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Weak 24-h periodicity of body temperature and increased plasma vasopressin in melancholic depression
European Neuropsychopharmacology 11 (2001) 7–14 www.elsevier.com / locate / euroneuro
Weak 24-h periodicity of body temperature and increased plasma vasopressin in melancholic depression Liesbeth van Londen
a,d ,
*, Jaap G. Goekoop a,d , Gerard A. Kerkhof b , Koos H. Zwinderman c , Victor M. Wiegant e , David De Wied e
a
Department of Psychiatry, Leiden University, P.O. Box 9600, 2300 RC Leiden, The Netherlands b Department of Physiology, Leiden University, 2300 RC Leiden, The Netherlands c Department of Medical Statistics, Leiden University, 2300 RC Leiden, The Netherlands d Endegeest Psychiatric Hospital, PO Box 1250, 2340 BG Oegstgeest, The Netherlands e Rudolf Magnus Institute for Neurosciences, Department of Pharmacology, Utrecht University, PO Box 80040, 3508 TA Utrecht, The Netherlands Received 13 July 1999; accepted 21 September 2000
Abstract Earlier work has shown that plasma vasopressin levels of depressed patients were higher than those of healthy controls. The aim of the present study was to determine whether plasma vasopressin levels were correlated to parameters of the circadian rhythm. Forty-one patients with major depression and twenty-five controls participated in a case–control design under natural circumstances in a field study to investigate plasma vasopressin levels three times daily, circadian motor activity, and the 24-h periodicity of body temperature for five consecutive 24-h periods. Temperature measurements consisted of at least five, but mostly six or more measurements every 24 h. Twenty-two percent of the patients, but none of the controls lacked 24-h periodicity of body temperature. In melancholic patients increased vasopressin levels in plasma correlated with a weak 24-h periodicity of body temperature. The role of vasopressin is discussed in the light of the present findings. 2001 Elsevier Science B.V. All rights reserved. Keywords: Major depression; Vasopressin; Circadian rhythm; Body temperature; Locomotor activity; Human
1. Introduction Depressed patients show changes in the circadian rhythm of body temperature (Avery et al., 1982; Anderson and Wirz-Justice, 1991; Bicakova-Rocher et al., 1996). It is not yet clear if they represent functional changes in the endogenous oscillator, or result from masking influences by external entraining environmental factors, or both (Van den Hoofdakker, 1994). Depressed patients have increased hypothalamic–pituitary–adrenocortical activity and vasopressin appears to play a role synergizing the CRH effects on corticotropic cells (Holsboer et al., 1995). In the human
*Corresponding author. Tel.: 131-71-517-2404; fax: 131-71-5172404. E-mail address: [email protected] (L. van Londen).
vasopressin and oxytocin neurons were found to be activated in the paraventricular nucleus (Purba et al., 1996). Subsequently, we reported that depressed patients had higher vasopressin concentrations in plasma than controls (Van Londen et al., 1997). These vasopressin levels were related to psychomotor retardation and to increased motor activity during sleep (Van Londen et al., 1998). In the present analysis body temperature rhythms of these patients were analysed. We sought to determine whether the increased plasma vasopressin levels were related to abnormalities in the 24-h periodicity of body temperature and to changes in the circadian motor activity pattern in these patients. Three questions were addressed: (1) did the patients have a weaker 24-h periodicity of body temperature than the controls? (2) If so, were weaker 24-h periodicities of body temperature related to psychomotor retardation and increased motor activity during sleep? (3)
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 00 )00124-3
L. van Londen et al. / European Neuropsychopharmacology 11 (2001) 7 – 14
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Was strength of the 24-h periodicity of body temperature related to plasma vasopressin concentrations?
2. Experimental procedures
2.1. Subjects Fifty-six patients with a major depressive episode and forty-eight healthy controls entered the study (Van Londen et al., 1997). Of these, 41 patients, 17 men and 24 women aged between 22 and 77 years (mean543, S.D.514) and 25 controls, 13 men and 12 women aged between 19 and 73 years (mean540, S.D.515), had complete datasets for psychopathological rating scales, plasma vasopressin levels, activity monitoring and temperature variables. There were no significant differences in age (t 5 0.95, P50.35) or sex ratio ( x 2 5 0.70, P50.40) between patients and controls. The ratio of premenopausal to postmenopausal women was comparable in patients (16:8) and controls (10:2) (Fisher’s exact test P50.44). Seven female patients used an oral contraceptive versus two of the female controls (Fisher’s exact test P50.69). Significantly more patients (n518) than controls (n54) were smokers (Fisher’s exact test P50.03). Patients were recruited from the in-patient depression unit and outpatient clinic of the Endegeest Psychiatric Hospital (Oegstgeest, The Netherlands). They were nine in-patients and thirty-two out-patients. Exclusion criteria were previously diagnosed endocrine disease, hypertension and orthostatic hypotension, and other diseases or medication that might affect plasma vasopressin levels. Antidepressant and anxiolytic medication had been discontinued at least 2 weeks before entrance to the study. Patients had to remain medication-free during the week of the study. Seven patients however, were allowed a maximum of 10 mg a day of clorazepate, oxazepam or temazepam, because of severe anxiety or insomnia. The controls were recruited through advertising in local newspapers, and were screened for past history of psychiatric illness. Further exclusion criteria were: current medical illness, use of medication, current stressful events or recent sleep shifts, including working at night. Controls underwent the same assessments as patients. All participating subjects refrained from alcohol use and from excessive motor activity (sports, cycling, etc.) during the 12-h period preceding the study procedures and during the subsequent measurement days. They were allowed to eat and drink freely and were free to move about. The study was approved by the Medical Ethical Committee of the Leiden University Medical Centre. Written informed consent was obtained after a complete description of the study.
2.2. Psychiatric assessment Diagnoses were made according to the DSM-III-R
criteria (APA, 1987) for a major depressive episode by a psychiatrist (L.V.L.). The sample consisted of six bipolar, three psychotic and thirty-two unipolar depressed patients. None of these showed seasonal patterns. Following DSMIII-R criteria, 19 (46.3%) of the 41 patients had a melancholic subtype depression. The Comprehensive Psy˚ chopathological Rating Scale (CPRS) (Asberg et al., ˚ 1978), the two subscales, the Montgomery and Asberg Depression Rating Scale (MADRS) (Montgomery and ˚ Asberg, 1979), and the Brief Anxiety Scale (BAS) (Tyrer et al., 1984) were applied in a semi-standardised interview for patients and controls. For patients, scores of at least 20 on the MADRS were required before entry. The ˆ ` Retardation Rating Scale (SRRS) (Widlocher, ¨ Salpetriere 1983) was used to rate psychomotor retardation. The means (6S.D.) of the ratings of questionnaires for the patients were: CPRS 65612; MADRS 3266; BAS 2066; SRRS 1968.
