ing to the standard criteria of Rechtschaffen and. Kales [1968]. Plasma melatonin ..... [Gerard et al., 1978; Allen et al., 19871 and the gen- eral increase in sleep ...
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J Pineal Res 1995; 19:116-122 Printed in the United Srates of Americ-11
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Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia Hajak G, Rodenbeck A, Staedt J, Bandelow B, Huether G, Riither E. Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia. J. Pineal Res. 1995; 19:116-122. 0 Munksgaard, Copenhagen
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Abstract: Polysomnographic sleep patterns and melatonin secretion were investigated in 10 patients (age: 41.3 f 9.5 years) who suffered from chronic primary insomnia and complained predominantly about difficulties in maintaining sleep and in five healthy controls (age 27.2 f 0.7 years). Nocturnal plasma melatonin concentrations were obtained hourly, measured by direct radioimmunoassay and statistically compared between insomniacs and controls with age as a covariate. Plasma melatonin levels in the patient group tended to begin increasing earlier in the evening and were significantly (P50.01) lower during the middle of the night (peak value 82.5 f 26.5 pg/ml) than in the healthy controls (peak value 116.8 f 13.5 pg/ml). Among the patients, the most severely reduced nocturnal plasma melatonin levels were found in those patients with a history of sleep disturbance lasting for longer than five years (N = 6; age 41.8 f 11.7 years; duration 15.3 f 5.9 years; peak value 72.1 f 25.0 pg/ml); whereas those chronic insomniacs affected for fewer than five years had relatively higher nocturnal levels (N = 4; age 40.6 f 6.5 years; duration 3.8 f 1.5 years; peak value 98.2 f 23.9 pg/ml). These results show that the circadian rhythm of melatonin secretion is disturbed in patients with chronic primary insomnia, and that the nocturnal plasma melatonin secretion is increasingly more affected the longer the patients are unable to maintain a regular sleep pattern.
Introduction
The circadian pattern of melatonin secretion has been widely accepted as a measure of the circadian clock in humans [Rosenthal, 19911 and it has been extensively proven to be a marker for circadian phase position [Lewy and Sack, 19891. An alteration in the circadian melatonin pattern is the most unambiguous indicator of the dissociation of the circadian system from environmental Zeitgebers [Wever, 19891. The circadian rhythm of melatonin with the highest levels occurring during the dark period of the day [Reiter, 19861 is thought to be triggered by a pacemaker anatomically located in the suprachiasmatic nucleus of the hypothalamus [Moore and Klein, 19741, where putative melatonin receptors are located in humans [Stankov and Reiter, 19901. Melatonin secretion is suppressed by bright light [Lewy et al. 19801, which is able to entrain the circadian melatonin rhythm to the environmental 24-
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Gbran Hajak, Andrea Rodenbeck, Jilrgen Staedt, Bonrvin Bandelow, Gerald Huether, and Eckart Rilther Department of Psychiatry, University of Gottingen, Germany
Key words: circadian rhythm chronobiology - insomnia - melatonin pineal gland - sleep-wake cycle Address reprint requests to Dr. Goran Hajak, Department of Psychiatry, University of Gottingen, von-Siebold-Str. 5, 37075, Gottingen, Germany. Received March 3, 1994; accepted July 11, 1995.
hr day-night cycle [Lynch et al., 19781. Since chronic insomniacs were found to have a reduced amplitude of body temperature rhythm [Lack et al., 19881, a general amplitude attenuation of the circadian system may also be reflected in their melatonin rhythm. Considering that melatonin promotes internal and external synchronization in humans [Arendt et al., 19861, it is possible that disturbances in central control mechanisms which also influence circadian sleep-wake functions may be related to changes in the waveform of melatonin secretion in insomniacs. However, no systematic study has considered the possible alterations of the secretion pattern of melatonin in insomniac patients suffering predominantly from difficulties in maintaining sleep. In order to test whether circadian functions are altered in such individuals, the present study investigated plasma melatonin levels in patients suffering from chronic primary insomnia with frequent nighttime awakenings as their predominating problem.
