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Nocturnal TSH and prolactin secretion during sleep deprivation and prediction of antidepressant response in patients with major depression
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Nocturnal TSH and Prolactin Secretion during Sleep Deprivation and Prediction of Antidepressant Response in Patients with Major Depression Siegfried Kasper, David A. Sack, Thomas A. Wehr, Hermes Kick, Gabriele Voll, and Antonio Vieira
In order to test the hypothesis that changes in the hypothalamic-pituitary axis during sleep deprivation are related to the antidepressant effects of this procedure, we measured thyroid-stimulating hormone (TSH) and pro~a~tin levels in 32 depressed patients at 2.90 AMduring a night before, during, and afrer total sleep deprivation (TSD). TSH levels increased significantly (p < 0.05) during TSD, and prolactin levels decreased significantly (p < 0.0001). When we divided the patients into responder and nonresponder groups based on a 30% reduction in the Hamilton Rating Scale, there was no difference between the two groups in their hormone levels on the baseline, TSD, or recovery nights. Changes in prolacti~ or TSH were not correlated with clinical improvement when the two groups were considered together or in the responder/ nonresponder groups separately. Baseline values of both hormones were signijkantly (p < 0.01) correlated with their respective levels during TSD and recovery sleep. These findings indicate that the relative levels of nocturnal TSH and prolactin are stable even within acutely depressed i~ividuals and that changes in their levels are not related to the clinical response to sleep deprivation.
Introduction A single night of total sleep deprivation (TSD) exerts an acute antidepressant effect in a majority of depressed patients (Kuhs and Tolie 1986), but its mechanism of action is not known. The clinical response to sleep deprivation has a rapid onset, but it can be reversed by sleeping (Wiegand et al. 1987). Many physiological processes are altered by sleep, including body temperature (Ptlug et al. 1981), neurotransmitter turnover (Mullen et al. 1981; FVinz et al. 1984), and hormone secretion (Golstein et al. 1980; Weitzman et al. 1981; O’MaIley et al. 1984a); interrupting the sleep-dependent regulation of these functions by sleep dep~vation may be related to its ~tidep~ss~t effect. Alterations in the hy~~~~ic-pituit~-thy~id (HPT) function may be of particular
From tbe Clinical Psychobiology Branch, NIMH, Bethesda, MD, and the Psychiatric Department of the University of Heidelberg, F.R.G. Suppti by the Geman Research Foundation (DFG) (S.K.). Address reprint requests to Dr. Siegfried Kasper, Clinical ~ychobiology Branch, National Institute of Mental He&b, Building 10, Room 4s239, Bethesda, MD 20892. Received June 30, 1987; revised December 21, 1987. 0 1988 Society of Biological Psychiatry
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irn~~ce in the antidepressant response to sleep dep~vation as: (1) the n~tumal rise in thyroid-stimulating hormone (TSH) secretion is reduced or absent in patients with depression (Golstein et al. 1980; Kjellman et al. 1984; Suetre et al. 1986; Sack et al. 1987); (2) TSH levels are increased by sleep deprivation in normals (Parker et al. 1976, 1987; Sack et al. 1987), possibly via increased thyrotropin-releasing hormone (TRH) secretion; (3) TRH exerts behavioral effects similar to tricyclic antidepressants in animal models (Ogawa et al. 1984) and may have antidep~ss~t effects in humans (Kastin et al. 1972; Prange et al. 1972; Furlong et al. 1976), although it is noteworthy that others have failed to replicate these antidepressant properties of TRH (Ehrensing et al. 1974; Montjoy et al. 1974); and (4) increased TSH secretion may be associated with transient increases in active thyroid hormones that may also have therapeutic effects (Prange et al. 1969; Goodwin et al. 1982). Recently, Baumgartner and Meinhold (1986) found that sleep deprivation significantly increased 8:00 AM TSH levels in depressed patients and that clinical improvement was correlated with the rise in TSH. In contrast to these findings, Sack et al. (1987) failed to find a correlation between clinical improvement and the change in TSH levels during sleep deprivation when TSH was measured every half hour during the night at baseline and during TSD. An alternative hy~~esis that might explain the therapeutic effects of sleep dep~vation is that sleep deprivation acts by increasing central dopaminergic activity. There is considerable evidence that central dopaminergic function is decreased in depression (Willner 1983), and in animal experiments, sleep deprivation produces behavioral supersensitivity to dopamine agonists (Tufik et al. 1983). One method for indirectly assessing dopamine activity is to measure serum prolactin levels (Leong et al. 1983; Ben-Jonathan 1985). Sleep-related secretion of prolactin can be inhibits by dop~ne agonists (Del Pozo et al. 1975; Chihara et al. 1976; Rindt et al. 1981), suggesting that the nycthemeral rise in prolactin is due to decreased dopamine. However, other factors are also known to stimulate (Bruni et al. 1977; Lewis and Sherman 1985) or inhibit (O’Malley et al. 1984b; Fink 1985; degli Uberti et al. 1985) prolactin secretion. Ordinarily, prolactin secretion markedly increases during sleep (Sassin et al. 1972; Parker et al. 1973; Franz 19’79), and total sleep deprivation, in contrast to selective REM sleep deprivation (Beck 198I), potently reduces prolactin levels in healthy subjects (Parker et al. 1981; Desir et al. 1982) and patients with major depression (Berger et al. 1986). If nocturnal prolactin secretion reflects dopamine activity in the tuberoinfindibular dopamine system, then the magnitude of the decrease in prolactin levels might provide a useful index of dopamine activity during TSD. In order to further test the hypotheses that TSD exerts its effects via changes in HPT or dopaminergic activation, we measured serum TSH and prolactin levels in 32 depressed patients at 2:00 AM during a baseline night, during TSD, and the night after TSD. The 2:OOAM time was chosen because TSH and prolactin levels tend to be highest during nighttime when the individual is asleep and thus may provide an estimate of peak activity in these hormone systems.
