Circadian rhythm in primary affective disorder

Circadian Rhythm in Primary Affective Disorder Carlo Faravelli,

Giampaolo La Malfa, and Salvatore

Roman0

The occurrence of circadian rhythm for physiological (oral temperature, systolic and diastolic blood pressure, and heart rate) and psychological variables (performance and mood) was investigated in 22 patients suffering from primary affective disorder. Patients were investigated both before and after treatment with tricyclic antidepressants. A comparison group of 11 mixed psychiatric patients was also investigated. Among the physiological variables only OT retained its normal circadian rhythm. Such a rhythm, conversely, was not detected for the other physiological variables (except SBP in mixed psychiatric cases) in any of the three groups subject to investigation. Blood pressure (both SBP and DBP) was higher in depressives than in nonaffective patients. Performance (measured by a speech test) and mood (assessed by a visual analogue scale) revealed a welldefined circadian rhythm in depressed patients before treatment. Such a daily variation pattern seems to be present, though not to a significant level, also in depressives after treatment and in nonaffective controls. The present data appear to confirm that the normal circadian rhythm of several physiological parameters is disrupted during depression; such abnormality seems to be trait-dependent rather than state-dependent since clinical recovery did not change the chronobiological profiles. The lack of normal circadian rhythm, however, does not seem to be specific to affective illness, as even nonaffective psychiatric patients showed the same abnormality. On the other hand, the typical symptomatic aspects of depression, such as depressed mood and impaired performance, show a precise daily rhythm, with early morning worsening. @ 1985 by Grune & Stratton, Inc.

F

ROM its earliest stages, clinical observation has described clear temporal patterns in the symptom course of affective disorders: the cyclical character of the phases of the illness, or the typical diurnal variations, with morning worsening of mood, could be mentioned as examples. These characteristics are thought to be dependent on underlying biohumoral changes.‘-5 In recent years chronobiology the study of the temporal aspects of the functions of living organisms, has provided both theoretical and technical tools for the study of these phenomena, thus allowing the rhythmic aspects of affective disorders to be studied in greater depth. Research comparing depressed patients with healthy subjects has shown various kinds of abnormalities of circadian rhythm in the former. Rhythm desynchronisation or phase shift have in fact been demonstrated in the case of several physiological, neurophysiological, and behavioral variables.“‘* HOWever, disturbances in circadian rhythm similar to those mentioned have also been identified, albeit sporadically, in other psychiatric conditions, such as schizophrenia, chronic alcoholism, and anxiety.19-** It would be interesting, therefore, to determine whether the abnormalities SO far collected are characteristic of affective disorders or whether they are in fact indicators of a more general disturbance common to other psychiatric illnesses. This knowledge would clarify the pathogenic importance of chronobiological findings for affective disorders.

From the Institute of Nervous and Mental Diseases, Chair of Clinical Psychiatry. University of Florence and Salvatore Roman0 is from the Center for Chronobiological Data at the University of Florence, Italy. Address reprint requests to Dr. C. Faravelli. Istituto delle Malattie Nervose e Mentali, Policlinico Careggi, K le Morgagni 35 50134 Florence, Italy. @ 1985 by Grune & Stratton, Inc. 0010.440X/85/2604-OM7%03.00/0 364

Comprehensive Psychiatry, Vol. 26, No. 4, (July/August)