2.3. Biochemical assay procedures The procedures were described earlier (Van Londen et al., 1997). Briefly, blood samples of 50 ml were drawn by venipuncture consecutively at three fixed times (08.00 h, 16.00 h and 23.00 h) in 1 day. The plasma was immediately separated at 48C, and stored at 2808C to await analysis. Samples were radioimmunoassayed (RIA) in duplicate following extraction of peptides from plasma (efficiency approximately 100%) using C 8 Bond Elut cartridges (Analytichem International, USA). RIA of vasopressin was carried out with a rabbit antiserum (coded W1E). The detection limit was 0.5 pg / tube, yielding a sensitivity of 0.5 pg / ml for plasma (extracted assay). Intraand interassay coefficients of variation were 9.9 and 15.9%, respectively. Clinical and laboratory results were obtained independently. Samples were coded, and in- and out-patients and controls were assayed together.
2.4. Activity monitor Spontaneous movements were assessed continuously with an activity monitor (Gaehwiler Electronic), worn on the wrist of the non-dominant hand. See Van Londen et al. (1998) for details of procedure. The monitor counts the occurrences of supra-threshold wrist activity per 30-s epoch and stores this count as a one-byte word in a 32-kbyte solid state memory. The data from the activity monitor were analysed with a computer program which calculated a number of activity indices separately for each day. Times when the monitor was not worn, as reported in the sleep / awake log, were excluded from the analyses. Table 1 presents the eight activity indices that were calculated. The indices were calculated separately for each day, then averaged over the days of the measurement period. This period started at 18:00 h on the day of blood
L. van Londen et al. / European Neuropsychopharmacology 11 (2001) 7 – 14 Table 1 Results of continuous motor activity monitoring correlated with strength of the circadian temperature rhythm for patients and controls (Spearman correlation coefficients) Motor activity indices
Mean activity during wakefulness Fragmentation a during wakefulness Total wake time Mean activity during sleep Fragmentation a during sleep Total sleep time Immobility b Awake / sleep activity ratio
Patients
Controls
r
P
r
P
0.071 0.366 0.395 20.407 20.286 20.034 0.400 0.433
0.66 0.020 0.012 0.009 0.073 0.834 0.011 0.005
0.09 20.22 20.14 0.38 0.48 0.32 20.43 20.43
0.70 0.32 0.53 0.08 0.023 0.15 0.044 0.044
a Fragmentation, the number of periods of consecutive zero-count epochs divided by the total number of zero-count epochs; expresses the extent to which the rest periods were interrupted by activity. b Immobility, the proportion of zero-count epochs relative to the total number of epochs during sleep; expresses the relative amount of rest during sleep.
sampling, and continued for the next 6 days up to 10.00 h on the last day, thus including five consecutive, complete 24-h periods. For the correlation analysis, we entered these eight variables.
2.5. Temperature measures Rectal temperature was measured with a digital thermometer (Phillips, Type HP 5316). The measurements were carried out on the same consecutive days as the activity monitor was worn. At least five, but mostly six or more measurements were made every 24 h. In order to promote uniform distribution of measurements over the waking part of the day, subjects were instructed to measure their temperature at three fixed moments in the day, i.e. 12.00, 16.00 and 20.00 h. Additionally, they took their temperature in the morning, immediately after awakening before leaving the bed and at night, in bed, when about to fall asleep. Measuring temperature was the last thing they were asked to do before turning out the lights with the intention of going to sleep. Patients and controls were not awakened to measure temperatures. When they woke up spontaneously during the night and early in the morning they also took their temperatures. Not to compromise the validity of these data, it was impressed on the subjects that a missing measurement was preferable to a nonvalid one. Patients were instructed to keep a written diary with the measurements. No temperatures were measured after hot baths or showers.
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rhythm. First, the resulting spectrum of spectral lines was analysed for the presence of the predominant 24-h component. There was no cut-off point concerning the height of the standardised line. A short spectral line at 24.00 h would still represent 24-h periodicity if it were the highest line compared to the other spectral lines. In the analyses the group of patients was divided into those with and those without the prominent 24-h component in the power spectrum. Fig. 1 shows an example of the resulting power spectrum of both a depressed patient, where the 24-h component did not dominate the spectrum, and of a normal control. Second, z scores were calculated for the height of the standardised spectral 24-h line, representing the strength of the circadian temperature rhythm. Only patients showing 24-h periodicity were entered in the subsequent analyses to compare z scores to those of the controls.
2.7. Statistical analysis For the comparisons between characteristics of patients and controls x 2 , Fisher’s exact test, and Student’s t-test were applied. Because the distribution of the plasma vasopressin levels and the z scores of the 24-h periodicities were skewed, the non-parametric Mann–Whitney U test and the Spearman correlation coefficient were used (twotailed). Significance was set at P,0.05. The Bonferroni equation is presented in case of multiple comparisons.
3. Results
3.1. Presence and strength of 24 -h periodicity of body temperature Twenty-five of the forty-one patients (61%) had complete temperature measurements compared to fourteen of the twenty-five controls (56%; Fisher’s exact test P5 0.80). Nine of the forty-one patients (22%), but none of the controls, lacked the 24-h predominant periodicity in body temperature (Fisher’s exact test P50.011; see also Fig. 1.). Since 24-h periodicity was absent in nine patients, these nine were excluded from comparison with the controls. The remaining 32 patients had significantly weaker 24-h periodicities than did the 25 controls (U 5 205.0, P50.0017; Fig. 2) indicating weaker circadian temperature rhythms in the patients than in the controls.
3.2. Psychomotor retardation rated by questionnaire 2.6. Calculation of temperature rhythm For each individual, the rectal temperature values were subjected to periodogram analysis (Lomb, 1976). The typical resulting spectrum shows a prominent peak with a 24-h period, signifying the presence of a clear 24-h
Severity of the depression (MADRS) ( r 5 2 0.3086, P50.05) and psychomotor retardation (SSRS) ( r 5 2 0.3639, P50.019; significant after Bonferroni correction P,0.025) correlated inversely with strength of 24-h periodicity in patients.
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Fig. 1. Examples of a temperature periodogram of a healthy control and that of one of the nine depressed patients lacking the predominant standardised spectral line at 24-h (the Lomb method for unevenly sampled data).