Methods Thirty-two psychiatric inpatients (22 women, 10 men; aged 29-76, mean 50.4 2 14) who met DSM-III criteria (American Psychiatric Association 1980) for major depression (n = 30) or dys~ymia (n = 2) participated in the study. Thirty patients met RDC (Spitzer et al. 1978) criteria for major depression (27 unipolar and 3 bipolar II), with a mean of 6.5 t- 1.4 on the Newcastle Scale (Carney et al. 1965).
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Patients were free of psychotropic drugs for at least 4 days (mean 7.2 zt 1.4) prior to the study, and only chloral hydrate was allowed for medication. Prior to admission, patients had been treated with various antidepressants, and one patient had been treated with ne~oleptic medication (melperon, 300 m~day). Blood samples were obtained via venipuncture at 2:00 AM on the night preceding TSD, during TSD, and on the night following TSD. On the baseline and recovery nights, patients were awakened for the 2:00 AM specimen and then permitted to go back to sleep. Specimens were assayed by irnmunoradiometric assay for TSH (IRMAclon Henning), and by RIA for prolactin (Serono). The sensitivity for the TSH assay was 0.03 &J TWliter, and the interassay coefficients of variation were 4.1% (at a level of 15.7 pJ.J/liter), 5.1% (at a level of 3.6 @/liter), and 13.5% (at a level of 0.508 @J/liter). The sensitivity for the prolactin assay was 6.0 @l/ml, and the interassay coefficient of variation was 4.0%-5.2%. The sleep deprivation procedure was as follows: Patients were awakened at 7:OOAM on the latent day and were kept continuously awake for the next 40 hr. Nursing staff closely observed the patients in order to ensure compliance with the procedure. Patients were rated at 9:00 AM and 500 PM on the day prior to and following the night of sleep deprivation using a modified version of the Hamilton Depression Rating Scale (HDRS) (Hamilton 1967). Items 4, 5, 6 (sleep), 16 (weight loss), and 18 (diurnal variation) were omitted because these symptoms cannot be meaningfully assessed on the day after TSD. Patients were divided into responders and no~s~nders according to whether or not their mean daily difference score (Tolle 1981) of the HDRS decreased by 30% with treatment. The hormone data and the psychopathological measurements were analyzed by a two-way Analysis of Variance (ANOVA) with repeated measures. Significant main effects and interactions were further tested with Neuwman-Keuls tests, with alpha correction for multiple comparisons. It is our experience that the clinical response to sleep dep~vation varies as a function of time of day, with some subjects showing improvement only in the morning, others only in the afternoon. For this reason, we calculated two additional outcome measures, the morning difference and the evening difference scores in HDRS (Tolle 1981). Relationships between hormone levels (absolute levels and Asleep deprivation-baseline) and the three outcome measures were assessed by Pearson’s correlation coefficient.
Results The severity of depression as measured by Newcastle Scale and HDRS total score did not differ on the baseline day between sleep deprivation responders and nonresponders. The mean & SD scoresbefore TSD were, for the Newcastle Scale, 6.3 * 1.1 and 6.6 & 1.4 (unpaired t-test, two-tailed, I = -0.78, df = 30, p = 0.43) and, for the HDRS total score, 25.5 ? 7.1 and 22.6 & 9.5 for responders and nonresponders, respectively (f = 0.93, df = 30,~ = 0.35). Using the mean daily difference of the modified version of HDRS to categorize clinical response to TSD, there were 16 responders and 16 nom-esponders. Sleep deprivation significantly decreased depression levels for all patients over the four time points measured (Time: F = 18.9, p < O.~l~, but the beneficial effects were significantly greater in the responder group (Group X Time interaction: F = 14.8, p < 0.00001) (Figure 1). TSH levels rose significantly during sleep deprivation compared to baseline and recovery night (Time: F = 4.5, p < 0.05), but there was no relationship between the change in TSH and clinical response (Group X Time interaction: F = 1.5, p = 0.22)
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o
25 -
Responder (n=16)
+
Nonresponder (n=16) Group x Time Interaction F = 14.8; p i 0.0001
g ._ B 5 g
2o
15-
B
10 -
5
:
’ 9am
5 pm Baseline Day
Sam
5pm
Day after TSD
Figure 1. Mean k SEM depression ratings as measured with a modified version (see text) of Hamilton Depression Rating Scale (HDRS) in total sleep deprivation responder and nonresponder.
(Table 1). Prolactin values were significantly lower during TSD (Time: F = 15.9, p -=LO.OOOOl),but, as with TSH, there was no significant relationship between prolactin levels and clinical response to TSD (Group X Time interaction: F = 0.29, p = 0.74) (Figure 2). The results were unchanged when pre- and postmenopausal women (n = 7 premenopausal and n = 15 postmenopausal) and men (n = 10) were analyzed separately . There were no significant correlations between clinical improvement (mean daily, morning, or evening difference scores) and the levels of either hormone at baseline, during sleep deprivation, or the change from baseline to sleep deprivation (Table 2, Figure 2), nor were hormone levels at 2:00 AM correlated with the severity of depression at baseline or during sleep deprivation (r = -0.09 for TSH, r = 0.03 for prolactin). Changes in TSH or prolactin were not correlated with the different applied clinical response measurements when the groups were considered together or in the responder/nonresponder groups alone.