1985

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Studies on this topic reveal some uncertainty as to whether depressives’ circadian rhythm abnormalities are stable over time. In other words, it has not yet been established whether such abnormalities are state-dependent, i.e., connected with the acute phases of symptoms, or whether they are stable characteristics of subjects affected by this illness. In the first case, improvement of symptoms due to treatment should be accompanied by restoration of normal circadian rhythm, while in the second case, antidepressant treatment would be without effect. This study aims to contribute to the examination of the problem of the specificity and stability of circadian rhythm disturbances in patients suffering from affective disorders by comparing affective patients examined both before and after treatment with other psychiatric patients. The starting point of this study is the research of Kripke and Mullaney,23.24 who compared depressive patients with patients affected by other psychiatric disorders for a number of physiological variables and failed to differentiate between them. METHOD Twenty-two patients meeting the diagnosis of Primary Affective Disorder (PAD) according to the St. Louis Criteriazs and 11 psychiatric patients randomly selected among those with no evidence of affective symptoms were investigated. All the patients were admitted to the Department of Clinical Psychiatry, Florence University Medical School, and their rest-activity schedules were synchronized for at least five days. During this period patients did not undergo any pharmacological treatment. Patients’ diurnal activity extended from 6 AM to 10 PM and night rest from 10 PM to 6 AM. The subjects had their meals at the times set by hospital routine (7 AM, 11 AM, 5 PM) with no dietary restriction. Two sessions of measurement were carried out, the first at the end of the synchronization period, and the second after four weeks of treatment with tricyclic antidepressants. For the comparison group of nonaffective patients only, the first session in baseline conditions was performed. The following variables were investigated: (1) oral temperature COT); (2) heart rate (HR); (3) systolic blood pressure (SBP): (4) diastolic blood pressure (DBP): (5) psychomotor performance according to the speech test as described by Szabadi*$ and (6) self-assessment of mood by means of a visual analogue scale.?’ Data were collected at 1% hour intervals for a total of 11 measurements (7 AM, 8:30 AM, 10 AM, 11:30 AM, 1 PM, 2:30 PM, 4 PM, 5:3O PM, 7 PM, 8:30 PM, and 10 PM). Night-time assessments were avoided since the patient’s active participation was needed to rate performance and mood. Circadian rhythm was assessed according to the Population Mean Cosinor Method.z8 In brief, for each subject, the time series data are fitted to a 24-hour period sinusoid curve by the least square method. By this procedure three parameters are obtained: individual Mesor (i.e., the baseline level of the curve, also called rhythm adjusted mean), individual Amplitude (i.e. l/2 of the peak-trough difference), and individual Acrophase (i.e., the time at which the peak occurs). The corresponding set of parameters relative to the population under study are inferred on the basis of the individual parameters, The probability of fitting is also measured. Circadian rhythm of the population is said to be detected when the accepted confidence limit (95% in our case) is attained.

RESULTS Tables 1 and 2 summarize the results. No circadian rhythm was detected in any of the three groups with respect to HR and SBP. Circadian rhythm was revealed for the depressives in baseline conditions for OT, performance, and mood. After four weeks of antidepressant therapy, when most of patients had shown substantial clinical improvement, the same parameters, with the exception of mood, also showed circadian rhythm. As far as the control group was concerned, circadian rhythm was identified for OT and mood. No significant differences in rhythm between groups were found on the basis of the overlap of confidence ellipses.

Table 1. Results of the Population Mean Cosinor Analysis for the Physiological (Blood Pressure, Oral Temperature, Heart Rate)

Mesor Mean f SE Systolic Blood Pressure Depressives before 149.5 + 3.90 treatment Depressives after 146.0 + 3.94 treatment Mixed psychiatric 128.4 k 2.63 patients Diastolic Blood Pressure (mm/Hg) Depressives before 95.7 * 1.88 treatment Depressives after 93.37 k 2.34 treatment Mixed psychiatric 82.59 + 2.03 patients Oral Temperature (Degrees centigrade) Depressives before 36.24 + .76 treatment Depressives after 36.28 + .79 treatment Mixed psychiatric 36.35 &- .71 patients Heart Rate (beat/min) Depressives before 80.36 + 2.87 treatment Depressives after 78.05 + 1.57 treatment Mixed psychiatric 74.92 k 1.39 patients Depressive

Amplitude Mean (95% confidence limits) 1.15

Acrophase Hours (95% confidence limits)

Rhythm Detection Level (P)

22.21

.77

2.71

3.37

.26

6.06 (2.6-9.5)

14.51 (13.08-l 9.07)

.02

2.87

4.17

.lQ

1.43

5.58

.55

2.60

12.58

.28

.21 (. 14-.28) .18 (1 l-.25) .18 (.58-.29)

16.25 (13.30-18.46) 14.48 (11 X-7.54) 17.14 (12.31-20.05)

.0007 .0012 ,009

.38

22.27

.94

1 .oo

18.27

.40

2.30

22.25

.27

patients: N = 22 both before and after treatment.

