- Email: [email protected]
Nocturnal secretion of prolactin and cortisol and the sleep EEG in patients with major endogenous depression during an acute episode and after full remission
Psychiatry Research 72 Ž1997. 81]88
Nocturnal secretion of prolactin and cortisol and the sleep EEG in patients with major endogenous depression during an acute episode and after full remission Axel Steiger U , Florian Holsboer Department of Psychiatry, Uni®ersity of Mainz, Mainz, Germany Received 21 June 1996; revised 18 March 1997; accepted 13 May 1997
Abstract We investigated the sleep electroencephalogram ŽEEG. and the nocturnal secretion of prolactin and cortisol in 25 normal subjects and 12 male inpatients with major depression before treatment and after remission and drug withdrawal. In the depressed patients, sleep-EEG disturbances persisted after recovery, whereas the cortisol concentration decreased. Prolactin variables in the patients did not differ between the two time points Ži.e. before treatment and after remission.. Compared with the normal subjects, the patients had significantly higher cortisol concentrations. The above findings were not altered when age was used as a covariate in statistical analysis. Our data suggest that neither depression nor aging exerts distinct effects on prolactin secretion. Q 1997 Elsevier Science Ireland Ltd. Keywords: disorders
Neuroendocrinology; Hypothalamic-pituitary-adrenocortical axis; Aging; Polysomnography; Affective
1. Introduction Psychiatric research has documented various hormonal disturbances in depressed patients, e.g.
U
Corresponding author, Department of Psychiatry, Clinical Institute, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany. Tel.: q49 89 30622236; fax: q49 89 30622548; e-mail: [email protected]
disturbances of the hypothalamic-pituitary-adrenocortical ŽHolsboer, 1995. and the hypothalamicpituitary-somatotrophic systems ŽMendlewicz et al., 1985; Jarrett et al., 1994.. Studies on prolactin secretion in depression have yielded conflicting results. Challenge tests have been performed in depressed patients to determine the response of prolactin to thyrotropin-releasing hormone,
0165-1781r97r$17.00 Q 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S0165-1781Ž97. 00097-8
82
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
methadone and serotonin, but findings have been inconsistent ŽExtein et al., 1980; Gerken et al., 1983; Unden ´ et al., 1987; Meltzer and Maes, 1994.. Sleep is known to be a physiological stimulus of prolactin secretion ŽSassin et al., 1973; Parker et al., 1974.. In several studies of depressed subjects, baseline secretion of prolactin was examined, but without monitoring of the sleep electroencephalogram ŽEEG. wfor a review, see Baumgartner et al. Ž1988.x. Most of these studies reported unchanged prolactin values in depression. The use of sleep endocrinological studies in research on affective disorders has been shown to be a successful way to investigate several biological axes simultaneously under physiologic conditions ŽKupfer et al., 1983; Linkowski et al., 1987; Steiger et al., 1989.. Until now, however, there have been only three studies of depressed patients in which both the sleep EEG and the nocturnal secretion of prolactin was examined. Mai et al. Ž1985., who restricted their study of prolactin secretion to the first 2 h of sleep, found a reduction in prolactin secretion in pre-menopausal women and an increase in post-menopausal women. In men, there was no difference in comparison to control values. Jarrett et al. Ž1987. found no significant differences in prolactin secretion between depressed inpatients and 20 agematched normal controls. Linkowski et al. Ž1989. compared the sleep EEG and the 24-h profiles of prolactin in men with major endogenous depression and in normal controls. They reported an advanced nocturnal secretory phase of prolactin and subnormal concentrations during the midsleep period in patients with the unipolar subtype of depression. Linkowksi et al. also reexamined a subgroup of these patients after remission and reported no significant differences in prolactin values between the first and second examination. Unfortunately, the latter results are of only limited value because the patients were not fully remitted and some of them Žfour of 11 subjects. were being treated with amitriptyline, which is known to prompt changes in both the sleep EEG ŽKupfer et al., 1978. and prolactin secretion ŽLisansky et al., 1987..
It is well documented that normal ageing leads to changes in the sleep EEG and in nocturnal hormone secretion ŽVan Coevorden et al., 1991. that are similar to those seen frequently in depression as shallow sleep, shortened rapid eye movement ŽREM. latency, advanced andror elevated cortisol release and blunted growth hormone secretion ŽRubin et al., 1981; Halbreich et al., 1985; Pfohl et al., 1985; Steiger et al., 1989; Benca et al., 1992.. Previous studies reported unchanged ŽRolandi et al., 1982; Zakria et al., 1988; Van Coevorden et al., 1991. or elevated ŽPollerie et al., 1981; Blackman et al., 1986. prolactin levels in elderly compared with young normal subjects. To examine further the question of whether prolactin secretion is altered in depression, we performed a longitudinal study in 12 male patients with an acute episode of major depression. We investigated the sleep EEG and the nocturnal secretion of prolactin and cortisol at two time points: Ž1. before treatment; and Ž2. after stable full remission of clinical symptomatology and cessation of antidepressant medication. To delineate effects of age and illness on prolactin release, we also compared the depressed patients with a group of normal controls. 2. Methods 2.1. Subjects Twelve men between 21 and 66 years of age Žmean s 46.4, S.D.s 11.3. who had been admitted as inpatients for evaluation and treatment of acute depression participated in the longitudinal study. At initial examination, all subjects met the criteria for major depression, endogenous subtype, according to Research Diagnostic Criteria ŽSpitzer et al., 1978.. Table 1 presents demographic and clinical data. The patients were admitted to the trial consecutively after passing a rigid medical examination to exclude factors that might render the study results ambiguous. Exclusion criteria were severe somatic illness and comorbidity with other psychiatric disorders. After an observation period of 2 weeks, during which
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
the patients remained unmedicated, a sleep-endocrinological examination was conducted. At that time Ž t 1 ., the mean score on the Hamilton Rating Scale for Depression ŽHAM-D. ŽHamilton, 1960. was 27.7 ŽS.D.s 6.5.. Before entering the study, all patients and controls gave their informed consent. The study protocol was approved by the local ethics committee. 2.2. Procedures After two nights of adaptation to the sleep laboratory, subjects were in supine position from 21.30 h on night 3. The sleep EEG was recorded between 23.00 Ž‘lights off’. and 07.00 h. Sleeping or napping was not permitted outside this time period. Simultaneous with sleep-EEG recording, blood samples were collected through a long catheter every 20 min between 22.00 and 07.00 h for later analysis of plasma concentrations of prolactin and cortisol. The procedure is described in detail elsewhere ŽSteiger et al., 1989..