Table 1. TSH and Prolactin Values during Sleep Deprivation Procedure Baseline night TSH ((IUlliter) TSD responder TSD nonresponder Prolactin (nglml) TSD responder TSD nonresponder
Sleep deprivation
Recovery
night
1.1 k 0.7 1.1 i 0.7
1.4 k 0.8 1.4 LY0.7
1.1 -+ 0.7 1.0 -t 0.7
NS
19.1 + 12 20.8 * 19
10.6 i 5 11.6 -e 8.7
24.2 k 18 22.6 2 18
NS
“Difference between TSD responder and TSD nonresponder (ANOVA, Group x Time interaction)
TSH and Pmlactin during Sleep Deprivation
635
2
y = 0.2278+0.001x R = 0.06 .
n=32
. 1
#m
z I e Q
. o-
1
* ‘ .
. Ic.
l
.
.
I
. ‘ l
l
.
’
.
l
s
. -1 ,',.r.t-r-I*r-t -100 -75 -50 -25 0 25 50 75 Mean dailydifference(HDRS)
10
100%
Y = - 8.0604-0.0329x
7
R= 0.10
n-32
.
-3
‘
-30 ‘
I
,
-4o-'-, -100 -75
-50 -25 0 25 50 Mean daily difference(HDRS)
75
100%
TSW and prolactin values during sfeep deprivation wery: sig~~c~~y correlated with their respective levels at baseline (p -K 0.01) and on the recovery night (‘Table 2). No correlations were found be&eon TSH and proMin tevels, either in absolute values or A values from baseline to TSD. The d~ti~u of w~hout was com~ble in the responders and nomponders (6.9 1 1.7 days in responders; 7.5 z.&0.8 days in nanresponders; unpaired r-test: t = - 1S, df = 30, p = 0.14).
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Table 2. Correlationsbetween Hormone Levels at 2:OOAM and between Hormones and Different Clinical Response Definitions Hormone levels at 2:00
TSH (sleep deprivation) Prolactin (sleep deprivation)
Response ratings”
AM
Baseline night
Recovery night
0.66’
0.63b
0.79h
0.606
Daily 0.14
-0.24
Morning --0.12
-0.19
Evening 0.07
- 0.09
“Mean difference scores(HDRS). bSignificant@ < 0.01).
Discussion TSD significantly reduced depression, raised TSH levels, and lowered prolactin levels during the sleep deprivation night, but the clinical response to TSD was unrelated to the changes in hormone levels. Our findings with respect to TSH are consistent with the observations of Sack et al. (1987), but are opposite to those of Baumgartner and Meinhold (1986), who found that the clinical improvement during TSD was correlated with increased TSH on the morning after TSD. The present study differed from that of the latter in three respects that might explain the divergent findings: (1) the time at which samples were obtained (2:00 AM versus 8:00 AM), (2) the medication status of the patients (drug-free versus medicated), and (3) the assay used for TSH estimation (immunoradiometric assay versus radioimmunoassay). We will discuss these aspects in further detail because they bear on some of the problems involved in sleep deprivation studies in which hormonal changes are related to outcome measurements. Previous circadian studies indicate that TSH levels are highest during the night (Weeke and Weeke 1976; Parker et al. 1976; Vanhaelst et al. 1979); thus, our 2:00 AM sample is more likely to reflect peak activity in this system than an 8:00 AM value. The TSH values we obtained at 2:00 AM were highly correlated with subsequent measures during TSD and on the recovery night, confirming our impression that it is a reliable index of nocturnal secretion. It is possible that changes in morning TSH levels with sleep deprivation may provide additional information not detected in the 2:00 AM sample alone. This would be the case if the phase of the TSH rhythm were more erratic in depressed patients than in controls, as has been reported by Golstein et al. (1980) but not by others (Kjellman et al. 1984; Sack et al. unpublished data). Antidepressant medication may also influence TSH levels. TSH levels increase and thyroid hormone levels decrease with antidepressant treatment (UndCn et al. 1986; Post et al. 1987; Kasper et al. unpublished data), and pretreatment with antidepressants has been reported to change the course after TSD with a prevention of the otherwise regularly occurring relapse (van den Hofdakker and Elsenga 1980). Thus, studies in which subjects are currently taking antidepressants may be measuring an interaction among antidepressants, TSH, and sleep deprivation, rather than the effect of sleep deprivation alone. The lack of sensitivity of radioimmunological methods has been a major problem in the measurement of TSH. The considerably higher sensitivity of the newly developed immunoradiometric assays (IRMA) (Wehmann and Nisula 1984) permits the detection
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of TSH values as low as 0.03 busier compared with 0.2 p&/liter with RIA. Morning TSH values fall close to the limits of detection of RIA assays, and it is possible that correlations between psychopathological measures and tbe difference of hormonal changes using RIAs are not reliable at this time of the day. The magnitude of the sleep deprivation-induced rise in TSH levels found in our predominantly unipolar depressed patients is similar to that found in rapid-cycling bipolar patients, but is considerably less than the TSD induced rise in TSH found in controls (Sack et al. 1987). Thus, a blunted TSH response to TSD does not appear to be restricted to a particular diagnostic subgroup of depression and may be physiologic~ly related to the blunted To-st~ulated TSH response observed in some depressed patients (Loosen and Prange 1982). The regulation of prolactin is complex, involving several neurotransmitters and neuropeptides. In light of the strong inhibitory influence that dopamine exerts on prolactin levels, an enhanced dopamine activity could be hypothesized to be responsible for the decline in prolactin levels during sleep deprivation. This hypothesis may be inconsistent with elevation of TSH during sleep deprivation, as dopaminergic agonists inhibit TSH secretion levels during the night. However, the physiological role of dopamine in the regulation of TSH has not been established (Morley 1981). In animal experiments, increased dop~inergic simulation is associated with an increase in motor activity, aggression, and activation (Antelmann and Caggiula 1977), and comparable behaviors are observed in depressed patients following sleep deprivation (Kasper et al. 1988). Gemer et al. (1979) found that CSF concentrations of the dopamine metabolite