3.3. Activity monitor Table 1 presents the results. The awake / sleep ratio, which is not a separate variable but the ratio between mean activity during wakefulness and mean activity during sleep, correlated to strength of the 24-h periodicity (significant after Bonferroni correction P,0.006). In the controls no significant correlations between these parameters were found.
3.4. Plasma vasopressin The 41 subjects with complete datasets reported on here
were a subset of those participating in a larger prospective study of the role of vasopressin and oxytocin in depression (Van Londen et al., 1997, 1998). The 41 depressed patients had significantly higher mean vasopressin concentrations in plasma than did the controls (the average of the three measurements: 7.2565.4 versus 4.6563.6 pg / ml; U 5 329.5, P50.016). No significant circadian variation in the vasopressin concentrations was found, but this is likely due to the low number of samples analysed per 24 h. In the 32 patients showing 24-h periodicity the average of the three plasma vasopressin measurements were not significantly correlated to the strength of the 24-h periodicity in temperature ( r 5 20.13, P50.40). There was a trend for
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3.6. Possible confounding factors
Fig. 2. Strength of the circadian temperature rhythm represented by z scores of the standardised spectral 24-h line in the 32 depressed patients with 24-h periodicity compared to those of the 25 controls. The patients show a significantly weaker circadian temperature rhythm than the controls (P50.0017).
significance in the 25 controls ( r 5 20.38 P50.06). Patients without 24-h periodicity had significantly higher mean vasopressin levels than both did patients with 24-h periodicity and controls together (9.3365.59 versus 5.7864.70 pg / ml; U 5 139.0, P50.028).
3.5. Melancholic subtype depression The 19 melancholic patients did not differ significantly from the 22 non-melancholic patients as to presence of a predominant 24-h component of the temperature rhythm. The melancholic patients had a significantly weaker 24-h periodicity of temperature (z score 2.5061.42) than the non-melancholic patients (z score 3.1361.15; U 5 130.0, P50.039). In the melancholic patients plasma vasopressin concentrations at all three time-points were significantly inversely related to the strength of the 24-h periodicity (with the mean of the three plasma vasopressin concentrations: r 5 20.5425, P50.016) (Fig. 3).
Fig. 3. Correlation between strength of the circadian temperature rhythm represented by z scores of the standardised spectral 24-h line and mean vasopressin (AVP) plasma level in the melancholic patients ( r 5 2 0.5425, P50.016).
Neither presence nor strength of the 24-h periodicity in body temperature was significantly related to sex, age, smoking, use of oral contraceptives, menopausal status, inor out-patient status, bi- or unipolar depression. Of the nine patients who lacked 24-h periodicity four were taking a benzodiazepine. Of the 32 others three were taking a benzodiazepine (Fisher’s exact test P50.031). Thus, among patients without 24-h periodicity were more subjects that could not do 6 days without a benzodiazepine than among patients with 24-h periodicity. The patients taking a benzodiazepine (z score 1.3561.58) had a significantly weaker 24-h periodicity than did the 34 medication-free patients (z score 3.1461.02; U 5 42.0, P50.0076). They were not significantly more depressed (P50.82) or more anxious (P50.51) according to the rating scales.
4. Discussion The answers to the three questions posed in the introduction are as follows: 22% of the depressed patients and none of the controls lacked the predominant 24-h periodicity in body temperature. The remaining patients had a weaker 24-h periodicity than the controls. These results are in keeping with most (Tsujimoto et al., 1990; Daimon et al., 1992), but not all (Monk et al., 1994) previous reports. A weak 24-h periodicity of body temperature correlated significantly with psychomotor retardation and increased motor activity during sleep. In the subgroup of melancholic patients, a weak 24-h periodicity was related to elevated concentrations of vasopressin in plasma. These results were controlled for the possible influence of smoking. A separate analysis excluding those patients who used a benzodiazepine was carried out and showed similar results. At least three hypotheses for these findings are presented: (i) central and / or peripheral vasopressin concentrations influence temperature regulation; (ii) all of the findings are caused by masking; (iii) increased vasopressin concentrations, circadian motor behaviour and circadian temperature rhythm are affected by a common factor, with or without influencing each other. In the healthy human the majority of motor activity takes place during wakefulness. Temperature declines during the night and sleep onset occurs on the falling limb of the temperature curve (Czeisler et al., 1980; Zulley and Wever, 1982; Campbell and Broughton, 1994; Murphy and Campbell, 1997). The best physiologic predictor of the onset of sleep is the degree of vasodilation of blood vessels in the skin of hands and feet (Krauchi et al., 1999). Vasodilation of these blood vessels increases heat loss at the extremities and core body temperature drops. The high nocturnal temperatures seen in depressed patients are not caused by decreased sweating (Avery et al., 1999). With regard to the first hypothesis (i) it is possible that increased
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levels of vasopressin cause poorer peripheral vasodilation by way of its vasoconstrictor action, thus leading to higher core temperatures and sleep disturbances. From animal research we know that centrally injected vasopressin does not affect body temperature in nonfebrile animals. Only very high dosages produced a fall in body temperature in normothermic animals. Diamant and De Wied (1993) found a mild hyperthermic response to a low dose of vasopressin, whereas a high dose caused immediate hypothermia. But these findings should not be compared to the situation in the depressed patients, where the increase in vasopressin was measured in the peripheral circulation and where the endogenous secretion was modest compared to the relatively high dosages injected exogenously in the laboratory animals. In the view of the second hypothesis (ii), one could argue that increased muscular activity at night raises the heatload of the body, resulting in a decreased amplitude of the circadian temperature. However, severe disruptions of sleep in patients with Alzheimer’s dementia do not result in changes in circadian temperature rhythm (Prinz et al., 1984). In discussing the third option (iii) one could hypothesise that changes in the circadian rhythms of both motor behaviour and body temperature could be the result of a decreased coupling force