83
After completion of the first phase of the study, the patients were treated with tricyclic antidepressants Žamitriptyline or imipramine. only. After full remission of depressive symptomatology, as defined by an HAM-D score - 5, they were discharged from the unit and seen at least monthly by a senior psychiatrist in our outpatient clinic. An identical control examination Ž t 2 . was performed after the patients had been in full remission for G 4 weeks and after discontinuation of antidepressant medication for G 2 weeks. To examine how and to what extent depressive illness may influence prolactin secretion, we compared the 12 male patients with a sample of 25 healthy male controls. The control subjects Žage range s 22]38 years, mean age s 27.1, S.D.s 3.0. were investigated in accordance with the same protocol. The sleep-EEG and cortisol and growth hormone parameters of this sample have been reported elsewhere ŽSteiger et al., 1987.. Blood samples were centrifuged immediately after collection at 48C and plasma was frozen at
Table 1 Demographic and clinical data for the longitudinally investigated sample of 12 male patients with major endogenous depression Patient number
Age Žyears.
ICD-9 code
Number of episodes
Duration of illness Žyears.
Time between onset of current episode and examination t1 Žweeks.
HRSD score t1
Interval t1 ]t 2 Žweeks.
HRSD score t 2
1 2 3 4 5 6 7 8 9 10 11 12
58 54 35 45 43 44 25 36 58 46 57 44
296.3 296.1 296.3 296.1 296.1 296.3 296.3 296.1 296.1 296.1 296.3 296.1
3 2 10 7 2 5 7 2 2 2 2 1
10 27 9 21 1 4 9 1 11 2 10 0.2
12 2 2 24 11 4 8 2 24 3 4 14
22 30 19 30 33 28 23 19 37 25 27 39
48 28 16 25 8 50 50 40 22 16 32 102
0 3 0 3 0 0 4 0 0 0 } 0
Mean S.D.
46.4 11.3
} }
3.7 2.8
8.8 8.3
9.2 8.1
27.7 6.5
36.4 25.0
0.8 1.5
Note: HRSD, Hamilton Rating Scale for Depression; t1 , admission to hospital; t 2 , full remission G 4 weeks, no medication G 2 weeks.
84
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
y258C. Plasma concentrations of prolactin and cortisol were analyzed in duplicate with a standard commercial radioimmunoassay that is routinely controlled in our laboratory for batch-tobatch variability and precision criteria. All samples from the same subject were analyzed in the same assay. The intraassay and interassay coefficients of variation for the prolactin assays were 2.7]4.8% and 3.9]7.3%, respectively; those for the cortisol assays were 4.4]7.9% and 5.2]9.7%, respectively. The sleep EEG was analyzed manually as described in detail elsewhere ŽSteiger et al., 1989.. Mean cortisol and prolactin concentrations were calculated for the whole night Ž23.00]07.00 h.. In addition, the period of examination of prolactin secretion was split into thirds Ž23.00]01.40, 01.40]03.20 and 03.20]07.00 h.. There were two reasons for this: Ž1. blunted prolactin secretion was found in patients with unipolar depression, particularly during midsleep ŽLinkowski et al., 1989. and Ž2. there is a controversy over whether maximum prolactin secretion occurs during the middle of the sleep period ŽVan Cauter et al., 1982. or during the final hours ŽRubin et al., 1974.. 2.3. Statistical analysis All values are expressed as the mean " S.D. Differences in the observed variables between the two time points Ž t 1 vs. t 2 . within the group of patients were evaluated by repeated measures one factorial multivariate analysis of variance ŽMANOVA. with repeated measures, with time as a within-subjects factor. Differences of the same variables between patients and controls were also tested by a one factorial MANOVA with group as a between-subjects factor. Since patients and controls were not age-matched, age was entered as a covariate in analysis of covariance to control for the effects of age. The nominal level of significance was set at a s 0.05. This level was reduced Žcorrected according to the Bonferroni procedure. for all post-hoc tests Žtests with contrasts or univariate F-tests . performed after significant main ‘time’ or ‘group’ effects emerged in the two MANOVAs.
3. Results The sleep structure in the depressed patients showed characteristic changes: a shortened REM latency, an increase in wakefulness and sleep stage 1, and a decrease in slow wave sleep Ždata not shown.. Table 2 summarizes the findings of our longitudinal comparison of sleep-EEG and cortisol and prolactin variables in men with major endogenous depression before treatment and after recovery. The sleep structure remained basically unchanged, with the only significant difference between the two assessments being a decrease in sleep stage 4 after remission. None of the prolactin variables changed significantly. The cortisol concentration was significantly lower after recovery. Table 3 presents the prolactin and cortisol variables for the 12 male patients with major endogenous depression and the 25 controls. No significant differences were detectable between the two groups in the mean prolactin secretion for the whole night or for any of the three thirds of the night. Mean comparisons of prolactin concentration between the three thirds of the night showed no significant differences in the patients either before treatment or after recovery, and none in the normal controls. Like the remitted patients, the controls exhibited significantly lower mean cortisol concentrations over the whole night than the acutely depressed patients Žunivariate F-tests, P-values 0.05.. Pearson’s correlation coefficients did not reveal a significant relationship between sleep variables and prolactin secretion Ždata not shown.. 4. Discussion The most notable finding in the present study is the lack of distinct changes in prolactin secretion in depressed patients. Neither during the whole night nor during the first or last third or the night } when the sleep structure shows its most prominent disturbances in depression ŽReynolds and Kupfer, 1987. } could a difference between
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
85
Table 2 Prolactin and cortisol secretion of the depressed patients before treatment and after recovery Ž n s 12. Before treatment Mean Sleep EEG Awake Ž%. Stage REM Ž%. Stage 1 Ž%. Stage 2 Ž%. Stage 3 Ž%. Stage 4 Ž%. REM latency Žmin. Prolactin concentration Ž23.00]07.00. Žngrml. 1st third of the night Ž23.00]01.40. Žngrml. 2nd third of the night Ž01.40]03.20. Žngrml. 3rd third of the night Ž03.20]07.00. Žngrml. Maximum Žngrml. Cortisol concentration 23.00]07.00 Žngrml. U
After recovery
Tests with contrasts in MANOVA
S.D.
Mean
S.D.
16.7 17.66 9.06 45.37 5.98 3.83 55.62
13.57 6.38 5.8 9.54 4.97 6.48 35.99
12.35 18.65 12.09 48.77 5.89 1.02 77.54
7.08 6.65 6.82 11.23 4.42 1.48 58.35
6.63 6.25
2.66 3.27
7.28 6.42
2.59 4.47
n.s. n.s.
7.07
2.76
8.02
2.5
n.s.
6.62
2.71
7.42
3.13
n.s.
11.84
4.83
12.71
8.12
n.s.
104.72
26.48
75.56
23.69
n.s. n.s. n.s. n.s. n.s.
U
n.s.
U
significant at the corrected level; n.s.s not significant.
the mean prolactin concentration of the acutely ill patients and the controls or between the acutely ill and remitted patients be found. Nor were any differences detectable during the middle third of
the night. This period is similar to the midsleep interval in the study of Linkowski et al. Ž1989., in which a decrease in prolactin secretion was found. This discrepancy may be explained by sample
Table 3 Prolactin concentration in the young normal controls and in the depressed patients
Age Žcovariate. Prolactin concentration 23.00]07.00 Žngrml. 1st third of the night Žngrml. 2nd third of the night Žngrml. 3rd third of the night Žngrml. Maximum Žngrml. Cortisol concentration 23.00]07.00 Žngrml.