homovanillic acid were significantly lower in TSD responders compared with nonresponders, but sleep deprivation failed to significantly alter HVA levels in either patient group. This latter finding is similar to our failure to find a relationship between altered prolactin secretion and the antidepressant effects of TSD. The indirect-acting dopamine agonist methylphenidate has acute mood-elevating properties analogous to those seen with TSD (Janowsky et al. 1973), but brom~~ptine, a direct-acting dopamine agonist that acutely suppresses prolactin secretion (Del Pozo et al. 197% has ~tidep~ss~t effects only when administered for several weeks (Post et al. 1978; Nordin et al. 1981; Schubert et al. 1982; Theohar et al. 1982). The temporal dissociation between the mood and hormonal effects of bromocryptine suggests either that (1) altered dopamine activity in the tuberoinfindibular system is not a useful measure of dopamine activity, which might be more closely related to mood in other brain areas, or (2) dopamine is not involved in the acutely occurring antidepressant effects of sleep deprivation. Among the different factors influencing the results of our study, a confounding variable might have been the relatively short washout phase. Discontinuation of tricyclic and ~tidepr~san~ is followed by gradual changes in neu~~smi~r lover that can last for several weeks (Charney et al. 19821, and such changes may have influenced p&a&n and TSH levels. As the washout period was comparable in SD responders and SD nonresponders, it seems that withdrawal effects alone would not explain our findings. Another factor that might have influenced our results is the fact that the majority of our group of patients were postmenopausal women, and the separate analysis according to the menopausal and gender status resulted in small subgroups with the possibility of a type II error. It is known that estrogens have a modulating effect on the secretion of prolactin (Judd et al. 1978), and nocturnal prolactin levels are higher in postmenopausal patients with major depression compared to control subjects (Mai et al. 1985). Additional
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studies that are homogeneous with respect to gender and menopausal status are needed to clarify whether or not there is a relationship between the effects of sleep dep~vation on TSH or prolactin secretion and its effects on mood. Our sampling procedure may also have influenced our results. In order to obtain 2:00 AM blood samples, our patients were awakened from sleep on the baseline and recovery nights. This awakening could have ~ifactu~ly raised TSH and decreased prolactin levels. In our study, prolactin levels were markedly higher during sleep than sleep deprivation and conversely, TSH levels were quite low (I . 1 mu/liter) during sleep, suggesting that the period of wakefulness preceding venipuncture was too brief to affect these hormone levels. It is possible that awakenings might have obscured differences of hormonal levels between SD responders and SD nonresponders during baseline and recovery night, but this seems unlikely, as the two groups underwent the same procedures. Various investigators have used a number of different outcome measures to define the clinical response to sleep deprivation making precise comparisons between studies difficult, We choose the total score of the Hamilton Depression Rating Scale (HDRS) (Hamilton 1967) to monitor clinical response because it is widely used and reproducible. It is possible that an item-~~ysis of HDRS or the self-rating scales would result in further subgroups, but the number of patients in this study is too small for such grouping to produce statistically meaningful results. The lack of correlation between hormonal changes and clinical improvement with TSD in our study does not support the hypo~esis that improvement in mood is due to altered regulation of neurohypophyseal function. Rather, we found that TSH and prolactin levels were highly consistent with individuals across conditions that might reflect the depressed patients’ adaptation to a physiological state that allows fluctuations only in a given range, which seems to be dependent on the baseline values. This finding is in accordance with TRH challenge tests showing that basal TSH levels are highly correlated with stimulated responses when sensitive and specific assays are used (Keller et al. 1986; Lukinac et al. 1986).
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states and daily temperature.
Some
Post RM, Gemer RI-I, Carman JS, Gillin JC, Jimerson DC, Goodwin FK, Bunney WE (1978): Effects of a dopamine agonist piribedil in depressed patients: Relationship of pretreatment HVA to antidepressant response. Arch Gen Psychiatry 35:609-615. Post RM, Kramlinger KG, Joffe RT, Gold PW, Uhde TW (1987): Effects of carbamazepine on thyroid function. 140th Annual Meeting of the American Psychiatric Association, Chicago, May 9-14, abstract 104D. Prange AJ, Wilson IC, Rabon AM (1969): Enhancement thyroid hormone. Am J Psychiatry 126:457-459.
of imipramine
antidepressant
Range AJ, Wilson IC, Lala PP, Alltrop LB, Breese GR (1972): Effects of thyrotropine hormone in depression. Lancet II:999-1002.
activity by releasing
Prinz
PN, Vitiello MV, Smallwood RG, Schoene BB, Halter JB (1984): Plasma norepinephrine in normal young and aged men: Relationship to sleep. J Gerontol 39:561-567.
Rindt W, Liicker PW, Treitz P, Bitsch M (1981): Klinische Aspekte der tagezeitlich unterschiedlichen Beeinflupbarkeit des Prolaktinsystems. Meth Find Expfl Clin Pharmacol 3(Suppl 1): 115s-I 18s.
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Sack DA, James SP, Rosenthal NE, Wehr TA (1988): Deficient nocturnal surge of TSH secretion during sleep and sleep deprivation in rapid-cycling bipolar illness. Psychiatr Res 23: 179-191. Sassin JF, Rantz AG, Weitzman ED, Kapen S (1972): Human prolactin: 24hour pattern with increased release during sleep. Science 177: 1205- 1207. Schubert H, Fleischhacker WW, Demel I (1982): Bromocriptin bei organischen depressionen. Pharmacopsychiurry 15:103-106. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 35:773-782.