Melatonin in chronic primary insomnia Methods Subjects
Five young healthy male subjects without problems in sleeping (age 27.2 f 0.7 years) and seven male and three female patients with chronic primary insomnia (age 41.3 _+ 9.5 years) took part in the study. The patient group included five young (age 33.0 f 3.1 years) and five middle-aged patients (age 49.6 f 4.7 years). The average duration of insomnia was 10.7 f 7.9 years. Four patients (age 40.5 k 6.5 years) suffered from sleep difficulties for less than 5 years (duration 3.8 f 1.5 years), while the other six patients (age 41.8 _+ 11.7 years) were affected for longer than 5 years (duration 15.3 f 5.9 years). The patients were diagnosed following the criteria of the Fourth Revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) [American Psychiatric Association, 19941, using a structured interview [Schramm et al., 19931and polysomnographc recording for two entire nights. The patients also fulfilled the criteria of psychophysiological or idiopathic insomnia according to the criteria of the International Classification of Sleep Disorders [American Sleep Disorders Association, 19901. All patients suffered predominantly from difficulties in maintaining sleep. None of the subjects had a history of a medical, neurological, or psychiatric disease other than primary insomnia, and especially did not fulfill the criteria of any type of depression according to DSM-IV. Neither the control subjects nor the patients had taken any hypnotic or sedative drugs in the 2 weeks prior to the study. Six patients had never taken any hypnotics, whereas one patient was free of hypnotic intake for at least 1 year and the remaining two patients had only intermittently used hypnotics (“a few times per month”) prior to the beginning of this study. Sleep laboratory procedure
Every patient and each healthy control took part in one nighttime session (5 PM to 8 AM)in the sleep laboratory that was preceded by one night without biochemical assessment to allow the subject to adapt to the laboratory conditions. Both groups refrained from alcohol and nicotine 24 hr prior to the sleep laboratory visit and during the whole of the recording session. During the same time period, the subjects were given a standardized protein- and carbohydrate-balanced diet. The subjects went to bed at their usual bedtime (designated as lights off). Light intensity was held constant at 1000 Lux from 4 hr before the usual bedtime of each individual onwards; after the lights were turned off and during the night, the light intensity was kept below 50 Lux.
Blood samples were obtained hourly by an indwelling catheter from an antebrachial vein from 5 PM to 8 AM. Plasma was rapidly separated and stored at -70°C. Status of vigilance and sleep was continuously measured during each session by polysomnography according to the criteria of Rechtschaffen and Kales [ 19681 and of the German Society of Sleep Research and Sleep Medicine [Penzel et al., 19931. Polysomnography recordings included electroencephalogram, electrooculogram, submental electromyogram, electrocardiogram, nasal and oral airflow, thoracic and abdominal breathing effort, arterial oxygen saturation and electromyogram of the anterior tibialis muscles. Data acquisition and analysis
Sleep parameters were evaluated manually according to the standard criteria of Rechtschaffen and Kales [1968]. Plasma melatonin was measured by direct radioimmunoassay [Fraser et al., 19831 using antibodies (GS 704-6483) from Guildhay Antisera (Guilford, U. K.). The detection limit of this assay (at which 5% of the ligand is displaced) was 1 pg/ 300 p1. Intra- and interassay variance (at melatonin concentrations of 10-30 pg/300 p1) were less than 6% and 12%, respectively. The hourly measured plasma melatonin levels were plotted as a function of real time (chronogram method) and additionally as a function of time related to when the lights were turned off (time = 0). The peak values for each group or subgroup were also calculated. The statistical analyses of the plasma melatonin levels were based on the multifactor analysis of covariance (ANOVA) with repeated measures and age as a covariate to offset the lack of age matching of the subjects. If the overall Fvalues for group effects of interaction between group and melatonin concentrations were significant, subsequent analysis was performed using the Mann-Whitney U test in order to compare melatonin values for each point of measurement and melatonin peak values between the groups. Furthermore, the time of melatonin onset was calculated using the time the melatonin levels exceeded the mean value between 3 to 5 hr before lights off, respectively 6 PM and 8 PM,for more than two standard deviations. Differences in sleep parameters between patients and controls were analyzed by the Mann-Whitney U test. Data from this analysis have been presented in part at the 1993 annual meetings of the European Sleep Research Society [Rodenbeck et al., 19941 and the German Society of Neuropharmacology and Pharmacopsychiatry [Hajak et al., 19931.