Normal controls Ž n s 25.
Depressed patients Ž n s 12.
Mean
S.D.
Mean
S.D.
27.7
1.3
46.4
11.3
8.01 6.5 8.85 8.72 13.36
2.49 2.17 23.12 3.32 7.84
6.63 6.25 7.07 6.62 11.84
2.66 3.27 2.76 2.71 4.83
67.89
15.21
104.72
26.48
Note: U s significant at the corrected level; n.s.s not significant.
Univariate F-tests in MANOVA
n.s. n.s. n.s. n.s. n.s. U
86
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
inhomogeneity, however, because only the unipolar patients in the study by Linkowski et al. showed this abnormality. The changes in sleep structure in the depressed patients are in accordance with many previous reports was reviewed by Reynolds and Kupfer Ž1987.x. The persistence of a disturbed sleep pattern after recovery is similar to the findings of other laboratories ŽHauri et al., 1974; Rush et al., 1986; Kupfer et al., 1993. and has been discussed in detail elsewhere ŽSteiger et al., 1989.. Our observation that sleep structure, but not prolactin secretion, differs between depressed patients and controls suggests that prolactin does not play a role in the pathophysiology of sleepEEG changes in depression, whereas preclinical data showed REM sleep-promoting effects of prolactin ŽObal ` et al., 1994; Roky et al., 1995.. The lack of correlation between prolactin secretion and specific sleep variables is in line with reports on normal controls ŽVan Cauter et al., 1982. and patients with depression ŽJarrett et al., 1987.. In a similar vein, Spiegel et al. Ž1994. reported that sleep quality does not affect the secretory profile of prolactin in normal control subjects. In contrast to prolactin, cortisol secretion is affected by depression. As expected, cortisol levels are elevated during the acute period and decline after recovery ŽRubin et al., 1981; Halbreich et al., 1985; Pfohl et al., 1985; Steiger et al., 1989.. Most but not all studies show that cortisol secretion Žvan Coevorden et al., 1991. does not increase during aging in normal controls, whereas there is an age-dependent elevation in patients with depression ŽAsnis et al., 1981.. Probably both age and acute illness contribute to the elevation of cortisol levels in the depressed patients in comparison to the younger normal controls. This view is supported by the observation that changes in neurobiological variables which are found in depression also occur with increasing age, as documented for shortened REM latency ŽKupfer et al., 1982; Lauer et al., 1991., a decrease in slow wave sleep ŽKupfer et al., 1982., shortened cortisol latency ŽSherman et al., 1985., blunted GH release ŽPrinz et al., 1983. and blunted testosterone secretion ŽSteiger et al., 1991.. On the other hand, neither differences in
age nor illness between the depressed patients and the controls result in differences in prolactin secretion. In accordance with this observation, no significant correlation was found between age and the prolactin variables. The present data suggest that the regulation of nocturnal prolactin secretion and that of the other sleep endocrine variables mentioned earlier are not closely linked. Taken together, our results are compatible with previous reports ŽJarrett et al., 1987; Unden ´ et al., 1987. that there are no characteristic changes in prolactin secretion during depression and hence provide further evidence that prolactin does not play a role in the sleep-EEG and endocrine changes commonly seen in this disorder. Acknowledgements This study was supported by grants Ho 940r1-2 and Ste 486r1-2 from the Deutsche Forschungsgemeinschaft. The authors thank Mr W. Hiller for excellent technical assistance with the sleepEEG recordings and Mrs. W. Friedrich and the other members of the nursing staff of the Research Unit of the Department of Psychiatry, University of Mainz for their invaluable contribution to this study. References Asnis, G.M., Sachar, E.J., Halbreich, U., Nathan, R.S., Novacenko, H., Ostrow, L.C., 1981. Cortisol secretion in relation to age in major depression. Psychosomatic Medicine 43, 235]242. Baumgartner, A., Graf, I., 1988. Prolactin in ¨ K.-J., Kurten, ¨ patients with major depressive disorder and in healthy subjects. II. Longitudinal study of basal prolactin and postTRH-stimulated prolactin levels. Biological Psychiatry 24, 268]285. Benca, R.M., Obermeyer, W.H., Thisted, R.A., Gillin, J.C., 1992. Sleep and psychiatric disorders. Archives of General Psychiatry 49, 651]668. Blackman, M.R., Kowatch, M.A., Wehmann, R.E., Harman, S.M., 1986. Basal serum prolactin levels and prolactin responses to constant infusions of thyrotropin releasing hormone in healthy aging men. Journal of Gerontology 41, 699]705. Extein, I., Pottash, A.L.C., Gold, M.S., Sweeney, D.R., Martin, D.M., Goodwin, F.K., 1980. Deficient prolactin response to morphine in depressed patients. American Journal of Psychiatry 137, 845]846.
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88 Gerken, A., Steiger, A., Holsboer, F., 1983. Within-patients comparison of prolactin response to methadone in depressives before, during and after tricyclic treatment with lofepramine. Neuroendocrinology Letters 5, 161. Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B., Nathan, R.S., 1985. Cortisol secretion in endogenous depression. II. Time-related functions. Archives of General Psychiatry 42, 909]914. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56]62. Hauri, P., Chernik, D., Hawkins, D., Mendels, J., 1974. Sleep of depressed patients in remission. Archives of General Psychiatry 31, 386]391. Holsboer, F., 1995. Neuroendocrinology of affective disorder. In: Bloom, F., Kupfer, D. ŽEds.., Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, pp. 957]969. Jarrett, D.B., Miewald, J.M., Fedorka, I.B., Coble, P.A., Kupfer, D.J., Greenhouse, J.B., 1987. Prolactin secretion during sleep: a comparison between depressed patients and healthy control subjects. Biological Psychiatry 22, 1216]1226. Jarrett, D.B., Kupfer, D.J., Miewald, J.M., Grochocinski, V.J., Franz, B., 1994. Sleep-related growth hormone secretion is persistently suppressed in women with recurrent depression: a preliminary longitudinal analysis. Journal of Psychiatric Research 28, 211]223. Kupfer, D.J., Reynolds, C.F., Ulrich, R.F., Shaw, D.H., Coble, P.A., 1982. EEG sleep, depression and aging. In: Artus, R.T. ŽEd.., Neurobiology of Aging: Experimental and Clinical Research. ANKHO International, Fayettesville, NY, pp. 351]360. Kupfer, D.J., Bulik, C.M., Jarrett, D.B., 1983. Nighttime plasma cortisol secretion and EEG sleep } are they associated?. Psychiatry Research 10, 191]199. Kupfer, D.J., Spiker, D.G., Coble, P.A., McPartland, R.J., 1978. Amitriptyline and EEG sleep in depressed patients: drug effect. Sleep 1, 149]159. Kupfer, D.J., Ehlers, C.L., Frank, E., Grochocinski, V.J., McEachran, A.B., Buhari, A., 1993. Electroencephalographic sleep studies in depressed patients during long-term recovery. Psychiatry Research 49, 121]138. Lauer, C.J., Riemann, D., Wiegand, M., Berger, M., 1991. From early to late adulthood. Changes in EEG sleep of depressed patients and healthy volunteers. Biological Psychiatry 29, 979]993. Linkowski, P., Mendlewicz, J., Kerhofs, M., Leclecq, R., Golstein, J., Brasseur, M., Copinschi, G., van Cauter, E., 1987. 24-hour profiles of adrenocorticotropic, cortisol and growth hormone in major depressive illness: effect of antidepressant treatment. Journal of Clinical Endocrinology and Metabolism 65, 141]152. Linkowksi, P., van Cauter, E., L’Hermite-Baleriaux, M., Kerhofs, M., Hubain, P., L’Hermite, M., Mendlewicz, J., 1989. The 24-hour profile of plasma prolactin in men with major endogenous depressive illness. Archives of General Psychiatry 46, 813]819.