of the endogenous pacemaker. Subsequently, they could influence each other, further weakening the reduced output of the central pacemaker. There is evidence for a mutual, bidirectional interaction between circadian rhythms of activity and deep body temperature (Zulley and Wever, 1982). In the present study we found a significant correlation between changes in the circadian rhythms of motor behaviour and body temperature, and the increased concentration of vasopressin in plasma of depressed patients. This latter finding could also, indirectly, be explained by a weakened output of the central endogenous pacemaker. Vasopressin in plasma originates from magnocellular neurons of the hypothalamic paraventricular (PVN), supraoptic (SON) and accessory nuclei. The peptide is transported through axons of these neurons that run via the internal zone of the median eminence to the posterior lobe of the pituitary, whence it is released into the bloodstream (De Wied et al., 1993). In experimental animals circulating vasopressin exhibits circadian variations (Windle et al., ˚ 1992). Most (George et al., 1975; Asplund and Aberg, 1991), but not all (Barreca et al., 1988) studies report a nocturnal increase of plasma vasopressin in humans. We did not find such a nocturnal rise of plasma vasopressin in the subjects, but this is not surprising as we measured only three times in 24 h, the latest of which was at 23.00 h. The circadian variations in plasma vasopressin levels (George et al., 1975; Windle et al., 1992) suggest that the circadian pacemaker influences the magnocellular vasopressinproducing neurons. The nucleus suprachiasmaticus (SCN) is seen as the main structure responsible for the circadian
temperature rhythm, although other structures, such as the adjacent preoptic area of the anterior hypothalamus and the influence of the pineal hormone melatonin may also be of importance (Buijs, 1996). In rats, there is evidence for monosynaptic transmission of information from the SCN to the PVN (Hermes et al., 1996). There is a substantial congruity between these projections in rat and hamster and the anatomical organisation in the human SCN projections (Dai et al., 1997). The neurons of a normally functioning SCN inhibit the production of vasopressin in magnocelullar neurons of the PVN (Hermes and Renaud, 1993). Weak functioning of the SCN would thus result in disinhibition of these magnocellular neurons producing increased levels of vasopressin in plasma. Chronobiological studies have suggested that circadian pacemaker function is altered, presumably weakened in depression (Healy, 1987; Van den Hoofdakker, 1994; Duncan, 1996). Recently, evidence for a disturbed function of the SCN was found in postmortem brain material of depressed patients (Zhou et al., 1998), showing that vasopressin neurons in the SCN were less active. The reason for such a change in pacemaker function remains unknown. It is unlikely that a disturbed endogenous pacemaker is the primary cause of the depressive state. Data from depressed patients (Pollak et al., 1989) and from experimental animals under free-running circumstances (Meerlo et al., 1997) do not support this hypothesis. However, a weak functioning endogenous pacemaker may be a vulnerability factor for the development of melancholic features, that appear during the behavioural process in which the individual is trying to adapt to stress. What begins as a functional stress response may thus result in nonadaptive changes of circadian rhythmicity and disinhibited vasopressin release, and may lead to, or maintain and complicate, the pathological depressive state with melancholic symptoms. Bright light therapy (Wirz-Justice et al., 1993) and induced motor activity by exercising (Miser, 2000), both capable of improving mood in depressed patients, might serve as exogenous stimulators of the function of the SCN. Our findings are in keeping with the hypothesis that in melancholic depression, the symptoms of disturbed circadian rhythms of sleep, motor behaviour and body temperature are caused by a weakened output of the endogenous circadian pacemaker. However, these data are correlative and causal attributions should not be made. Several issues regarding our methodology should be considered. First, our study was undertaken under ‘everyday’ conditions with the inevitable limitations of the hospital setting and of an out-patient clinic. Thus, we did not control for environmental lighting, that is known to influence the circadian clock and its output rhythms and one should keep this in mind in interpreting the results of our study. However, we did find robust significant differences between patients and controls, that deserve attention. The increased plasma vasopressin levels we found in these patients could not be explained by sex and age differences,
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smoking, hypertension, hypovolaemia, hyperosmolality or dehydration (Van Londen et al., 1997). Second, we did not use rectal probes for continuous temperature measurement, because we feared dropping out of patients due to physiological and psychological discomfort. Therefore, subjects took their own temperatures and sometimes missed out measurements. Yet, more than half of the patients as well as of the controls had complete datasets. Patients and controls were equally diligent in measuring temperature. Although sparse and irregular sampling introduces a methodological weakness, reliable estimates of the circadian temperature rhythm can be made (Monk, 1987). Third, we did not control for phase of the menstrual cycle in women. It is however reported that the menstrual cycle influences temperature levels (Wagner et al., 1992), but not the phase of the temperature rhythm (Kattapong et al., 1995; Parry et al., 1997). Finally, the fact that seven patients took a benzodiazepine could have influenced the results. Those seven had a weaker 24-h periodicity of body temperature than did the medication-free patients. It is known that benzodiazepines can have phase-shifting effects on the sleep–wake cycle (Duncan, 1996). However the fact that the dosages that were used by these patients were very low, a separate analysis eliminating those seven patients was carried out, showing similar results.
Acknowledgements This work was supported by a grant from the Netherlands Organisation for Scientific Research (NWO; KWO 900-548-117). The authors thank R.M. Buijs, Professor, Netherlands Institute for Brain Research, Amsterdam, for advice and comments. We are grateful to Ilonka Tolboom who helped collect and program data.