Mixed psychiatric

patients: N = 11.

Table 2. Results of the Population Mean Cosinor Analysis for the Psychological (Speech Test and Mood)

Mesor Mean + SE Speech Test (set) Depressives before treatment Depressives after treatment Mixed psychiatric patients Mood Self Assessment Depressives before treatment Depressives after treatment Mixed psychiatric patients Depressive

366

6.09 + .47 5.32 k

.38

5.34 + .62 (cm) 5.59 + .47

Variables

Variables

Amplitude Mean (95% confidence limits)

Acrophase Hours (95% confidence limits)

.53 (.l O-1.05) .43 (.31-.54) .39

6.05 (1.02-l 1.52) 2.48 (23.31-4.14) 5.24

.047

8.21 (6.38-l 0.19) 8.40

.0002

7.10

2.65 k

.52

.88 (.64-1.12) .32

1.58 f

.50

.59

patients: N = 22 both before and after treatment.

Mixed psychiatric

Rhythm Detection Level (P)

.0002 .18

.07 .54

patients: N = 11.

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With regard to blood pressure (both SBP and DBP) the Mesors of the depressed patients before treatment were significantly higher than those of the comparison group (for SBP: r = 3.65, u” = 32, P < .OOl; for DBP: t = 4.40, df = 32, P < .OOl). This difference persisted even when four weeks of treatment with tricyclics had elapsed (respectively t = 3.02, df = 32, P < .Ol, and t = 3.03, df = 32, P < ,011. COMMENTS

AND CONCLUSION

To evaluate these results it seems advisable to distinguish the physiological variables (OT, SBP, DBP, HR) from the psychological ones (mood and performance). Among the former only oral temperature retained its normal circadian rhythm in all three groups. For the other variables, with the exception of SBP in controls, circadian rhythm was not detected. Since the same variables show well-defined circadian rhythm in normal subjects,‘9 our findings are in agreement with other studies that have reported rhythm desynchronization in depressives, as well as in patients with other psychiattic illnesses. Our data, therefore, do not support the hypothesis that circadian rhythm desynchronization is specific to affective illness. Whether the lack of circadian rhythm is due to specific changes in frequencies, such as ultradian and/or infradian rhythms, cannot be determined on the basis of our results. The possible occurrence of noncircadian rhythm, in fact, was not investigated. What is interesting is that antidepressant treatment, although effective upon the clinical picture (most patients showed a substantial improvement after the therapy), did not modify the chronobiological pattern. For the psychological variables, circadian rhythm was detected among depressives before treatment and, for performance only, among the same patients after treatment. It is well known that depressive symptoms worsen during the early morning: our data seem to show that such a worsening persists, though not to a significant level, after treatment, when most patients have recovered from symptoms. Even the comparison group of mixed psychiatric patients seems to show a circadian variation of mood and performance with acrophases situated in the same period (early morning) as depressives (in this case, too, results closely approached significance). Possible sources of bias have, however, to be considered in order to evaluate our results. Since we did not account for the possible occurrence of infradian rhythms, phenomena of alterliasing might influence the data. Furthermore, the lack of nighttime measurements reduces the power of the statistical analyses. On the other hand, waking the patients up during the night would have influenced the course of the parameters under investigation. Finally, the failure to detect mean circadian rhythm could be attributed either to the occurrence of free-running rhythms or to phenomena of ecphasia. The latter possibility, in turn, might be related to the heterogeneity of the samples: the comparison group included patients suffering from a variety of different psychiatric disorders. Even the depressed patients, though selected according to operational criteria, did not form a clinically homogeneous sample: there were patients with an endogenous symptom pattern (12 cases), and nonendogenous patients (ten cases). In addition six were bipolars and 16 were unipolars.