87
Lisansky, J., Fava, G.A., Zielezny, M.A., Morphy, M.A., Keller, R., 1987. Nocturnal prolactin and cortisol secretion and recovery form melancholia. Psychoneuroendocrinology 12, 303]311. Mai, F.M., Shaw, B.F., Jenner, M.R., Wielgosz, G., Giles, D., 1985. Nocturnal prolactin secretion in depression. British Journal of Psychiatry 147, 314]317. Meltzer, H.Y., Maes, M., 1994. Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biological Psychiatry 35, 316]323. Mendlewicz, J., Linkowski, P., Kerkhofs, M., Desmedt, D., Golstein, J., Copinschi, G., Van Cauter, E., 1985. Diurnal hypersecretion of growth hormone in depression. Journal of Clinical Endocrinology and Metabolism 60, 505]512. Obal, ´ F., Jr., Payne, L., Kacsoh, B., Opp, M., Kapas, ´ L., Grosvenor, C.E., Krueger, J.M., 1994. Involvement of prolactin in the REM sleep-promoting activity of systemic vasoactive intestinal peptide ŽVIP.. Brain Research 645, 143]149. Parker, D.C., Rossman, L.G., Vanderlaan, E.F., 1974. Relation of sleep-entrained human prolactin release to REMNonREM cycles. Journal of Clinical Endocrinology and Metabolism 38, 646]651. Pfohl, B., Sherman, B., Schlechte, J., Stone, R., 1985. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Archives of General Psychiatry 42, 897]903. Pollerie, A.P., Masturzo, P., Murialdo, G., Agnoli, A., 1981. Circadian rhythmicity of prolactin secretion in elderly subjects: changes during bromocriptine treatment. Journal of Endocrinological Investigation 4, 317]321. Prinz, P.N., Weitzman, E.D., Cunningham, G.R., Karacan, I., 1983. Plasma growth hormone during sleep in young and aged men. Journal of Gerontology 38, 519]524. Reynolds, C.F., Kupfer, D.J., 1987. Sleep research in affective illness: state of the art circa 1987. Sleep 10, 199]215. Roky, R., Obal, F., Valatx, J.-L., Bredow, S., Jidong, F., Pagano, L.-P., Krueger, J.M., 1995. Prolactin and rapid eye movement sleep regulation. Sleep 18, 536]542. Rolandi, E., Magnani, G., Sannia, A., Barreca, T., 1982. Evaluation of prolactin secretion in elderly subjects. Acta Endocrinologica ŽCopenhagen. 100, 351]357. Rubin, R.T., Poland, R.E., Rubin, L.E., Gouin, P.R., 1974. The neuroendocrinology of human sleep. Life Sciences 14, 1041]1052. Rubin, R.T., Poland, R.E., Tower, B.B., Hart, P.A., Blodgett, A.L.N., Forster, B., 1981. Hypothalamo-pituitary-gonadal function in primary endogenously depressed men: Preliminary findings. In: Fuxe, K., Gustafsson, J.A., Wetterberg, L. ŽEds.., Steroid Hormone Regulation of the Brain. Pergamon Press, Oxford, pp. 387]397. Rush, A.J., Erman, M.K., Giles, D.E., Schlesser, M.A., Carpenter, G., Vasavada, N., Roffwarg, H.P., 1986. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Archives of General Psychiatry 43, 878]884. Sassin, J.F., Frantz, A.G., Kapen, S., Weitzman, E.D., 1973. The nocturnal rise of human prolactin is dependent on
88
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
sleep. Journal of Clinical Endocrinology and Metabolism 37, 436. Sherman, B., Wysham, C., Pfohl, B., 1985. Age-related changes in the circadian rhythm of plasma cortisol in man. Journal of Clinical Endocrinology and Metabolism 61, 439. Spiegel, K., Follenius, M., Simon, C., Saini, J., Ehrhart, J., Brandenberger, G., 1994. Prolactin secretion and sleep. Sleep 17, 20]27. Spitzer, R.L., Endicott, J., Robins, E., 1978. Research Diagnostic Criteria: rationale and reliability. Archives of General Psychiatry 35, 773]782. Steiger, A., Herth, T., Holsboer, F., 1987. Sleep-electroencephalography and the secretion of cortisol and growth hormone in normal controls. Acta Endocrinologica ŽCopenhagen. 116, 36]42. Steiger, A., von Bardeleben, U., Herth, T., Holsboer, F., 1989. Sleep-EEG and nocturnal secretion of cortisol and growth hormone in male patients with endogenous depression before treatment and after recovery. Journal of Affective Disorders 16, 189]195. Steiger, A., von Bardeleben, U., Wiedemann, K., Holsboer, F., 1991. Sleep-EEG and nocturnal secretin of testosterone
and cortisol in patients with major endogenous depression during the acute state and after remission. Journal of Psychiatric Research 25, 169]177. Unden, ´ F., Ljunggren, J.-G., Kjellman, B.F., Beck-Friis, J., Wetterberg, L., 1987. Unaltered 24 h serum PRL levels and PRL response to TRH in contrast to decreased 24 h serum TSH levels and TSH response to TRH in major depressive disorder. Acta Psychiatrica Scandinavica 75, 131]138. Van Cauter, E., Desir, D., Refetoff, S., Spire, J.-P., Noel, P., L’Hermite, M., Robyn, C., Copinschi, G., 1982. The relationship between episodic variations of plasma prolactin and REM-non-REM cyclicity is an artifact. Journal of Clinical Endocrinology and Metabolism 54, 70]75. Van Coevorden, A., Mockel, J., Laurent, E., Kerkhofs, M., L’Hermite-Baleriaux, M., Decoster, C., Neve, P., van ´ ` Cauter, E., 1991. Neuroendocrine rhythms and sleep in aging men. American Journal of Physiology 260, E651]E661. Zakria, F., Stern, N., McGinty, D., Beahm, E., Littner, M., Sowers, J.R., 1988. Effect of age on circadian rhythm of prolactin in normal men. Chronobiologia 15, 219]222.