Suetre E, Salvati E, Pringuey D, Krebs B, Plasse Y, Darcourt G (1986): The circadian rhythm of plasma thyrotropin in depression and recovery. Chronobiol Int 3: 197-205. Theohar C, Fischer-Comelsse K, Brosch H, Fischer EK, Petrovic D (1982): A comparative, multicenter trial between btomocriptine and amitriptyline in the treatment of endogenous depression. Arzneim ForschlDrug Res 32 (11):783-789. TolIe R (1981): Sleep deprivation and sleep treatment. In: van Praag HM (ed), Handbook of Biological Psychiatry. Part VI. New YorkBasel: Marcel Dekker. Tufik S, Lindsay CJ, Carlini EA (1978): Does REM sleep deprivation induce a supersensitivity of dopaminergic receptors in the rat brain? Pharmacology 16:98-105. Unden F, Ljunggren J-G, Kjellman BF, Beck-Friis H, Wetterberg L (1986): 24h serum levels of T4 and T3 in relation to decreased TSH serum levels and decreased TSH response to TRH in affective disorders. Acta Psychiatr Stand 73:358-365. Vanhaelst L, Van Cauter E, Degaute JP, Goldstein J (1972): Circadian variations of serum thyrotropin levels in man. J Clin Endocrinol Metab 35:479-482. Weeke A, Weeke J (1976): Disturbed circadian variation of serum thyrotropin in patients with endogenous depression. Acta Psychiatr Stand 57~281-289. Wehmann RE, Nisula BC (1984): Radioimmunoassays of human thyrotropin: Analytical and clinical developments. Cr Rev Clin Lab Sci 20:243-283. Weitzman ED, Czeisler CA, Merman JC, Ronda JM (1981): The sleep-wake cycle of cortisol and growth hormone secretion during non-entrained (free running) conditions in man. In: Van Cauter E, Copinschi G (eds), Human Pituitary Hormones, vol 1. Boston: Martinus Nijhoff, pp 29-41. Wiegand M, Berger M, Zulley L, Lauer C, von Zerssen D (1987): The influence of daytime naps on the therapeutic effect of sleep deprivation. Biol Psychiatry 22:386-389. Willner P (1983): Dopamine and depression: A review of recent evidence. I. Empirical studies. Brain Res Rev 6:21 l-224.
631
Nocturnal TSH and Prolactin Secretion during Sleep Deprivation and Prediction of Antidepressant Response in Patients with Major Depression Siegfried Kasper, David A. Sack, Thomas A. Wehr, Hermes Kick, Gabriele Voll, and Antonio Vieira
In order to test the hypothesis that changes in the hypothalamic-pituitary axis during sleep deprivation are related to the antidepressant effects of this procedure, we measured thyroid-stimulating hormone (TSH) and pro~a~tin levels in 32 depressed patients at 2.90 AMduring a night before, during, and afrer total sleep deprivation (TSD). TSH levels increased significantly (p < 0.05) during TSD, and prolactin levels decreased significantly (p < 0.0001). When we divided the patients into responder and nonresponder groups based on a 30% reduction in the Hamilton Rating Scale, there was no difference between the two groups in their hormone levels on the baseline, TSD, or recovery nights. Changes in prolacti~ or TSH were not correlated with clinical improvement when the two groups were considered together or in the responder/ nonresponder groups separately. Baseline values of both hormones were signijkantly (p < 0.01) correlated with their respective levels during TSD and recovery sleep. These findings indicate that the relative levels of nocturnal TSH and prolactin are stable even within acutely depressed i~ividuals and that changes in their levels are not related to the clinical response to sleep deprivation.
Introduction A single night of total sleep deprivation (TSD) exerts an acute antidepressant effect in a majority of depressed patients (Kuhs and Tolie 1986), but its mechanism of action is not known. The clinical response to sleep deprivation has a rapid onset, but it can be reversed by sleeping (Wiegand et al. 1987). Many physiological processes are altered by sleep, including body temperature (Ptlug et al. 1981), neurotransmitter turnover (Mullen et al. 1981; FVinz et al. 1984), and hormone secretion (Golstein et al. 1980; Weitzman et al. 1981; O’MaIley et al. 1984a); interrupting the sleep-dependent regulation of these functions by sleep dep~vation may be related to its ~tidep~ss~t effect. Alterations in the hy~~~~ic-pituit~-thy~id (HPT) function may be of particular
From tbe Clinical Psychobiology Branch, NIMH, Bethesda, MD, and the Psychiatric Department of the University of Heidelberg, F.R.G. Suppti by the Geman Research Foundation (DFG) (S.K.). Address reprint requests to Dr. Siegfried Kasper, Clinical ~ychobiology Branch, National Institute of Mental He&b, Building 10, Room 4s239, Bethesda, MD 20892. Received June 30, 1987; revised December 21, 1987. 0 1988 Society of Biological Psychiatry
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irn~~ce in the antidepressant response to sleep dep~vation as: (1) the n~tumal rise in thyroid-stimulating hormone (TSH) secretion is reduced or absent in patients with depression (Golstein et al. 1980; Kjellman et al. 1984; Suetre et al. 1986; Sack et al. 1987); (2) TSH levels are increased by sleep deprivation in normals (Parker et al. 1976, 1987; Sack et al. 1987), possibly via increased thyrotropin-releasing hormone (TRH) secretion; (3) TRH exerts behavioral effects similar to tricyclic antidepressants in animal models (Ogawa et al. 1984) and may have antidep~ss~t effects in humans (Kastin et al. 1972; Prange et al. 1972; Furlong et al. 1976), although it is noteworthy that others have failed to replicate these antidepressant properties of TRH (Ehrensing et al. 1974; Montjoy et al. 1974); and (4) increased TSH secretion may be associated with transient