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Murphy, P.J., Campbell, S.S., 1997. Nighttime drop in body temperature: a physiological trigger for sleep onset? Sleep 20, 505–511. Parry, B.L., LeVeau, B., Mostofi, N., Naham, H.C., Loving, R., Clopton, P., Gillin, J.C., 1997. Temperature circadian rhythms during the menstrual cycle and sleep deprivation in premenstrual dysphoric disorder and normal comparison subjects. J. Biol. Rhythms 12, 34–46. Pollak, C.P., Alexopoulos, G.S., Moline, M.L., Wagner, D.R., 1989. Level, amplitude and waveform of free-running body temperature and cortisol rhythms in depressives living in isolation from all temporal cues. Sleep Res. 18, 437. Prinz, P.N., Christie, C., Smallwood, R., Vitalino, P., Bokan, J., Vitiello, M.V., Martin, D., 1984. Circadian temperature variation in healthy aged and in Alzheimer’s disease. J. Gerontol. 39, 30–35. Purba, J.S., Hoogendijk, W.J.G., Hofman, M.A., Swaab, D.F., 1996. Increased numbers of vasopressin and oxytocin expressing neurons in the paraventricular nucleus of the human hypothalamus in depression. Arch Gen Psychiatry 53, 137–143. Tsujimoto, T., Yamada, N., Shimoda, K., Hanada, K., Takahashi, S., 1990. Circadian rhythms in depression. Part II: Circadian rhythms in inpatients with various mental disorders. J. Affect. Disord. 18, 199– 210. Tyrer, P., Owen, R.T., Cichetti, D.V., 1984. The brief scale for anxiety: a subdivision of the Comprehensive Psychopathological Rating Scale. J. Neurol. Neurosurg. Psychiatry 47, 970–975. Van den Hoofdakker, R.H., 1994. Chronobiological theories of nonseasonal affective disorders and their implications for treatment. J. Biol. Rhythms 9, 157–183. Van Londen, L., Goekoop, J.G., Van Kempen, G.M.J., FrankhuijzenSierevogel, A.C., Wiegant, V.M., Van der Velde, E.A., De Wied, D.,
1997. Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology 17, 284–292. Van Londen, L., Kerkhof, G.A., Van den Berg, F., Goekoop, J.G., Zwinderman, A.H., Frankhuijzen-Sierevogel, A.C., Wiegant, V.M., De Wied, D., 1998. Plasma arginine vasopressin and motor activity in major depression. Biol. Psychiatry 43, 196–204. Wagner, D.R., Zindell, S., Hurt, S., Pollak, C., Severino, S., Moline, M., 1992. Circadian temperature phase variability and the menstrual cycle. Sleep Res. 21, 391. ¨ Widlocher, D.J., 1983. Psychomotor retardation: clinical, theoretical and psychometric aspects. Psychiatr. Clin. North Am. 6, 27–40. Windle, R.J., Forsling, M.L., Guzek, J.W., 1992. Daily rhythms in the hormone content of the neurohypophysial system and release of oxytocin and vasopressin in the male rat: effect of constant light. J. Endocrinol. 133, 283–290. Wirz-Justice, A., Graw, P., Krauchi, K., Gisin, B., Jochum, A., Arendt, J., Fisch, H.U., Buddeberg, C., Poldinger, W., 1993. Light therapy in seasonal affective disorder is independent of time of day or circadian phase. Arch. Gen. Psychiatry 50, 929–937. Zhou, J.-N., Riemersma, R., Unmehopa, U., Pool, Ch., Hoogendijk, W.J.G., Te Bulte, L., Hofman M.A., Swaab, D.F. (1998). A disorder in the biological clock of the brain in depression. In: Hoogendijk W.J.G. Brain changes in depression. Ph.D. Thesis, Vrije Universiteit Amsterdam. Zulley, J., Wever, R.A., 1982. Interaction between the sleep–wake cycle and the rhythm of rectal temperature. In: Aschoff, J., Daan, S., Groos, G. (Eds.), Vertebrate Circadian Systems. Springer-Verlag, Berlin, Heidelberg, New York, pp. 253–261.
Weak 24-h periodicity of body temperature and increased plasma vasopressin in melancholic depression Liesbeth van Londen
a,d ,
*, Jaap G. Goekoop a,d , Gerard A. Kerkhof b , Koos H. Zwinderman c , Victor M. Wiegant e , David De Wied e
a
Department of Psychiatry, Leiden University, P.O. Box 9600, 2300 RC Leiden, The Netherlands b Department of Physiology, Leiden University, 2300 RC Leiden, The Netherlands c Department of Medical Statistics, Leiden University, 2300 RC Leiden, The Netherlands d Endegeest Psychiatric Hospital, PO Box 1250, 2340 BG Oegstgeest, The Netherlands e Rudolf Magnus Institute for Neurosciences, Department of Pharmacology, Utrecht University, PO Box 80040, 3508 TA Utrecht, The Netherlands Received 13 July 1999; accepted 21 September 2000
Abstract Earlier work has shown that plasma vasopressin levels of depressed patients were higher than those of healthy controls. The aim of the present study was to determine whether plasma vasopressin levels were correlated to parameters of the circadian rhythm. Forty-one patients with major depression and twenty-five controls participated in a case–control design under natural circumstances in a field study to investigate plasma vasopressin levels three times daily, circadian motor activity, and the 24-h periodicity of body temperature for five consecutive 24-h periods. Temperature measurements consisted of at least five, but mostly six or more measurements every 24 h. Twenty-two percent of the patients, but none of the controls lacked 24-h periodicity of body temperature. In melancholic patients increased vasopressin levels in plasma correlated with a weak 24-h periodicity of body temperature. The role of vasopressin is discussed in the light of the present findings. 2001 Elsevier Science B.V. All rights reserved. Keywords: Major depression; Vasopressin; Circadian rhythm; Body temperature; Locomotor activity; Human
1. Introduction Depressed patients show changes in the circadian rhythm of body temperature (Avery et al., 1982; Anderson and Wirz-Justice, 1991; Bicakova-Rocher et al., 1996). It is not yet clear if they represent functional changes in the endogenous oscillator, or result from masking influences by external entraining environmental factors, or both (Van den Hoofdakker, 1994). Depressed patients have increased hypothalamic–pituitary–adrenocortical activity and vasopressin appears to play a role synergizing the CRH effects on corticotropic cells (Holsboer et al., 1995). In the human
*Corresponding author. Tel.: 131-71-517-2404; fax: 131-71-5172404. E-mail address: [email protected] (L. van Londen).
vasopressin and oxytocin neurons were found to be activated in the paraventricular nucleus (Purba et al., 1996). Subsequently, we reported that depressed patients had higher vasopressin concentrations in plasma than controls (Van Londen et al., 1997). These vasopressin levels were related to psychomotor retardation and to increased motor activity during sleep (Van Londen et al., 1998). In the present analysis body temperature rhythms of these patients were analysed. We sought to determine whether the increased plasma vasopressin levels were related to abnormalities in the 24-h periodicity of body temperature and to changes in the circadian motor activity pattern in these patients. Three questions were addressed: (1) did the patients have a weaker 24-h periodicity of body temperature than the controls? (2) If so, were weaker 24-h periodicities of body temperature related to psychomotor retardation and increased motor activity during sleep? (3)
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 00 )00124-3
L. van Londen et al. / European Neuropsychopharmacology 11 (2001) 7 – 14
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Was strength of the 24-h periodicity of body temperature related to plasma vasopressin concentrations?