Nocturnal secretion of prolactin and cortisol and the sleep EEG in patients with major endogenous depression during an acute episode and after full remission Axel Steiger U , Florian Holsboer Department of Psychiatry, Uni®ersity of Mainz, Mainz, Germany Received 21 June 1996; revised 18 March 1997; accepted 13 May 1997
Abstract We investigated the sleep electroencephalogram ŽEEG. and the nocturnal secretion of prolactin and cortisol in 25 normal subjects and 12 male inpatients with major depression before treatment and after remission and drug withdrawal. In the depressed patients, sleep-EEG disturbances persisted after recovery, whereas the cortisol concentration decreased. Prolactin variables in the patients did not differ between the two time points Ži.e. before treatment and after remission.. Compared with the normal subjects, the patients had significantly higher cortisol concentrations. The above findings were not altered when age was used as a covariate in statistical analysis. Our data suggest that neither depression nor aging exerts distinct effects on prolactin secretion. Q 1997 Elsevier Science Ireland Ltd. Keywords: disorders
Neuroendocrinology; Hypothalamic-pituitary-adrenocortical axis; Aging; Polysomnography; Affective
1. Introduction Psychiatric research has documented various hormonal disturbances in depressed patients, e.g.
U
Corresponding author, Department of Psychiatry, Clinical Institute, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany. Tel.: q49 89 30622236; fax: q49 89 30622548; e-mail: [email protected]
disturbances of the hypothalamic-pituitary-adrenocortical ŽHolsboer, 1995. and the hypothalamicpituitary-somatotrophic systems ŽMendlewicz et al., 1985; Jarrett et al., 1994.. Studies on prolactin secretion in depression have yielded conflicting results. Challenge tests have been performed in depressed patients to determine the response of prolactin to thyrotropin-releasing hormone,
0165-1781r97r$17.00 Q 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S0165-1781Ž97. 00097-8
82
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
methadone and serotonin, but findings have been inconsistent ŽExtein et al., 1980; Gerken et al., 1983; Unden ´ et al., 1987; Meltzer and Maes, 1994.. Sleep is known to be a physiological stimulus of prolactin secretion ŽSassin et al., 1973; Parker et al., 1974.. In several studies of depressed subjects, baseline secretion of prolactin was examined, but without monitoring of the sleep electroencephalogram ŽEEG. wfor a review, see Baumgartner et al. Ž1988.x. Most of these studies reported unchanged prolactin values in depression. The use of sleep endocrinological studies in research on affective disorders has been shown to be a successful way to investigate several biological axes simultaneously under physiologic conditions ŽKupfer et al., 1983; Linkowski et al., 1987; Steiger et al., 1989.. Until now, however, there have been only three studies of depressed patients in which both the sleep EEG and the nocturnal secretion of prolactin was examined. Mai et al. Ž1985., who restricted their study of prolactin secretion to the first 2 h of sleep, found a reduction in prolactin secretion in pre-menopausal women and an increase in post-menopausal women. In men, there was no difference in comparison to control values. Jarrett et al. Ž1987. found no significant differences in prolactin secretion between depressed inpatients and 20 agematched normal controls. Linkowski et al. Ž1989. compared the sleep EEG and the 24-h profiles of prolactin in men with major endogenous depression and in normal controls. They reported an advanced nocturnal secretory phase of prolactin and subnormal concentrations during the midsleep period in patients with the unipolar subtype of depression. Linkowksi et al. also reexamined a subgroup of these patients after remission and reported no significant differences in prolactin values between the first and second examination. Unfortunately, the latter results are of only limited value because the patients were not fully remitted and some of them Žfour of 11 subjects. were being treated with amitriptyline, which is known to prompt changes in both the sleep EEG ŽKupfer et al., 1978. and prolactin secretion ŽLisansky et al., 1987..
It is well documented that normal ageing leads to changes in the sleep EEG and in nocturnal hormone secretion ŽVan Coevorden et al., 1991. that are similar to those seen frequently in depression as shallow sleep, shortened rapid eye movement ŽREM. latency, advanced andror elevated cortisol release and blunted growth hormone secretion ŽRubin et al., 1981; Halbreich et al., 1985; Pfohl et al., 1985; Steiger et al., 1989; Benca et al., 1992.. Previous studies reported unchanged ŽRolandi et al., 1982; Zakria et al., 1988; Van Coevorden et al., 1991. or elevated ŽPollerie et al., 1981; Blackman et al., 1986. prolactin levels in elderly compared with young normal subjects. To examine further the question of whether prolactin secretion is altered in depression, we performed a longitudinal study in 12 male patients with an acute episode of major depression. We investigated the sleep EEG and the nocturnal secretion of prolactin and cortisol at two time points: Ž1. before treatment; and Ž2. after stable full remission of clinical symptomatology and cessation of antidepressant medication. To delineate effects of age and illness on prolactin release, we also compared the depressed patients with a group of normal controls. 2. Methods 2.1. Subjects Twelve men between 21 and 66 years of age Žmean s 46.4, S.D.s 11.3. who had been admitted as inpatients for evaluation and treatment of acute depression participated in the longitudinal study. At initial examination, all subjects met the criteria for major depression, endogenous subtype, according to Research Diagnostic Criteria ŽSpitzer et al., 1978.. Table 1 presents demographic and clinical data. The patients were admitted to the trial consecutively after passing a rigid medical examination to exclude factors that might render the study results ambiguous. Exclusion criteria were severe somatic illness and comorbidity with other psychiatric disorders. After an observation period of 2 weeks, during which
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
the patients remained unmedicated, a sleep-endocrinological examination was conducted. At that time Ž t 1 ., the mean score on the Hamilton Rating Scale for Depression ŽHAM-D. ŽHamilton, 1960. was 27.7 ŽS.D.s 6.5.. Before entering the study, all patients and controls gave their informed consent. The study protocol was approved by the local ethics committee. 2.2. Procedures After two nights of adaptation to the sleep laboratory, subjects were in supine position from 21.30 h on night 3. The sleep EEG was recorded between 23.00 Ž‘lights off’. and 07.00 h. Sleeping or napping was not permitted outside this time period. Simultaneous with sleep-EEG recording, blood samples were collected through a long catheter every 20 min between 22.00 and 07.00 h for later analysis of plasma concentrations of prolactin and cortisol. The procedure is described in detail elsewhere ŽSteiger et al., 1989..
83
After completion of the first phase of the study, the patients were treated with tricyclic antidepressants Žamitriptyline or imipramine. only. After full remission of depressive symptomatology, as defined by an HAM-D score - 5, they were discharged from the unit and seen at least monthly by a senior psychiatrist in our outpatient clinic. An identical control examination Ž t 2 . was performed after the patients had been in full remission for G 4 weeks and after discontinuation of antidepressant medication for G 2 weeks. To examine how and to what extent depressive illness may influence prolactin secretion, we compared the 12 male patients with a sample of 25 healthy male controls. The control subjects Žage range s 22]38 years, mean age s 27.1, S.D.s 3.0. were investigated in accordance with the same protocol. The sleep-EEG and cortisol and growth hormone parameters of this sample have been reported elsewhere ŽSteiger et al., 1987.. Blood samples were centrifuged immediately after collection at 48C and plasma was frozen at
Table 1 Demographic and clinical data for the longitudinally investigated sample of 12 male patients with major endogenous depression Patient number
Age Žyears.