increases in active thyroid hormones that may also have therapeutic effects (Prange et al. 1969; Goodwin et al. 1982). Recently, Baumgartner and Meinhold (1986) found that sleep deprivation significantly increased 8:00 AM TSH levels in depressed patients and that clinical improvement was correlated with the rise in TSH. In contrast to these findings, Sack et al. (1987) failed to find a correlation between clinical improvement and the change in TSH levels during sleep deprivation when TSH was measured every half hour during the night at baseline and during TSD. An alternative hy~~esis that might explain the therapeutic effects of sleep dep~vation is that sleep deprivation acts by increasing central dopaminergic activity. There is considerable evidence that central dopaminergic function is decreased in depression (Willner 1983), and in animal experiments, sleep deprivation produces behavioral supersensitivity to dopamine agonists (Tufik et al. 1983). One method for indirectly assessing dopamine activity is to measure serum prolactin levels (Leong et al. 1983; Ben-Jonathan 1985). Sleep-related secretion of prolactin can be inhibits by dop~ne agonists (Del Pozo et al. 1975; Chihara et al. 1976; Rindt et al. 1981), suggesting that the nycthemeral rise in prolactin is due to decreased dopamine. However, other factors are also known to stimulate (Bruni et al. 1977; Lewis and Sherman 1985) or inhibit (O’Malley et al. 1984b; Fink 1985; degli Uberti et al. 1985) prolactin secretion. Ordinarily, prolactin secretion markedly increases during sleep (Sassin et al. 1972; Parker et al. 1973; Franz 19’79), and total sleep deprivation, in contrast to selective REM sleep deprivation (Beck 198I), potently reduces prolactin levels in healthy subjects (Parker et al. 1981; Desir et al. 1982) and patients with major depression (Berger et al. 1986). If nocturnal prolactin secretion reflects dopamine activity in the tuberoinfindibular dopamine system, then the magnitude of the decrease in prolactin levels might provide a useful index of dopamine activity during TSD. In order to further test the hypotheses that TSD exerts its effects via changes in HPT or dopaminergic activation, we measured serum TSH and prolactin levels in 32 depressed patients at 2:00 AM during a baseline night, during TSD, and the night after TSD. The 2:OOAM time was chosen because TSH and prolactin levels tend to be highest during nighttime when the individual is asleep and thus may provide an estimate of peak activity in these hormone systems.
Methods Thirty-two psychiatric inpatients (22 women, 10 men; aged 29-76, mean 50.4 2 14) who met DSM-III criteria (American Psychiatric Association 1980) for major depression (n = 30) or dys~ymia (n = 2) participated in the study. Thirty patients met RDC (Spitzer et al. 1978) criteria for major depression (27 unipolar and 3 bipolar II), with a mean of 6.5 t- 1.4 on the Newcastle Scale (Carney et al. 1965).
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Patients were free of psychotropic drugs for at least 4 days (mean 7.2 zt 1.4) prior to the study, and only chloral hydrate was allowed for medication. Prior to admission, patients had been treated with various antidepressants, and one patient had been treated with ne~oleptic medication (melperon, 300 m~day). Blood samples were obtained via venipuncture at 2:00 AM on the night preceding TSD, during TSD, and on the night following TSD. On the baseline and recovery nights, patients were awakened for the 2:00 AM specimen and then permitted to go back to sleep. Specimens were assayed by irnmunoradiometric assay for TSH (IRMAclon Henning), and by RIA for prolactin (Serono). The sensitivity for the TSH assay was 0.03 &J TWliter, and the interassay coefficients of variation were 4.1% (at a level of 15.7 pJ.J/liter), 5.1% (at a level of 3.6 @/liter), and 13.5% (at a level of 0.508 @J/liter). The sensitivity for the prolactin assay was 6.0 @l/ml, and the interassay coefficient of variation was 4.0%-5.2%. The sleep deprivation procedure was as follows: Patients were awakened at 7:OOAM on the latent day and were kept continuously awake for the next 40 hr. Nursing staff closely observed the patients in order to ensure compliance with the procedure. Patients were rated at 9:00 AM and 500 PM on the day prior to and following the night of sleep deprivation using a modified version of the Hamilton Depression Rating Scale (HDRS) (Hamilton 1967). Items 4, 5, 6 (sleep), 16 (weight loss), and 18 (diurnal variation) were omitted because these symptoms cannot be meaningfully assessed on the day after TSD. Patients were divided into responders and no~s~nders according to whether or not their mean daily difference score (Tolle 1981) of the HDRS decreased by 30% with treatment. The hormone data and the psychopathological measurements were analyzed by a two-way Analysis of Variance (ANOVA) with repeated measures. Significant main effects and interactions were further tested with Neuwman-Keuls tests, with alpha correction for multiple comparisons. It is our experience that the clinical response to sleep dep~vation varies as a function of time of day, with some subjects showing improvement only in the morning, others only in the afternoon. For this reason, we calculated two additional outcome measures, the morning difference and the evening difference scores in HDRS (Tolle 1981). Relationships between hormone levels (absolute levels and Asleep deprivation-baseline) and the three outcome measures were assessed by Pearson’s correlation coefficient.