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Hajak et a].
Results Sleep
For all the subjects, a total of 30 sessions, including adaptation nights, were conducted in the sleep laboratory. Recordings of the 15 nights, when the biochemical measurements were undertaken, were used for data analysis. The insomniac patients slept worse than the healthy controls. Sleep efficiency (total sleep time/time in bed) and slow wave sleep stage IV were decreased and the percentage time awake of total time in bed and the number of awakenings were increased. Patients suffering from insomnia for less than 5 years did not differ from those affected for a longer period in respect to their sleep parameters (Table 1). Melatonin
The comparison of patients and controls with the ANOVA showed a significant interaction between the factors both for the lights off analysis (df = 13, F = 9.655, P 50.001) and the real time analysis (df = 16, F = 8.619, P I O . O O l ) , indicating a different time course of the plasma melatonin concentration in the two groups. The difference in plasma melatonin concentration was statistically significant in the Mann-Whitney U test for all measurements from
four to seven hours after lights off ( P 50.05 and P 5 0.01, respectively) (Fig. la) and in the real-time analysis between 3 AM and 8 AM ( P I 0.05 and P 5 0.01, respectively) (Fig. 1b). Peak values in patients (lights off analysis: 85.4 f 30.5 pg/ml; real time analysis: 82.5 f 26.9 pg/ml) were significantly lower than in healthy controls (lights off analysis: 114.1 f 14.3 pg/ml, P 5 0.05; real time analysis: 116.8 f 13.5 pg/ml, P 50.01). In the real time analysis, the increase in plasma melatonin concentration occurred earlier in the evening in the insomniac group than in the healthy subjects. Plasma melatonin levels in the insomniacs were significantly higher at 9 PM, 10 PM ( P I 0.01) and 11 PM ( P 5 0.05) than in the controls, but time of melatonin onset did not differ significantly in patients and controls. Standard deviation and standard error of mean of nighttime plasma melatonin levels in the group of insomniacs was found to be slightly larger than in the control group. This was obviously due to the inhomogeneity among the insomniac patients with respect to age and the duration of their disorder. The older patients in this group (mean age 49.6 f 4.7 years) had somewhat lower nocturnal plasma melatonin levels than the younger patients (mean age 33.0 f 3.1 years) (Fig. 2). Of even greater impact on the nocturnal plasma melatonin levels in insomniac patients, however,
Table 1. Sleep parameters (mean values * standard deviation) in 10 patients with chronic primary sleep maintenance insomnia and five healthy controlsa Healthy controls TIB (min) SPT (min) TST (min) SE (TSTTTIB) SL I (min) SL II (min) SL SWS (min) SL REM (min) W (YoTlB) I (YoTIB) II (YoTIB) Ill (YoTlB) IV (YoTIB) SWS (YoTIB) REM (YoTIB) Cycles Awakenings
* * * *
476.3 39.8 429.4 68.5 402.9 * 60.4 84.3 8.2 18.8 11.5 28.0 14.5 41.0 9.8 111.9 26.4 14.4 7.6 10.5 3.4 41.9 2 4.4 8.2 1.4 6.7 2.9 14.9 f 3.8 17.3 4.3 3.8 0.8 18.2 t 8.9
*
* *
* *
*
Insomniac patients total
* * * *
465.3 36.7 426.6 + 42.7 345.5 66.9 74.3 14.2 13.7 6.1 23.9 i 7.4 75.7 t 66.gb 133.1 * 79.8 24.3 14.2 10.8 3.9 37.8 i 3.3 9.4 9.0 2.9 4.2 12.3 i 10.3 14.1 5.0 3.9 1.2 30.8 13.3
