It is seen that the daily mean temperature value is about the same when the self-rating is 0 and 1, but higher when the patient is depressed (self-rating 2).

Plusses give mean values for the depressed and manic state of Patient 2. The patient was either manic or depressed without normal days (see case history). The daily mean temperature is evidently highest during the manic period.

Squares show mean values for Patient 3. Here too the depressive periods are correlated with higher daily mean temperature.

Crosses represent mean values for Patient 4, who showed both depressive and manic periods. Her state was judged on a scale 0, 1, 2, !hypomania, and mania. The daily mean temperature shows a gradual increase as depression becomes deeper or mania evident.

Altogether the new data confirm that depression is associated with a higher daily mean temperature than the normal state. Manic states seem to be con- nected with even higher temperatures than depressive ones.

Daily mean temperature and sleep deprivation Patient 1 was given sleep deprivation for one night at a time on several oc- casions (see case history). This led to a considerable improvement but, in her case, only for a short period after each treatment. From the relationship found in Fig. 5 between daily mean temperature and self-rating, one would predict that the patients daily temperatures would be lower during the days after the sleep deprivation, since the treatment lowered the self-rating. Thii was tested on the data from a total of 16 sleep deprivations.

283

I t

Mood

SD

i I

1

! c I

0 !

2 E

Temperature

SD

360 I I I I

320E

36n '?OE

37.0 E 361) I

i 360 3ZOE

Fig. 6. Sleep deprivation; its effect on mood and temperature. Left: the influence of sleep deprivation on mood. Right: the influence on temperature. The small diagrams include data for successive days before and after sleep deprivation (SD). 6a: Data from sleep deprivation June 29, 1974; 6b: Data from sleep deprivation July 9, 1974; 6c: Data from sleep deprivation November 7 , 1974; 6d: Average data from 16 sleep

deprivations.

Fig. 6 shows some representative measurements (6a-6~) and mean values for all the sleep deprivations available (6d). The figure is divided into two parts, mood and temperature, showing the patient data some days before and some days after sleep deprivation (SD). For example, 6a shows that the self-rating was 2 for 4 days before SD, but changed to 0 for the next 5 days. The SD was thus very effective. Accompanying this change in the self-rating is also a lowering of the temperature, see right-hand side of the figure. In the same way, the sleep deprivations on other occasions (Fig. 6b and 6c) were successful in bringing the patient - temporarily - from a depressive state to a normal state. 6b specifies that the self-rating was 2 during 2 days immediately before SD but 0 for the following 3 days, etc. The temperature recordings show that the tendency to increased mean temperature is broken by the SD.

The mean values for all SD-treatments, Fig. 6d, support the conclusion that SD was a valuable treatment for this patient and do not weaken the hypothesis that the daily mean temperature is lowered by the treatment.

Time of daily temperature maximum. Relation to depressive state The time of the temperature maximum was of interest, since it seemed to vary with the depressive state (Pflug et al. (1976)). Figs. 7, 8 and 9 present data from

284

TIME

Fig. 7. Time of daily temperature maximum, Pafient 1. The time of the temperature maximum is plotted for subsequent days (circles). On the left of each row are the self-ratings for each day. Black areas: self-rating of 2 (depression); hatched areas: self-rating of I (not feeling well); white areas: self-rating of 0 (feeling

details in the text. dl). Further

Fig. 8. Time of daily temperature maximum, Patient 3. See legend to Fig. 7.

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Patient 1 (later experimental period), Patient 3 and Patient 4 respectively. Only parts of the total experimental periods are shown. (Data are not reproduced for Patient 2, since we do not have data for longer continuous periods; speci- fically, it was not possible to determine the time for the temperature maximum when the patient was normal).

Fig. 7 shows that Patient 1 has her temperature maximum at 19.00 h when in a normal state (see e.g. good period after Aug. 1, 1975). Only the normal periods are correlated with a stable pattern.

The same observation as reported by Pflug et al. (1976) might be found in the present data: the patients mood seems to improve, but the patient is not aware of it or ready to accept it. An example of this is seen at the end of April 1975 (Fig. 7): the temperature maximum is stable and indicates a normal state several days before the patient gives stable self-ratings of 0.

Fig. 8 shows that Patient 3 has her daily maximum at 12.00 h during normal periods, see period after Jan. 1, 1977. Also in her case, normal periods are correlated with a stable pattern, while depressive periods are characterized by an unstable back and forth movement of the maximum from day to day.

As seen in Fig. 9, Patient 4 has her temperature maximum at 17.00 h on most days during her good periods. However, the pattern is less stable than that during the good periods of Patients 1 and 3. During depression and hypomania,

TIME 8 I4 20

1977 24. Jun Nor 0.c

978

971 .MI

MI

Fig. 9. Time of daily temperature maximum, Patient 4. See legend to Fig. 7. Symbols used in the row to the left fin addition to those explained in Fig. 7): Obliquely hatched

areas: hypomania; Crossed lines: mania.