2. Experimental procedures
2.1. Subjects Fifty-six patients with a major depressive episode and forty-eight healthy controls entered the study (Van Londen et al., 1997). Of these, 41 patients, 17 men and 24 women aged between 22 and 77 years (mean543, S.D.514) and 25 controls, 13 men and 12 women aged between 19 and 73 years (mean540, S.D.515), had complete datasets for psychopathological rating scales, plasma vasopressin levels, activity monitoring and temperature variables. There were no significant differences in age (t 5 0.95, P50.35) or sex ratio ( x 2 5 0.70, P50.40) between patients and controls. The ratio of premenopausal to postmenopausal women was comparable in patients (16:8) and controls (10:2) (Fisher’s exact test P50.44). Seven female patients used an oral contraceptive versus two of the female controls (Fisher’s exact test P50.69). Significantly more patients (n518) than controls (n54) were smokers (Fisher’s exact test P50.03). Patients were recruited from the in-patient depression unit and outpatient clinic of the Endegeest Psychiatric Hospital (Oegstgeest, The Netherlands). They were nine in-patients and thirty-two out-patients. Exclusion criteria were previously diagnosed endocrine disease, hypertension and orthostatic hypotension, and other diseases or medication that might affect plasma vasopressin levels. Antidepressant and anxiolytic medication had been discontinued at least 2 weeks before entrance to the study. Patients had to remain medication-free during the week of the study. Seven patients however, were allowed a maximum of 10 mg a day of clorazepate, oxazepam or temazepam, because of severe anxiety or insomnia. The controls were recruited through advertising in local newspapers, and were screened for past history of psychiatric illness. Further exclusion criteria were: current medical illness, use of medication, current stressful events or recent sleep shifts, including working at night. Controls underwent the same assessments as patients. All participating subjects refrained from alcohol use and from excessive motor activity (sports, cycling, etc.) during the 12-h period preceding the study procedures and during the subsequent measurement days. They were allowed to eat and drink freely and were free to move about. The study was approved by the Medical Ethical Committee of the Leiden University Medical Centre. Written informed consent was obtained after a complete description of the study.
2.2. Psychiatric assessment Diagnoses were made according to the DSM-III-R
criteria (APA, 1987) for a major depressive episode by a psychiatrist (L.V.L.). The sample consisted of six bipolar, three psychotic and thirty-two unipolar depressed patients. None of these showed seasonal patterns. Following DSMIII-R criteria, 19 (46.3%) of the 41 patients had a melancholic subtype depression. The Comprehensive Psy˚ chopathological Rating Scale (CPRS) (Asberg et al., ˚ 1978), the two subscales, the Montgomery and Asberg Depression Rating Scale (MADRS) (Montgomery and ˚ Asberg, 1979), and the Brief Anxiety Scale (BAS) (Tyrer et al., 1984) were applied in a semi-standardised interview for patients and controls. For patients, scores of at least 20 on the MADRS were required before entry. The ˆ ` Retardation Rating Scale (SRRS) (Widlocher, ¨ Salpetriere 1983) was used to rate psychomotor retardation. The means (6S.D.) of the ratings of questionnaires for the patients were: CPRS 65612; MADRS 3266; BAS 2066; SRRS 1968.
2.3. Biochemical assay procedures The procedures were described earlier (Van Londen et al., 1997). Briefly, blood samples of 50 ml were drawn by venipuncture consecutively at three fixed times (08.00 h, 16.00 h and 23.00 h) in 1 day. The plasma was immediately separated at 48C, and stored at 2808C to await analysis. Samples were radioimmunoassayed (RIA) in duplicate following extraction of peptides from plasma (efficiency approximately 100%) using C 8 Bond Elut cartridges (Analytichem International, USA). RIA of vasopressin was carried out with a rabbit antiserum (coded W1E). The detection limit was 0.5 pg / tube, yielding a sensitivity of 0.5 pg / ml for plasma (extracted assay). Intraand interassay coefficients of variation were 9.9 and 15.9%, respectively. Clinical and laboratory results were obtained independently. Samples were coded, and in- and out-patients and controls were assayed together.
2.4. Activity monitor Spontaneous movements were assessed continuously with an activity monitor (Gaehwiler Electronic), worn on the wrist of the non-dominant hand. See Van Londen et al. (1998) for details of procedure. The monitor counts the occurrences of supra-threshold wrist activity per 30-s epoch and stores this count as a one-byte word in a 32-kbyte solid state memory. The data from the activity monitor were analysed with a computer program which calculated a number of activity indices separately for each day. Times when the monitor was not worn, as reported in the sleep / awake log, were excluded from the analyses. Table 1 presents the eight activity indices that were calculated. The indices were calculated separately for each day, then averaged over the days of the measurement period. This period started at 18:00 h on the day of blood
L. van Londen et al. / European Neuropsychopharmacology 11 (2001) 7 – 14 Table 1 Results of continuous motor activity monitoring correlated with strength of the circadian temperature rhythm for patients and controls (Spearman correlation coefficients) Motor activity indices
Mean activity during wakefulness Fragmentation a during wakefulness Total wake time Mean activity during sleep Fragmentation a during sleep Total sleep time Immobility b Awake / sleep activity ratio
Patients
Controls
r
P
r
P
0.071 0.366 0.395 20.407 20.286 20.034 0.400 0.433
0.66 0.020 0.012 0.009 0.073 0.834 0.011 0.005
0.09 20.22 20.14 0.38 0.48 0.32 20.43 20.43
0.70 0.32 0.53 0.08 0.023 0.15 0.044 0.044
a Fragmentation, the number of periods of consecutive zero-count epochs divided by the total number of zero-count epochs; expresses the extent to which the rest periods were interrupted by activity. b Immobility, the proportion of zero-count epochs relative to the total number of epochs during sleep; expresses the relative amount of rest during sleep.
sampling, and continued for the next 6 days up to 10.00 h on the last day, thus including five consecutive, complete 24-h periods. For the correlation analysis, we entered these eight variables.
2.5. Temperature measures Rectal temperature was measured with a digital thermometer (Phillips, Type HP 5316). The measurements were carried out on the same consecutive days as the activity monitor was worn. At least five, but mostly six or more measurements were made every 24 h. In order to promote uniform distribution of measurements over the waking part of the day, subjects were instructed to measure their temperature at three fixed moments in the day, i.e. 12.00, 16.00 and 20.00 h. Additionally, they took their temperature in the morning, immediately after awakening before leaving the bed and at night, in bed, when about to fall asleep. Measuring temperature was the last thing they were asked to do before turning out the lights with the intention of going to sleep. Patients and controls were not awakened to measure temperatures. When they woke up spontaneously during the night and early in the morning they also took their temperatures. Not to compromise the validity of these data, it was impressed on the subjects that a missing measurement was preferable to a nonvalid one. Patients were instructed to keep a written diary with the measurements. No temperatures were measured after hot baths or showers.
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rhythm. First, the resulting spectrum of spectral lines was analysed for the presence of the predominant 24-h component. There was no cut-off point concerning the height of the standardised line. A short spectral line at 24.00 h would still represent 24-h periodicity if it were the highest line compared to the other spectral lines. In the analyses the group of patients was divided into those with and those without the prominent 24-h component in the power spectrum. Fig. 1 shows an example of the resulting power spectrum of both a depressed patient, where the 24-h component did not dominate the spectrum, and of a normal control. Second, z scores were calculated for the height of the standardised spectral 24-h line, representing the strength of the circadian temperature rhythm. Only patients showing 24-h periodicity were entered in the subsequent analyses to compare z scores to those of the controls.