* * * * * * *
P
Patients complaints 5 5 years
* * *
444.5 27.1 339.1 42.2 317.5 98.1 71.7 -L 22.8 11.1 * 7.2 24.1 + 9.4 93.6 99.0 160.1 * 121.3 27.2 * 22.6 10.3 4.5 34.1 i 21.5 13.9 12.3 2.5 3.6 16.4 t 12.0 12.2 i 4.9 3.8 1.9 24.0 13.5
*
* *
*
Patients complaints 2 5 years 479.2 444.8 364.1 76.1 15.4 23.7 61.3 115.0 22.4 11.2 40.3 6.5 3.2 9.7 15.4 4.0 35.3
P
* 37.5 * 34.9 * 35.3 * 6.4 * 5.2 * 6.7 * 32.1' * 40.8 * 6.6 * 3.8 i t
* * * *
*
4.5 5.5 4.8 9.0 5.2 0.6 12.2
a T w subgroups ~ of patients divided according to the duration of their insomnia (less or more than 5 years) are also included. P-values were calculated using Mann-Whitney U test (- = not significant; t = P s 0.05). TIB = time in bed; SPT = sleep period time (total sleep time t nocturnal wake time); TST = total sleep time; SE = sleep efficiency (TSTTTIB); SWS = slow wave sleep (stage Ill t stage IV); SL I, SL II, SL SWS, SL REM = sleep latency stage I , I I , SWS, REM (time from lights off to beginning of respective sleep stage ): W (OhTIB) = percentage total stage wake/TlB; I (D/,TlB), II (%TIB), Ill (%TIB), IV (YoTIB), SWS (YoTIB), REM (YoTIB) = percentage of respective sleep stageTTlB; cycles = number of non-REM-sleep cycles (one cycle lasts from the beginning of sleep stage I to the end of a period of REM sleep); Awakenings = number of nocturnal awakenings. bn = 9 (one patient without slow wave sleep). 'n = 5 (one patient without slow wave sleep).
118
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Fig. I . Variation in nocturnal plasma melatonin concentrations (mean values f standard error of mean) in 10 patients with chronic primary insomnia (age 41.3 f 9.5 years) and five healthy controls (age 27.2 f 0.7 years) with respect either to when the lights were turned off (Fig, la) or to real time (Fig lb). P-values were calculated by multifactor analysis of covariance (ANOVA) with repeated measures and age as a covariate, and with subsequent Mann-Whitney U test (+ = P 5 0.05; * = P S 0.01).
was the duration of their complaints. The ANOVA showed a significant interaction between the factors for the analysis of the plasma melatonin concentration related to lights off (df = 13, F = 2.444, P I O.OOl), but not for the real time analysis (df = 16, F = 0.601, P 50.879). Those patients who reported to have had difficulties in sleep maintenance for more than five years (age 41.8 f 11.7 years; duration 15.3 f 5.9 years) showed significantly ( P 5 0.05) lower melatonin levels for 0, 2, 3, 6 and 7 hr after lights off compared to the patients with a shorter duration of insomnia (age 40.5 f 6.5 years; duration 3.8 f 1.5 years) (Fig. 3a). Peak plasma melatonin values in patients suffering more than 5 years from insomnia were also remarkably lower (lights off analysis: 72.5 f 22.9 pgl ml; real time analysis: 72.1 f 25.0 pg/ml) than in patients with insomnia for less than 5 years (lights off analysis: 104.7 f 17.5 pg/ml; real time analysis: 98.2 f 23.9 pg/ml).
Fig. 2 . Variation in nocturnal plasma melatonin concentrations (mean values f standard error of mean) in five young (age 33.0 f 3.1 years) and five older patients (age 49.6 f 4.7 years) suffering from chronic primary insomnia with respect either to when the lights were turned off (Fig. 2a) or to real time (Fig 2b).