Results The severity of depression as measured by Newcastle Scale and HDRS total score did not differ on the baseline day between sleep deprivation responders and nonresponders. The mean & SD scoresbefore TSD were, for the Newcastle Scale, 6.3 * 1.1 and 6.6 & 1.4 (unpaired t-test, two-tailed, I = -0.78, df = 30, p = 0.43) and, for the HDRS total score, 25.5 ? 7.1 and 22.6 & 9.5 for responders and nonresponders, respectively (f = 0.93, df = 30,~ = 0.35). Using the mean daily difference of the modified version of HDRS to categorize clinical response to TSD, there were 16 responders and 16 nom-esponders. Sleep deprivation significantly decreased depression levels for all patients over the four time points measured (Time: F = 18.9, p < O.~l~, but the beneficial effects were significantly greater in the responder group (Group X Time interaction: F = 14.8, p < 0.00001) (Figure 1). TSH levels rose significantly during sleep deprivation compared to baseline and recovery night (Time: F = 4.5, p < 0.05), but there was no relationship between the change in TSH and clinical response (Group X Time interaction: F = 1.5, p = 0.22)
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o
25 -
Responder (n=16)
+
Nonresponder (n=16) Group x Time Interaction F = 14.8; p i 0.0001
g ._ B 5 g
2o
15-
B
10 -
5
:
’ 9am
5 pm Baseline Day
Sam
5pm
Day after TSD
Figure 1. Mean k SEM depression ratings as measured with a modified version (see text) of Hamilton Depression Rating Scale (HDRS) in total sleep deprivation responder and nonresponder.
(Table 1). Prolactin values were significantly lower during TSD (Time: F = 15.9, p -=LO.OOOOl),but, as with TSH, there was no significant relationship between prolactin levels and clinical response to TSD (Group X Time interaction: F = 0.29, p = 0.74) (Figure 2). The results were unchanged when pre- and postmenopausal women (n = 7 premenopausal and n = 15 postmenopausal) and men (n = 10) were analyzed separately . There were no significant correlations between clinical improvement (mean daily, morning, or evening difference scores) and the levels of either hormone at baseline, during sleep deprivation, or the change from baseline to sleep deprivation (Table 2, Figure 2), nor were hormone levels at 2:00 AM correlated with the severity of depression at baseline or during sleep deprivation (r = -0.09 for TSH, r = 0.03 for prolactin). Changes in TSH or prolactin were not correlated with the different applied clinical response measurements when the groups were considered together or in the responder/nonresponder groups alone.
Table 1. TSH and Prolactin Values during Sleep Deprivation Procedure Baseline night TSH ((IUlliter) TSD responder TSD nonresponder Prolactin (nglml) TSD responder TSD nonresponder
Sleep deprivation
Recovery
night
1.1 k 0.7 1.1 i 0.7
1.4 k 0.8 1.4 LY0.7
1.1 -+ 0.7 1.0 -t 0.7
NS
19.1 + 12 20.8 * 19
10.6 i 5 11.6 -e 8.7
24.2 k 18 22.6 2 18
NS
“Difference between TSD responder and TSD nonresponder (ANOVA, Group x Time interaction)
TSH and Pmlactin during Sleep Deprivation
635
2
y = 0.2278+0.001x R = 0.06 .
n=32
. 1
#m
z I e Q
. o-
1
* ‘ .
. Ic.
l
.
.
I
. ‘ l
l
.
’
.
l
s
. -1 ,',.r.t-r-I*r-t -100 -75 -50 -25 0 25 50 75 Mean dailydifference(HDRS)
10
100%
Y = - 8.0604-0.0329x
7
R= 0.10
n-32
.
-3
‘
-30 ‘
I
,
-4o-'-, -100 -75
-50 -25 0 25 50 Mean daily difference(HDRS)
75
100%
TSW and prolactin values during sfeep deprivation wery: sig~~c~~y correlated with their respective levels at baseline (p -K 0.01) and on the recovery night (‘Table 2). No correlations were found be&eon TSH and proMin tevels, either in absolute values or A values from baseline to TSD. The d~ti~u of w~hout was com~ble in the responders and nomponders (6.9 1 1.7 days in responders; 7.5 z.&0.8 days in nanresponders; unpaired r-test: t = - 1S, df = 30, p = 0.14).
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Table 2. Correlationsbetween Hormone Levels at 2:OOAM and between Hormones and Different Clinical Response Definitions Hormone levels at 2:00
TSH (sleep deprivation) Prolactin (sleep deprivation)
Response ratings”
AM
Baseline night
Recovery night
0.66’
0.63b
0.79h
0.606
Daily 0.14
-0.24
Morning --0.12
-0.19
Evening 0.07
- 0.09
“Mean difference scores(HDRS). bSignificant@ < 0.01).