2.7. Statistical analysis For the comparisons between characteristics of patients and controls x 2 , Fisher’s exact test, and Student’s t-test were applied. Because the distribution of the plasma vasopressin levels and the z scores of the 24-h periodicities were skewed, the non-parametric Mann–Whitney U test and the Spearman correlation coefficient were used (twotailed). Significance was set at P,0.05. The Bonferroni equation is presented in case of multiple comparisons.
3. Results
3.1. Presence and strength of 24 -h periodicity of body temperature Twenty-five of the forty-one patients (61%) had complete temperature measurements compared to fourteen of the twenty-five controls (56%; Fisher’s exact test P5 0.80). Nine of the forty-one patients (22%), but none of the controls, lacked the 24-h predominant periodicity in body temperature (Fisher’s exact test P50.011; see also Fig. 1.). Since 24-h periodicity was absent in nine patients, these nine were excluded from comparison with the controls. The remaining 32 patients had significantly weaker 24-h periodicities than did the 25 controls (U 5 205.0, P50.0017; Fig. 2) indicating weaker circadian temperature rhythms in the patients than in the controls.
3.2. Psychomotor retardation rated by questionnaire 2.6. Calculation of temperature rhythm For each individual, the rectal temperature values were subjected to periodogram analysis (Lomb, 1976). The typical resulting spectrum shows a prominent peak with a 24-h period, signifying the presence of a clear 24-h
Severity of the depression (MADRS) ( r 5 2 0.3086, P50.05) and psychomotor retardation (SSRS) ( r 5 2 0.3639, P50.019; significant after Bonferroni correction P,0.025) correlated inversely with strength of 24-h periodicity in patients.
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Fig. 1. Examples of a temperature periodogram of a healthy control and that of one of the nine depressed patients lacking the predominant standardised spectral line at 24-h (the Lomb method for unevenly sampled data).
3.3. Activity monitor Table 1 presents the results. The awake / sleep ratio, which is not a separate variable but the ratio between mean activity during wakefulness and mean activity during sleep, correlated to strength of the 24-h periodicity (significant after Bonferroni correction P,0.006). In the controls no significant correlations between these parameters were found.
3.4. Plasma vasopressin The 41 subjects with complete datasets reported on here
were a subset of those participating in a larger prospective study of the role of vasopressin and oxytocin in depression (Van Londen et al., 1997, 1998). The 41 depressed patients had significantly higher mean vasopressin concentrations in plasma than did the controls (the average of the three measurements: 7.2565.4 versus 4.6563.6 pg / ml; U 5 329.5, P50.016). No significant circadian variation in the vasopressin concentrations was found, but this is likely due to the low number of samples analysed per 24 h. In the 32 patients showing 24-h periodicity the average of the three plasma vasopressin measurements were not significantly correlated to the strength of the 24-h periodicity in temperature ( r 5 20.13, P50.40). There was a trend for
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3.6. Possible confounding factors
Fig. 2. Strength of the circadian temperature rhythm represented by z scores of the standardised spectral 24-h line in the 32 depressed patients with 24-h periodicity compared to those of the 25 controls. The patients show a significantly weaker circadian temperature rhythm than the controls (P50.0017).
significance in the 25 controls ( r 5 20.38 P50.06). Patients without 24-h periodicity had significantly higher mean vasopressin levels than both did patients with 24-h periodicity and controls together (9.3365.59 versus 5.7864.70 pg / ml; U 5 139.0, P50.028).
3.5. Melancholic subtype depression The 19 melancholic patients did not differ significantly from the 22 non-melancholic patients as to presence of a predominant 24-h component of the temperature rhythm. The melancholic patients had a significantly weaker 24-h periodicity of temperature (z score 2.5061.42) than the non-melancholic patients (z score 3.1361.15; U 5 130.0, P50.039). In the melancholic patients plasma vasopressin concentrations at all three time-points were significantly inversely related to the strength of the 24-h periodicity (with the mean of the three plasma vasopressin concentrations: r 5 20.5425, P50.016) (Fig. 3).
Fig. 3. Correlation between strength of the circadian temperature rhythm represented by z scores of the standardised spectral 24-h line and mean vasopressin (AVP) plasma level in the melancholic patients ( r 5 2 0.5425, P50.016).
Neither presence nor strength of the 24-h periodicity in body temperature was significantly related to sex, age, smoking, use of oral contraceptives, menopausal status, inor out-patient status, bi- or unipolar depression. Of the nine patients who lacked 24-h periodicity four were taking a benzodiazepine. Of the 32 others three were taking a benzodiazepine (Fisher’s exact test P50.031). Thus, among patients without 24-h periodicity were more subjects that could not do 6 days without a benzodiazepine than among patients with 24-h periodicity. The patients taking a benzodiazepine (z score 1.3561.58) had a significantly weaker 24-h periodicity than did the 34 medication-free patients (z score 3.1461.02; U 5 42.0, P50.0076). They were not significantly more depressed (P50.82) or more anxious (P50.51) according to the rating scales.