Discussion It was rather unexpected to find that the circadian rhythm and especially the nocturnal secretion of melatonin were not affected very much in patients suffering from severe insomnia and who had been unable to maintain normal sleep patterns for a period up to 5 years. These results suggest that it takes a long time (at least more than 5 yearsfrom this study, on average about 15 years) until such a disturbance of the sleep-wake cycle is paralleled by a significant decline of nocturnal plasma melatonin levels. The decreased nocturnal melatonin secretion seen in the long-term sleepmaintainance insomniacs provides strong evidence for the presence of a disturbance in the processes regulating circadian rhythms and an alteration in the entrainment of internal and external (e.g., light-dark) cycles. Our results clearly show that the disturbed night sleep alone is not responsible for the decreased nocturnal melatonin secretion in long-term insomniac patients. Abnor-
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Hajak et al. a) fitted to lights off Melatonin (pg/ml)
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Fig. 3 . Nocturnal plasma melatonin concentration (mean values f standard error of mean) in four patients with chronic primary insomnia with a short duration of less than 5 years (age 40.6 f 6.5 years; duration 3.8 f 1.5 years) and six patients with long-term insomnia lasting more than 5 years (age 41.8 f 11.7 years; duration 15.3 f 5.9 years) with respect either to when the lights were turned off (Fig. 3a) or to real time (Fig 3b). P-values were calculated by multifactor analysis of covariance (ANOVA) with repeated measures and age as a covariate, and with subsequent Mann-Whitney U test (+ = P 2 0.05; * = P 50.01).
ma1 circadian time pattern or reduced amplitude of nocturnal melatonin secretion have been reported in age-matched studies for depression [e.g., Beck-Friis et al., 1985; Sodtre et al., 1989; Parry et al., 19901, schizophrenia [Ferrier et al., 19821, panic disorder [McIntyre et al., 19871, alcoholism [Wetterberg et al., 19921 and cluster headache [Chazot et al., 19841. All these diseases are accompanied by disturbances of sleep and circadian rhythmicity. Diminished evening plasma melatonin concentrations have also been found in patients suffering from midwinter insomnia [Hansen et al., 19871. Decreased nocturnal plasma melatonin is also associated with reduced sleep quality in old age [Haimov et al., 19931 and a pattern of insidious change in plasma melatonin and a desynchronisation of temperature rhythm and sleep has been reported in chronic insomniac patients [MacFarlane et al., 19841.
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Our finding that disturbed sleep alone is not associated with changes in melatonin secretion patterns is also supported by several studies on the acute interaction between sleep and nocturnal melatonin secretion. While blunting of the circadian temperature rhythm has been reported during experimental sleep deprivation [Aschoff, 19811, this was not the case with nocturnal melatonin secretion [Jimerson et al., 1977; Akerstedt et al., 1979; SalinPascual et al., 19881. In dim light, constant routine experiments, sleep had no effect on total nighttime melatonin excretion compared to subjects during bed rest with continual wakefulness [Morris et al., 19901. Even pinealectomy did not affect rest-activity patterns in animals [Quay 1968; Underwood and Siopes, 19841. Obviously, sleep is not an essential prerequisite for the physiological increase in nocturnal melatonin plasma levels [see also Jimerson et al., 1977; Akerstedt et al., 19791. The reduced efficiency of sleep and increased number of nocturnal awakenings do not therefore directly account for the blunting of the nocturnal melatonin secretion observed in the insomniacs included in this study. The decrease in the plasma melatonin levels was slightly more profound in the middle-aged patients compared to the young patients in the present study. This may be due to the physiological reduction in melatonin secretion that occurs with aging [Iguchi et al., 1982; Sharma et al., 19891. The decline in melatonin secretion with advancing age is paralleled by a deterioration of the normal sleeping patterns [Vitiello and Prinz, 19901. Age-related decreases of nocturnal plasma melatonin may therefore be indicative for the attenuation of the sleep-wake rhythm with increased nighttime awakenings [Carskadon et al., 19821, the increasing number of daytime naps [Gerard et al., 1978; Allen et al., 19871 and the general increase in sleep problems that occur with advancing age [Hajak et al., 19911. It is of special interest for the understanding of insomnia that the marked melatonin decreases observed in this study were only found in patients with a very long duration of sleep problems. Chronic insomnia is known as a disorder, extending over years, of progressively increasing somatized tension and learned sleep-preventing association, which may lead to conditioned arousal long after the precipitating factors have been removed [Hauri and Fischer, 1986; American Sleep Disorders Association, 19901. It is obvious that long-lasting and chronic sleep disturbances provide a condition that may lead, although only after a considerably long period, to severely altered circadian functions that also involve a reduced nocturnal secretion of melatonin.
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