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a

= t

.. 1 2

SELF-RATING

b

c 1 2

SELF- RATING n

Fig. 10. Phase deviation and self-rating during subsequent 2-week intervals. For each 2-week interval, the phase deviation is plotted versus the self-rating of Patient I ( I0 a)

or Patient 3 ( I0 b).

the temperature pattern is very unstable, in the manic state, the temperature maxima often occur at 17.00 h. To quantify the findings of a more unstable temperature pattern during de-

pressive states, the daily phase deviation was averaged for successive fort- nights and plotted versus averaged self-rating for the same periods, see Fig. 10a and lob.

Fig. 10a gives new data for Patient 1 (data not included in Pfiug et al. (1976)). The correlation coefficient is 0.72, i.e. the same as for earlier measure- ments on this patient (PfIug et d. (1976)).

Fig. 10b shows the results for Patient 3. The correlation between phase deviation and self-rating is fairly good, correlation coefficient 0.78.

The few data for the depressive periods of Patient 4 do not allow a reliable calculation between phase deviation and self-rating (although the correlation coefficient was of the same magnitude as for Patients 1 and 3). The data are therefore not reproduced here.

Period analysis We analysed the period content in the temperature data from Patients 1, 3 and

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4. The aim was to determine whether the period content was the same during depression as during intervals (cf. Pflug et al. (1976)).

Autocorrelation analysis was performed on data from normal and bad peri- ods. In general, the analysis confirmed what could be seen from the original temperature plottings: during normal periods the temperature pattern was more stable than during depressive periods. The autocorrelation function, there fore, has a more evident 24-h periodicity during normal states than during de- pressive ones (cf. representative curves 7b and 7c in Pfiug et al. (1976)); 7b represents a normal period, 7c a depressive period).

The period content of the temperature data showed the expected 24-h period but no systematic Occurrence of other periods around 24 h were found. Since Pfiug et al. (1976) reported an unusually high content of 22.5-h rhythm for a de- pressive period in Patient 1, special care was taken to analyse for rhythms in this regimen. We were not able to find in the new data a significant presence of such a 22.5-h period, either under normal or under depressive conditions.

DISCUSSION

A summary of the findings will perhaps give answers to the questions posed in the introduction. On the basis of our findings, it is evident that oral daily temperature is connected to the depressive state. The higher the self-rating, the more depressive the state, and the higher the temperature. Furthermore, if sleep deprivations are used to lower the self-rating, the daily mean temperature seems also to be lowered. From these results, one would predict that whatever suc- cessful treatment is used to help a manic-depressive patient, it also lowers the temperature. Manic phases produced even higher oral temperatures in some of our patients.

The temperature increase in the depressive or manic episodes might, in gen- eral, be the expression of changed conditions in parts of the CNS (e.g. hypo- thalamus, limbic system). These changed conditions could, in turn, be the result of counter-acting regulatory mechanisms of disturbed vegetative func- tions, or could also be direct indicators of stress. The higher mean temperatures are not a result of thymoleptic or neuroleptic drugs. This is shown by the tem- perature measurement of Patient 3, who was not treated with these drugs (Fig. 3).

We would like to mention a finding not directly connected with the tem- perature measurements. For Patient 3, the weight data show an interesting development during the time she was under observation: the body weight in- creased steadily during periods with self-rating 0 or even 1, but stopped in- creasing, or even diminished, when self-rating was 2, i.e. in the depressive state. It is, however, difficult to conclude whether this behaviour is due to the mood, to changed food-intake or to increased metabolism (and temperature!) during depressive states.

The differences in daily temperature patterns between normal and bad periods are continned in the present study. We find it striking that the temperature maximum changes its position so markedly during bad periods, and interpret

19

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this as an indication of disturbances of the circadian functions of the patients. However, in the new data, we could not find a significant presence of non-24-h rhythms in the neighbourhood of 24 h, as found for Patient 1 in her worst depressive period (Pjlug et al. (1976)). In the worst period, the temperature was not recorded by the patient herself but by the staff. It might be that the later oral measurements by the patient every 3rd h acted as a Zeitgeber and in- fluenced the period content of the rhythm, excluding non-24-h periods. This must be clarified in future work. If such non-24-h rhythms exist in the present data, they are so weak as to preclude any use of them as a diagnostic tool.

The origin of the changes found in the temperature pattern is not clear. It could be, for example, that they are the results of disturbances in the coupling between different oscillators in a circadian system, as discussed by Wever (1975). However, at the present stage, it seems premature to exclude other explanations.

ACKNOWLEDGEMENT We would like to thank Prof. Dr. W . Engelmann for his continuous interest in this work.

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Kripke, D . F., D . J . Mullaney, M . Atkinson & S. Wolf (1978): Circadian rhythm dis- orders in manic-depressives. Biol. Psychiat. 13, 335-351.

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Received June 30, 1980 Burkhard PRug University Psychiatric Hospital Osianderstr. 22 D-7400 Tiibmgen W. Germany

Anders Johnsson A . Tveito Ekse Institute of Physics NJXT University of Trmdheim N-7000 Trondheim Norway