Discussion TSD significantly reduced depression, raised TSH levels, and lowered prolactin levels during the sleep deprivation night, but the clinical response to TSD was unrelated to the changes in hormone levels. Our findings with respect to TSH are consistent with the observations of Sack et al. (1987), but are opposite to those of Baumgartner and Meinhold (1986), who found that the clinical improvement during TSD was correlated with increased TSH on the morning after TSD. The present study differed from that of the latter in three respects that might explain the divergent findings: (1) the time at which samples were obtained (2:00 AM versus 8:00 AM), (2) the medication status of the patients (drug-free versus medicated), and (3) the assay used for TSH estimation (immunoradiometric assay versus radioimmunoassay). We will discuss these aspects in further detail because they bear on some of the problems involved in sleep deprivation studies in which hormonal changes are related to outcome measurements. Previous circadian studies indicate that TSH levels are highest during the night (Weeke and Weeke 1976; Parker et al. 1976; Vanhaelst et al. 1979); thus, our 2:00 AM sample is more likely to reflect peak activity in this system than an 8:00 AM value. The TSH values we obtained at 2:00 AM were highly correlated with subsequent measures during TSD and on the recovery night, confirming our impression that it is a reliable index of nocturnal secretion. It is possible that changes in morning TSH levels with sleep deprivation may provide additional information not detected in the 2:00 AM sample alone. This would be the case if the phase of the TSH rhythm were more erratic in depressed patients than in controls, as has been reported by Golstein et al. (1980) but not by others (Kjellman et al. 1984; Sack et al. unpublished data). Antidepressant medication may also influence TSH levels. TSH levels increase and thyroid hormone levels decrease with antidepressant treatment (UndCn et al. 1986; Post et al. 1987; Kasper et al. unpublished data), and pretreatment with antidepressants has been reported to change the course after TSD with a prevention of the otherwise regularly occurring relapse (van den Hofdakker and Elsenga 1980). Thus, studies in which subjects are currently taking antidepressants may be measuring an interaction among antidepressants, TSH, and sleep deprivation, rather than the effect of sleep deprivation alone. The lack of sensitivity of radioimmunological methods has been a major problem in the measurement of TSH. The considerably higher sensitivity of the newly developed immunoradiometric assays (IRMA) (Wehmann and Nisula 1984) permits the detection
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of TSH values as low as 0.03 busier compared with 0.2 p&/liter with RIA. Morning TSH values fall close to the limits of detection of RIA assays, and it is possible that correlations between psychopathological measures and tbe difference of hormonal changes using RIAs are not reliable at this time of the day. The magnitude of the sleep deprivation-induced rise in TSH levels found in our predominantly unipolar depressed patients is similar to that found in rapid-cycling bipolar patients, but is considerably less than the TSD induced rise in TSH found in controls (Sack et al. 1987). Thus, a blunted TSH response to TSD does not appear to be restricted to a particular diagnostic subgroup of depression and may be physiologic~ly related to the blunted To-st~ulated TSH response observed in some depressed patients (Loosen and Prange 1982). The regulation of prolactin is complex, involving several neurotransmitters and neuropeptides. In light of the strong inhibitory influence that dopamine exerts on prolactin levels, an enhanced dopamine activity could be hypothesized to be responsible for the decline in prolactin levels during sleep deprivation. This hypothesis may be inconsistent with elevation of TSH during sleep deprivation, as dopaminergic agonists inhibit TSH secretion levels during the night. However, the physiological role of dopamine in the regulation of TSH has not been established (Morley 1981). In animal experiments, increased dop~inergic simulation is associated with an increase in motor activity, aggression, and activation (Antelmann and Caggiula 1977), and comparable behaviors are observed in depressed patients following sleep deprivation (Kasper et al. 1988). Gemer et al. (1979) found that CSF concentrations of the dopamine metabolite homovanillic acid were significantly lower in TSD responders compared with nonresponders, but sleep deprivation failed to significantly alter HVA levels in either patient group. This latter finding is similar to our failure to find a relationship between altered prolactin secretion and the antidepressant effects of TSD. The indirect-acting dopamine agonist methylphenidate has acute mood-elevating properties analogous to those seen with TSD (Janowsky et al. 1973), but brom~~ptine, a direct-acting dopamine agonist that acutely suppresses prolactin secretion (Del Pozo et al. 197% has ~tidep~ss~t effects only when administered for several weeks (Post et al. 1978; Nordin et al. 1981; Schubert et al. 1982; Theohar et al. 1982). The temporal dissociation between the mood and hormonal effects of bromocryptine suggests either that (1) altered dopamine activity in the tuberoinfindibular system is not a useful measure of dopamine activity, which might be more closely related to mood in other brain areas, or (2) dopamine is not involved in the acutely occurring antidepressant effects of sleep deprivation. Among the different factors influencing the results of our study, a confounding variable might have been the relatively short washout phase. Discontinuation of tricyclic and ~tidepr~san~ is followed by gradual changes in neu~~smi~r lover that can last for several weeks (Charney et al. 19821, and such changes may have influenced p&a&n and TSH levels. As the washout period was comparable in SD responders and SD nonresponders, it seems that withdrawal effects alone would not explain our findings. Another factor that might have influenced our results is the fact that the majority of our group of patients were postmenopausal women, and the separate analysis according to the menopausal and gender status resulted in small subgroups with the possibility of a type II error. It is known that estrogens have a modulating effect on the secretion of prolactin (Judd et al. 1978), and nocturnal prolactin levels are higher in postmenopausal patients with major depression compared to control subjects (Mai et al. 1985). Additional
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studies that are homogeneous with respect to gender and menopausal status are needed to clarify whether or not there is a relationship between the effects of sleep dep~vation on TSH or prolactin secretion and its effects on mood. Our sampling procedure may also have influenced our results. In order to obtain 2:00 AM blood samples, our patients were awakened from sleep on the baseline and recovery nights. This awakening could have ~ifactu~ly raised TSH and decreased prolactin levels. In our study, prolactin levels were markedly higher during sleep than sleep deprivation and conversely, TSH levels were quite low (I . 1 mu/liter) during sleep, suggesting that the period of wakefulness preceding venipuncture was too brief to affect these hormone levels. It is possible that awakenings might have obscured differences of hormonal levels between SD responders and SD nonresponders during baseline and recovery night, but this seems unlikely, as the two groups underwent the same procedures. Various investigators have used a number of different outcome measures to define the clinical response to sleep deprivation making precise comparisons between studies difficult, We choose the total score of the Hamilton Depression Rating Scale (HDRS) (Hamilton 1967) to monitor clinical response because it is widely used and reproducible. It is possible that an item-~~ysis of HDRS or the self-rating scales would result in further subgroups, but the number of patients in this study is too small for such grouping to produce statistically meaningful results. The lack of correlation between hormonal changes and clinical improvement with TSD in our study does not support the hypo~esis that improvement in mood is due to altered regulation of neurohypophyseal function. Rather, we found that TSH and prolactin levels were highly consistent with individuals across conditions that might reflect the depressed patients’ adaptation to a physiological state that allows fluctuations only in a given range, which seems to be dependent on the baseline values. This finding is in accordance with TRH challenge tests showing that basal TSH levels are highly correlated with stimulated responses when sensitive and specific assays are used (Keller et al. 1986; Lukinac et al. 1986).
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