ICD-9 code
Number of episodes
Duration of illness Žyears.
Time between onset of current episode and examination t1 Žweeks.
HRSD score t1
Interval t1 ]t 2 Žweeks.
HRSD score t 2
1 2 3 4 5 6 7 8 9 10 11 12
58 54 35 45 43 44 25 36 58 46 57 44
296.3 296.1 296.3 296.1 296.1 296.3 296.3 296.1 296.1 296.1 296.3 296.1
3 2 10 7 2 5 7 2 2 2 2 1
10 27 9 21 1 4 9 1 11 2 10 0.2
12 2 2 24 11 4 8 2 24 3 4 14
22 30 19 30 33 28 23 19 37 25 27 39
48 28 16 25 8 50 50 40 22 16 32 102
0 3 0 3 0 0 4 0 0 0 } 0
Mean S.D.
46.4 11.3
} }
3.7 2.8
8.8 8.3
9.2 8.1
27.7 6.5
36.4 25.0
0.8 1.5
Note: HRSD, Hamilton Rating Scale for Depression; t1 , admission to hospital; t 2 , full remission G 4 weeks, no medication G 2 weeks.
84
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
y258C. Plasma concentrations of prolactin and cortisol were analyzed in duplicate with a standard commercial radioimmunoassay that is routinely controlled in our laboratory for batch-tobatch variability and precision criteria. All samples from the same subject were analyzed in the same assay. The intraassay and interassay coefficients of variation for the prolactin assays were 2.7]4.8% and 3.9]7.3%, respectively; those for the cortisol assays were 4.4]7.9% and 5.2]9.7%, respectively. The sleep EEG was analyzed manually as described in detail elsewhere ŽSteiger et al., 1989.. Mean cortisol and prolactin concentrations were calculated for the whole night Ž23.00]07.00 h.. In addition, the period of examination of prolactin secretion was split into thirds Ž23.00]01.40, 01.40]03.20 and 03.20]07.00 h.. There were two reasons for this: Ž1. blunted prolactin secretion was found in patients with unipolar depression, particularly during midsleep ŽLinkowski et al., 1989. and Ž2. there is a controversy over whether maximum prolactin secretion occurs during the middle of the sleep period ŽVan Cauter et al., 1982. or during the final hours ŽRubin et al., 1974.. 2.3. Statistical analysis All values are expressed as the mean " S.D. Differences in the observed variables between the two time points Ž t 1 vs. t 2 . within the group of patients were evaluated by repeated measures one factorial multivariate analysis of variance ŽMANOVA. with repeated measures, with time as a within-subjects factor. Differences of the same variables between patients and controls were also tested by a one factorial MANOVA with group as a between-subjects factor. Since patients and controls were not age-matched, age was entered as a covariate in analysis of covariance to control for the effects of age. The nominal level of significance was set at a s 0.05. This level was reduced Žcorrected according to the Bonferroni procedure. for all post-hoc tests Žtests with contrasts or univariate F-tests . performed after significant main ‘time’ or ‘group’ effects emerged in the two MANOVAs.
3. Results The sleep structure in the depressed patients showed characteristic changes: a shortened REM latency, an increase in wakefulness and sleep stage 1, and a decrease in slow wave sleep Ždata not shown.. Table 2 summarizes the findings of our longitudinal comparison of sleep-EEG and cortisol and prolactin variables in men with major endogenous depression before treatment and after recovery. The sleep structure remained basically unchanged, with the only significant difference between the two assessments being a decrease in sleep stage 4 after remission. None of the prolactin variables changed significantly. The cortisol concentration was significantly lower after recovery. Table 3 presents the prolactin and cortisol variables for the 12 male patients with major endogenous depression and the 25 controls. No significant differences were detectable between the two groups in the mean prolactin secretion for the whole night or for any of the three thirds of the night. Mean comparisons of prolactin concentration between the three thirds of the night showed no significant differences in the patients either before treatment or after recovery, and none in the normal controls. Like the remitted patients, the controls exhibited significantly lower mean cortisol concentrations over the whole night than the acutely depressed patients Žunivariate F-tests, P-values 0.05.. Pearson’s correlation coefficients did not reveal a significant relationship between sleep variables and prolactin secretion Ždata not shown.. 4. Discussion The most notable finding in the present study is the lack of distinct changes in prolactin secretion in depressed patients. Neither during the whole night nor during the first or last third or the night } when the sleep structure shows its most prominent disturbances in depression ŽReynolds and Kupfer, 1987. } could a difference between
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
85
Table 2 Prolactin and cortisol secretion of the depressed patients before treatment and after recovery Ž n s 12. Before treatment Mean Sleep EEG Awake Ž%. Stage REM Ž%. Stage 1 Ž%. Stage 2 Ž%. Stage 3 Ž%. Stage 4 Ž%. REM latency Žmin. Prolactin concentration Ž23.00]07.00. Žngrml. 1st third of the night Ž23.00]01.40. Žngrml. 2nd third of the night Ž01.40]03.20. Žngrml. 3rd third of the night Ž03.20]07.00. Žngrml. Maximum Žngrml. Cortisol concentration 23.00]07.00 Žngrml. U
After recovery
Tests with contrasts in MANOVA
S.D.
Mean
S.D.
16.7 17.66 9.06 45.37 5.98 3.83 55.62
13.57 6.38 5.8 9.54 4.97 6.48 35.99
12.35 18.65 12.09 48.77 5.89 1.02 77.54
7.08 6.65 6.82 11.23 4.42 1.48 58.35
6.63 6.25
2.66 3.27
7.28 6.42
2.59 4.47
n.s. n.s.
7.07
2.76
8.02
2.5
n.s.
6.62
2.71
7.42
3.13
n.s.
11.84
4.83
12.71
8.12
n.s.
104.72
26.48
75.56
23.69
n.s. n.s. n.s. n.s. n.s.
U
n.s.
U
significant at the corrected level; n.s.s not significant.
the mean prolactin concentration of the acutely ill patients and the controls or between the acutely ill and remitted patients be found. Nor were any differences detectable during the middle third of
the night. This period is similar to the midsleep interval in the study of Linkowski et al. Ž1989., in which a decrease in prolactin secretion was found. This discrepancy may be explained by sample
Table 3 Prolactin concentration in the young normal controls and in the depressed patients
Age Žcovariate. Prolactin concentration 23.00]07.00 Žngrml. 1st third of the night Žngrml. 2nd third of the night Žngrml. 3rd third of the night Žngrml. Maximum Žngrml. Cortisol concentration 23.00]07.00 Žngrml.