4. Discussion The answers to the three questions posed in the introduction are as follows: 22% of the depressed patients and none of the controls lacked the predominant 24-h periodicity in body temperature. The remaining patients had a weaker 24-h periodicity than the controls. These results are in keeping with most (Tsujimoto et al., 1990; Daimon et al., 1992), but not all (Monk et al., 1994) previous reports. A weak 24-h periodicity of body temperature correlated significantly with psychomotor retardation and increased motor activity during sleep. In the subgroup of melancholic patients, a weak 24-h periodicity was related to elevated concentrations of vasopressin in plasma. These results were controlled for the possible influence of smoking. A separate analysis excluding those patients who used a benzodiazepine was carried out and showed similar results. At least three hypotheses for these findings are presented: (i) central and / or peripheral vasopressin concentrations influence temperature regulation; (ii) all of the findings are caused by masking; (iii) increased vasopressin concentrations, circadian motor behaviour and circadian temperature rhythm are affected by a common factor, with or without influencing each other. In the healthy human the majority of motor activity takes place during wakefulness. Temperature declines during the night and sleep onset occurs on the falling limb of the temperature curve (Czeisler et al., 1980; Zulley and Wever, 1982; Campbell and Broughton, 1994; Murphy and Campbell, 1997). The best physiologic predictor of the onset of sleep is the degree of vasodilation of blood vessels in the skin of hands and feet (Krauchi et al., 1999). Vasodilation of these blood vessels increases heat loss at the extremities and core body temperature drops. The high nocturnal temperatures seen in depressed patients are not caused by decreased sweating (Avery et al., 1999). With regard to the first hypothesis (i) it is possible that increased
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levels of vasopressin cause poorer peripheral vasodilation by way of its vasoconstrictor action, thus leading to higher core temperatures and sleep disturbances. From animal research we know that centrally injected vasopressin does not affect body temperature in nonfebrile animals. Only very high dosages produced a fall in body temperature in normothermic animals. Diamant and De Wied (1993) found a mild hyperthermic response to a low dose of vasopressin, whereas a high dose caused immediate hypothermia. But these findings should not be compared to the situation in the depressed patients, where the increase in vasopressin was measured in the peripheral circulation and where the endogenous secretion was modest compared to the relatively high dosages injected exogenously in the laboratory animals. In the view of the second hypothesis (ii), one could argue that increased muscular activity at night raises the heatload of the body, resulting in a decreased amplitude of the circadian temperature. However, severe disruptions of sleep in patients with Alzheimer’s dementia do not result in changes in circadian temperature rhythm (Prinz et al., 1984). In discussing the third option (iii) one could hypothesise that changes in the circadian rhythms of both motor behaviour and body temperature could be the result of a decreased coupling force of the endogenous pacemaker. Subsequently, they could influence each other, further weakening the reduced output of the central pacemaker. There is evidence for a mutual, bidirectional interaction between circadian rhythms of activity and deep body temperature (Zulley and Wever, 1982). In the present study we found a significant correlation between changes in the circadian rhythms of motor behaviour and body temperature, and the increased concentration of vasopressin in plasma of depressed patients. This latter finding could also, indirectly, be explained by a weakened output of the central endogenous pacemaker. Vasopressin in plasma originates from magnocellular neurons of the hypothalamic paraventricular (PVN), supraoptic (SON) and accessory nuclei. The peptide is transported through axons of these neurons that run via the internal zone of the median eminence to the posterior lobe of the pituitary, whence it is released into the bloodstream (De Wied et al., 1993). In experimental animals circulating vasopressin exhibits circadian variations (Windle et al., ˚ 1992). Most (George et al., 1975; Asplund and Aberg, 1991), but not all (Barreca et al., 1988) studies report a nocturnal increase of plasma vasopressin in humans. We did not find such a nocturnal rise of plasma vasopressin in the subjects, but this is not surprising as we measured only three times in 24 h, the latest of which was at 23.00 h. The circadian variations in plasma vasopressin levels (George et al., 1975; Windle et al., 1992) suggest that the circadian pacemaker influences the magnocellular vasopressinproducing neurons. The nucleus suprachiasmaticus (SCN) is seen as the main structure responsible for the circadian
temperature rhythm, although other structures, such as the adjacent preoptic area of the anterior hypothalamus and the influence of the pineal hormone melatonin may also be of importance (Buijs, 1996). In rats, there is evidence for monosynaptic transmission of information from the SCN to the PVN (Hermes et al., 1996). There is a substantial congruity between these projections in rat and hamster and the anatomical organisation in the human SCN projections (Dai et al., 1997). The neurons of a normally functioning SCN inhibit the production of vasopressin in magnocelullar neurons of the PVN (Hermes and Renaud, 1993). Weak functioning of the SCN would thus result in disinhibition of these magnocellular neurons producing increased levels of vasopressin in plasma. Chronobiological studies have suggested that circadian pacemaker function is altered, presumably weakened in depression (Healy, 1987; Van den Hoofdakker, 1994; Duncan, 1996). Recently, evidence for a disturbed function of the SCN was found in postmortem brain material of depressed patients (Zhou et al., 1998), showing that vasopressin neurons in the SCN were less active. The reason for such a change in pacemaker function remains unknown. It is unlikely that a disturbed endogenous pacemaker is the primary cause of the depressive state. Data from depressed patients (Pollak et al., 1989) and from experimental animals under free-running circumstances (Meerlo et al., 1997) do not support this hypothesis. However, a weak functioning endogenous pacemaker may be a vulnerability factor for the development of melancholic features, that appear during the behavioural process in which the individual is trying to adapt to stress. What begins as a functional stress response may thus result in nonadaptive changes of circadian rhythmicity and disinhibited vasopressin release, and may lead to, or maintain and complicate, the pathological depressive state with melancholic symptoms. Bright light therapy (Wirz-Justice et al., 1993) and induced motor activity by exercising (Miser, 2000), both capable of improving mood in depressed patients, might serve as exogenous stimulators of the function of the SCN. Our findings are in keeping with the hypothesis that in melancholic depression, the symptoms of disturbed circadian rhythms of sleep, motor behaviour and body temperature are caused by a weakened output of the endogenous circadian pacemaker. However, these data are correlative and causal attributions should not be made. Several issues regarding our methodology should be considered. First, our study was undertaken under ‘everyday’ conditions with the inevitable limitations of the hospital setting and of an out-patient clinic. Thus, we did not control for environmental lighting, that is known to influence the circadian clock and its output rhythms and one should keep this in mind in interpreting the results of our study. However, we did find robust significant differences between patients and controls, that deserve attention. The increased plasma vasopressin levels we found in these patients could not be explained by sex and age differences,
L. van Londen et al. / European Neuropsychopharmacology 11 (2001) 7 – 14
smoking, hypertension, hypovolaemia, hyperosmolality or dehydration (Van Londen et al., 1997). Second, we did not use rectal probes for continuous temperature measurement, because we feared dropping out of patients due to physiological and psychological discomfort. Therefore, subjects took their own temperatures and sometimes missed out measurements. Yet, more than half of the patients as well as of the controls had complete datasets. Patients and controls were equally diligent in measuring temperature. Although sparse and irregular sampling introduces a methodological weakness, reliable estimates of the circadian temperature rhythm can be made (Monk, 1987). Third, we did not control for phase of the menstrual cycle in women. It is however reported that the menstrual cycle influences temperature levels (Wagner et al., 1992), but not the phase of the temperature rhythm (Kattapong et al., 1995; Parry et al., 1997). Finally, the fact that seven patients took a benzodiazepine could have influenced the results. Those seven had a weaker 24-h periodicity of body temperature than did the medication-free patients. It is known that benzodiazepines can have phase-shifting effects on the sleep–wake cycle (Duncan, 1996). However the fact that the dosages that were used by these patients were very low, a separate analysis eliminating those seven patients was carried out, showing similar results.
Acknowledgements This work was supported by a grant from the Netherlands Organisation for Scientific Research (NWO; KWO 900-548-117). The authors thank R.M. Buijs, Professor, Netherlands Institute for Brain Research, Amsterdam, for advice and comments. We are grateful to Ilonka Tolboom who helped collect and program data.
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