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However, when circadian rhythm was revealed, no differences in its features were found either between depressives and controls or between depressives before and after treatment. Thus the only significant differences (apart from the obvious ones involving mood and performances) were those in the Mesors of blood pressure (both SBP and DBP). Depressives showed higher values than nonaffective patients. This finding also supports previous nonchronobiological reports that indicated an increase of blood pressure in depressives. 30,31It is noteworthy that in the case of blood pressure too, the treatment did not influence the data. In conclusion, our data support the view that the normal circadian rhythm of several variables is disrupted in depression. Rhythm abnormalities seem to be persistent over time, irrespective of whether the patients are or are not symptomatic, taking the aspect of a trait-characteristic rather than that of a state-variable. Such abnormalities, however, do not appear to be specific to affective disorders, since patients affected by different psychiatric disorders present the same rhythm disturbances. REFERENCES 1. Carrol BJ, Curtis GC, Mendels J: Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction. Arch Gen Psychiat 33:1039-1044, 1976 2. Carrol BJ, Curtis GC, Mendels J: Neuroendocrine regulation in depression. II. discrimination of depressed from nondepressed patients. Arch Gen Psychiat 33:1051-1058, 1976 3. Bunney WE, Murphy DL, Goodwin FK, et al: The “switch-process” in manic-depressive illness. I. A systematic study of sequential behavioral changes. Arch Gen Psychiat 27:295302, 1972 4. Bunney WE, Goodwin FK, Murphy DL, et al: The “switch-process” in manic-depressive illness. II. Relationship to catecholamines, REM sleep and drugs. Arch Gen Psychiat 27:304309, 1972 5. Bunney WE, Goodwin FK, Murphy DL, et al: The “switch-process” in manic-depressive illness. III. Theoretical implications. Arch Gen Psychiat 27:312-317, 1972 6. De Ajuraguerra S: Cycles biologiques et psychiatric. Paris, Masson et C., 1968 7. Atkinson M, Kripke DF, Wolf SR: Autorhythmometry in manic-depressives. Chronobiologia 2:325-335, 1975 8. Grow P: Diurnal variations in hospitalized depressive patients during depression and when healthy. Arch Psychiat Nervenk 228:329-399, 1980. 9. Halberg F, Trap G: Psychophysiologic circadian rhythmometry on manic-depressive twins. Chronobiologia 6:387-396, 1979 10. Kramer BA, Katz JL: Circadian temperature variation and depressive illness. J Clin Psychiat 39:439-444, 1978 11. Nikitopoulo G, Crammer JL: Change in diurnal temperature rhythm in manicdepressive illness. Brit Med J 1:1311-1314, 1976 12. Pflug B, Erikson R, Johnson A: Depression and daily temperature. A long-term study. Acta Psychiat Sand 54:254-266, 1976 13. Pflug B, Martin W: Analysis of circadian temperature rhythms in endogenous depressive illness. Arch Psych Nervenkr 229:127-132, 1980 14. Pflug B: Manic-depressive state and daily temperature. Some circadian studies. Acta Psychiat Stand, 63:277-289, 1981 15. Rudolf GA, Bischofs W, Blaszkiewitz, et al: Kreislauffunktionen im unbeeinflussten und modifizierten zirkadianen rhythmus bei depressionen. Vorlanfige Mitteilung Arzn Forsch 26:1174-1177, 1976 16. Rudolf GA, Toelle R: Circadian rhythm of circulatory functions in depressives and on sleep deprivation. Int Pharmacopsych 12:174-183, 1977

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