Normal controls Ž n s 25.
Depressed patients Ž n s 12.
Mean
S.D.
Mean
S.D.
27.7
1.3
46.4
11.3
8.01 6.5 8.85 8.72 13.36
2.49 2.17 23.12 3.32 7.84
6.63 6.25 7.07 6.62 11.84
2.66 3.27 2.76 2.71 4.83
67.89
15.21
104.72
26.48
Note: U s significant at the corrected level; n.s.s not significant.
Univariate F-tests in MANOVA
n.s. n.s. n.s. n.s. n.s. U
86
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
inhomogeneity, however, because only the unipolar patients in the study by Linkowski et al. showed this abnormality. The changes in sleep structure in the depressed patients are in accordance with many previous reports was reviewed by Reynolds and Kupfer Ž1987.x. The persistence of a disturbed sleep pattern after recovery is similar to the findings of other laboratories ŽHauri et al., 1974; Rush et al., 1986; Kupfer et al., 1993. and has been discussed in detail elsewhere ŽSteiger et al., 1989.. Our observation that sleep structure, but not prolactin secretion, differs between depressed patients and controls suggests that prolactin does not play a role in the pathophysiology of sleepEEG changes in depression, whereas preclinical data showed REM sleep-promoting effects of prolactin ŽObal ` et al., 1994; Roky et al., 1995.. The lack of correlation between prolactin secretion and specific sleep variables is in line with reports on normal controls ŽVan Cauter et al., 1982. and patients with depression ŽJarrett et al., 1987.. In a similar vein, Spiegel et al. Ž1994. reported that sleep quality does not affect the secretory profile of prolactin in normal control subjects. In contrast to prolactin, cortisol secretion is affected by depression. As expected, cortisol levels are elevated during the acute period and decline after recovery ŽRubin et al., 1981; Halbreich et al., 1985; Pfohl et al., 1985; Steiger et al., 1989.. Most but not all studies show that cortisol secretion Žvan Coevorden et al., 1991. does not increase during aging in normal controls, whereas there is an age-dependent elevation in patients with depression ŽAsnis et al., 1981.. Probably both age and acute illness contribute to the elevation of cortisol levels in the depressed patients in comparison to the younger normal controls. This view is supported by the observation that changes in neurobiological variables which are found in depression also occur with increasing age, as documented for shortened REM latency ŽKupfer et al., 1982; Lauer et al., 1991., a decrease in slow wave sleep ŽKupfer et al., 1982., shortened cortisol latency ŽSherman et al., 1985., blunted GH release ŽPrinz et al., 1983. and blunted testosterone secretion ŽSteiger et al., 1991.. On the other hand, neither differences in
age nor illness between the depressed patients and the controls result in differences in prolactin secretion. In accordance with this observation, no significant correlation was found between age and the prolactin variables. The present data suggest that the regulation of nocturnal prolactin secretion and that of the other sleep endocrine variables mentioned earlier are not closely linked. Taken together, our results are compatible with previous reports ŽJarrett et al., 1987; Unden ´ et al., 1987. that there are no characteristic changes in prolactin secretion during depression and hence provide further evidence that prolactin does not play a role in the sleep-EEG and endocrine changes commonly seen in this disorder. Acknowledgements This study was supported by grants Ho 940r1-2 and Ste 486r1-2 from the Deutsche Forschungsgemeinschaft. The authors thank Mr W. Hiller for excellent technical assistance with the sleepEEG recordings and Mrs. W. Friedrich and the other members of the nursing staff of the Research Unit of the Department of Psychiatry, University of Mainz for their invaluable contribution to this study. References Asnis, G.M., Sachar, E.J., Halbreich, U., Nathan, R.S., Novacenko, H., Ostrow, L.C., 1981. Cortisol secretion in relation to age in major depression. Psychosomatic Medicine 43, 235]242. Baumgartner, A., Graf, I., 1988. Prolactin in ¨ K.-J., Kurten, ¨ patients with major depressive disorder and in healthy subjects. II. Longitudinal study of basal prolactin and postTRH-stimulated prolactin levels. Biological Psychiatry 24, 268]285. Benca, R.M., Obermeyer, W.H., Thisted, R.A., Gillin, J.C., 1992. Sleep and psychiatric disorders. Archives of General Psychiatry 49, 651]668. Blackman, M.R., Kowatch, M.A., Wehmann, R.E., Harman, S.M., 1986. Basal serum prolactin levels and prolactin responses to constant infusions of thyrotropin releasing hormone in healthy aging men. Journal of Gerontology 41, 699]705. Extein, I., Pottash, A.L.C., Gold, M.S., Sweeney, D.R., Martin, D.M., Goodwin, F.K., 1980. Deficient prolactin response to morphine in depressed patients. American Journal of Psychiatry 137, 845]846.
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88 Gerken, A., Steiger, A., Holsboer, F., 1983. Within-patients comparison of prolactin response to methadone in depressives before, during and after tricyclic treatment with lofepramine. Neuroendocrinology Letters 5, 161. Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B., Nathan, R.S., 1985. Cortisol secretion in endogenous depression. II. Time-related functions. Archives of General Psychiatry 42, 909]914. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56]62. Hauri, P., Chernik, D., Hawkins, D., Mendels, J., 1974. Sleep of depressed patients in remission. Archives of General Psychiatry 31, 386]391. Holsboer, F., 1995. Neuroendocrinology of affective disorder. In: Bloom, F., Kupfer, D. ŽEds.., Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, pp. 957]969. Jarrett, D.B., Miewald, J.M., Fedorka, I.B., Coble, P.A., Kupfer, D.J., Greenhouse, J.B., 1987. Prolactin secretion during sleep: a comparison between depressed patients and healthy control subjects. Biological Psychiatry 22, 1216]1226. Jarrett, D.B., Kupfer, D.J., Miewald, J.M., Grochocinski, V.J., Franz, B., 1994. Sleep-related growth hormone secretion is persistently suppressed in women with recurrent depression: a preliminary longitudinal analysis. Journal of Psychiatric Research 28, 211]223. Kupfer, D.J., Reynolds, C.F., Ulrich, R.F., Shaw, D.H., Coble, P.A., 1982. EEG sleep, depression and aging. In: Artus, R.T. ŽEd.., Neurobiology of Aging: Experimental and Clinical Research. ANKHO International, Fayettesville, NY, pp. 351]360. Kupfer, D.J., Bulik, C.M., Jarrett, D.B., 1983. Nighttime plasma cortisol secretion and EEG sleep } are they associated?. Psychiatry Research 10, 191]199. Kupfer, D.J., Spiker, D.G., Coble, P.A., McPartland, R.J., 1978. Amitriptyline and EEG sleep in depressed patients: drug effect. Sleep 1, 149]159. Kupfer, D.J., Ehlers, C.L., Frank, E., Grochocinski, V.J., McEachran, A.B., Buhari, A., 1993. Electroencephalographic sleep studies in depressed patients during long-term recovery. Psychiatry Research 49, 121]138. Lauer, C.J., Riemann, D., Wiegand, M., Berger, M., 1991. From early to late adulthood. Changes in EEG sleep of depressed patients and healthy volunteers. Biological Psychiatry 29, 979]993. Linkowski, P., Mendlewicz, J., Kerhofs, M., Leclecq, R., Golstein, J., Brasseur, M., Copinschi, G., van Cauter, E., 1987. 24-hour profiles of adrenocorticotropic, cortisol and growth hormone in major depressive illness: effect of antidepressant treatment. Journal of Clinical Endocrinology and Metabolism 65, 141]152. Linkowksi, P., van Cauter, E., L’Hermite-Baleriaux, M., Kerhofs, M., Hubain, P., L’Hermite, M., Mendlewicz, J., 1989. The 24-hour profile of plasma prolactin in men with major endogenous depressive illness. Archives of General Psychiatry 46, 813]819.
87
Lisansky, J., Fava, G.A., Zielezny, M.A., Morphy, M.A., Keller, R., 1987. Nocturnal prolactin and cortisol secretion and recovery form melancholia. Psychoneuroendocrinology 12, 303]311. Mai, F.M., Shaw, B.F., Jenner, M.R., Wielgosz, G., Giles, D., 1985. Nocturnal prolactin secretion in depression. British Journal of Psychiatry 147, 314]317. Meltzer, H.Y., Maes, M., 1994. Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biological Psychiatry 35, 316]323. Mendlewicz, J., Linkowski, P., Kerkhofs, M., Desmedt, D., Golstein, J., Copinschi, G., Van Cauter, E., 1985. Diurnal hypersecretion of growth hormone in depression. Journal of Clinical Endocrinology and Metabolism 60, 505]512. Obal, ´ F., Jr., Payne, L., Kacsoh, B., Opp, M., Kapas, ´ L., Grosvenor, C.E., Krueger, J.M., 1994. Involvement of prolactin in the REM sleep-promoting activity of systemic vasoactive intestinal peptide ŽVIP.. Brain Research 645, 143]149. Parker, D.C., Rossman, L.G., Vanderlaan, E.F., 1974. Relation of sleep-entrained human prolactin release to REMNonREM cycles. Journal of Clinical Endocrinology and Metabolism 38, 646]651. Pfohl, B., Sherman, B., Schlechte, J., Stone, R., 1985. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Archives of General Psychiatry 42, 897]903. Pollerie, A.P., Masturzo, P., Murialdo, G., Agnoli, A., 1981. Circadian rhythmicity of prolactin secretion in elderly subjects: changes during bromocriptine treatment. Journal of Endocrinological Investigation 4, 317]321. Prinz, P.N., Weitzman, E.D., Cunningham, G.R., Karacan, I., 1983. Plasma growth hormone during sleep in young and aged men. Journal of Gerontology 38, 519]524. Reynolds, C.F., Kupfer, D.J., 1987. Sleep research in affective illness: state of the art circa 1987. Sleep 10, 199]215. Roky, R., Obal, F., Valatx, J.-L., Bredow, S., Jidong, F., Pagano, L.-P., Krueger, J.M., 1995. Prolactin and rapid eye movement sleep regulation. Sleep 18, 536]542. Rolandi, E., Magnani, G., Sannia, A., Barreca, T., 1982. Evaluation of prolactin secretion in elderly subjects. Acta Endocrinologica ŽCopenhagen. 100, 351]357. Rubin, R.T., Poland, R.E., Rubin, L.E., Gouin, P.R., 1974. The neuroendocrinology of human sleep. Life Sciences 14, 1041]1052. Rubin, R.T., Poland, R.E., Tower, B.B., Hart, P.A., Blodgett, A.L.N., Forster, B., 1981. Hypothalamo-pituitary-gonadal function in primary endogenously depressed men: Preliminary findings. In: Fuxe, K., Gustafsson, J.A., Wetterberg, L. ŽEds.., Steroid Hormone Regulation of the Brain. Pergamon Press, Oxford, pp. 387]397. Rush, A.J., Erman, M.K., Giles, D.E., Schlesser, M.A., Carpenter, G., Vasavada, N., Roffwarg, H.P., 1986. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Archives of General Psychiatry 43, 878]884. Sassin, J.F., Frantz, A.G., Kapen, S., Weitzman, E.D., 1973. The nocturnal rise of human prolactin is dependent on
88
A. Steiger, F. Holsboer r Psychiatry Research 72 (1997) 81]88
sleep. Journal of Clinical Endocrinology and Metabolism 37, 436. Sherman, B., Wysham, C., Pfohl, B., 1985. Age-related changes in the circadian rhythm of plasma cortisol in man. Journal of Clinical Endocrinology and Metabolism 61, 439. Spiegel, K., Follenius, M., Simon, C., Saini, J., Ehrhart, J., Brandenberger, G., 1994. Prolactin secretion and sleep. Sleep 17, 20]27. Spitzer, R.L., Endicott, J., Robins, E., 1978. Research Diagnostic Criteria: rationale and reliability. Archives of General Psychiatry 35, 773]782. Steiger, A., Herth, T., Holsboer, F., 1987. Sleep-electroencephalography and the secretion of cortisol and growth hormone in normal controls. Acta Endocrinologica ŽCopenhagen. 116, 36]42. Steiger, A., von Bardeleben, U., Herth, T., Holsboer, F., 1989. Sleep-EEG and nocturnal secretion of cortisol and growth hormone in male patients with endogenous depression before treatment and after recovery. Journal of Affective Disorders 16, 189]195. Steiger, A., von Bardeleben, U., Wiedemann, K., Holsboer, F., 1991. Sleep-EEG and nocturnal secretin of testosterone
and cortisol in patients with major endogenous depression during the acute state and after remission. Journal of Psychiatric Research 25, 169]177. Unden, ´ F., Ljunggren, J.-G., Kjellman, B.F., Beck-Friis, J., Wetterberg, L., 1987. Unaltered 24 h serum PRL levels and PRL response to TRH in contrast to decreased 24 h serum TSH levels and TSH response to TRH in major depressive disorder. Acta Psychiatrica Scandinavica 75, 131]138. Van Cauter, E., Desir, D., Refetoff, S., Spire, J.-P., Noel, P., L’Hermite, M., Robyn, C., Copinschi, G., 1982. The relationship between episodic variations of plasma prolactin and REM-non-REM cyclicity is an artifact. Journal of Clinical Endocrinology and Metabolism 54, 70]75. Van Coevorden, A., Mockel, J., Laurent, E., Kerkhofs, M., L’Hermite-Baleriaux, M., Decoster, C., Neve, P., van ´ ` Cauter, E., 1991. Neuroendocrine rhythms and sleep in aging men. American Journal of Physiology 260, E651]E661. Zakria, F., Stern, N., McGinty, D., Beahm, E., Littner, M., Sowers, J.R., 1988. Effect of age on circadian rhythm of prolactin in normal men. Chronobiologia 15, 219]222.