~L psychiat. Res., Vol. 25, No. 3, pp. 109-116, 1991.
0022-3956/91 $3.00 + .00 Pergamon Press plc
Printed in Great Britain.
SERUM POSTDEXAMETHASONE
PROLACTIN
DEPRESSIVE PATIENTS AND CONTROL M.
M A E S , 1,3 C .
SCHOTTE, 1
D. PEETERS, 1 P.
D'HONDT, l
M.
MEASURES
IN
SUBJECTS MARTIN, 2
P.
BLOCKX, 2
B. MINNER, 3 E. SuY 3 and P. CosYys 1 1Department of Psychiatry, 2Department of Nuclear Medicine, University Hospital of Antwerp and 3psychiatric Centre, Munsterbilzen ( R e c e i v e d 23 N o v e m b e r 1990; revised 17 M a r c h 1991)
S u m m a r y - - R e c e n t l y , some researchers noted significant positive relationships between postdexamethasone serum cortisol and prolactin levels, whilst endogenous depressives exhibited a significantly lower suppression of prolactin by dexamethasone than non-endogenous patients or normal controls. To ascertain the extent of prolactin responses to dexamethasone in severely depressed patients, we measured 8 a.m. pre- and postdexamethasone prolactin levels in 104 depressed and 42 normal subjects. Serum cortisol levels were also determined in depressed patients before and after dexamethasone administration. We found a significant suppressive effect of dexamethasone on prolactin levels. There were no significant differences either in pre- or postdexamethasone prolactin, or in actual dexamethasone-induced decrements in prolactin between normal controls, melancholics, simple major or minor depressed subjects. We have not found any significant relationships between cortisol and prolactin, either under baseline or postdexamethasone conditions.
Introduction SEVERE depression (melancholia) is frequently accompanied by dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis. The best-documented abnormalities are the resistance of HPA-axis hormones, such as adrenocorticotropic hormone, ¢3-endorphin and cortisol, to the suppressive effects of dexamethasone (Carroll, 1982; Feinberg & Carroll, 1984; Maes, De Ruyter, & Suy, 1987; Maes et al., 1990a; Maes et al., 1990b). Recently, a significant suppressive effect of dexamethasone on baseline levels of thyroid secreting hormone (TSH) was observed (Rupprecht, Rupprecht, Rupprecht, Noder, & Mahlstedt, 1989; Maes, Vandewoude, Schotte, Martin, & Blockx, 1990c). In addition, we noted less suppression of TSH by dexamethasone in cortisol nonsuppressors compared with suppressors (Maes et al., 1990c). We (Maes et al., in press), and others (Lowy, Reder, Gormley, & Meltzer, 1988) also reported a partial resistance of immune cell function in depressive patients to the suppressive effects of glucocorticoids. All these findings lend support to the existence of more generalized, partial glucocorticoid resistance in some severely depressed patients (Maes et al., 1990c). Previous work has revealed that severe depression may be associated with abnormalities in another pituitary hormone, i.e. prolactin. These abnormalities include, amongst others, * Address for correspondence: Dr. M. Maes, University Hospital of Antwerp, UZA, Wilrijkstraat, 10, B-2650 Edegem, Belgium. 109
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et al.
alterations in baseline prolactin secretion (Mendlewicz, Linkowski, & Brauman, 1980; De la Fuente, & Rosenbaum, 1981 ; Garbutt, Loosen, Blacharsh, & Prange, 1986). In addition, some groups have reported a higher degree of prolactin nonsuppression in endogenously depressed patients compared with controls (Meltzer, Fang, Tricou, Robertson, & Piyaka, 1982; Klein et al., 1984; Rupprecht, Barocka, Jecht, Noder, Pichl, & Schwartz, 1987; Risch et al., 1987). Atkinson, Kremer, Risch, and Janowsky (1986) observed a significant positive correlation between postdexamethasone prolactin values and severity of depression in pain patients. Baumgartner, Graf, and Kurten (1988) and Rubin, Poland, Lesser, and Martin (1989), on the other hand, were unable to find prolactin nonsuppression in endogenous depressed subjects. In cortisol nonsuppressors, dexamethasone administration had a less pronounced suppressant effect, no effect, or even an enhancing effect upon prolactin secretion (Meltzer et al., 1982; Klein et al., 1984; Joyce, Donald, & Livesey, 1985). Joyce et al. (1985) described a positive correlation between postdexamethasone cortisol and prolactin values. Others failed to detect any relationship between cortisol and prolactin nonsuppression (Atkinson et al., 1986; Baumgartner et al., 1988; Rubin et al., 1989). This prospective study has been conducted in order to determine whether (1) melancholia is characterized by less prolactin suppression by dexamethasone, compared with the healthy state or minor depression and (2) cortisol nonsuppression is related to prolactin responses to dexamethasone. Subjects and Methods
Subjects One hundred and forty-six subjects participated in this study. The depressed patients (n = 104) were evaluated in the Psychiatric Ward of the University Hospital of Antwerp. They were consecutively admitted to Hospital from January 1988 to July 1990. Forty-two normal control subjects, staff or their family members, were also examined. None were regular drinkers and all had been free from medication for at least one month before the dexamethasone suppression test (DST). They were free of significant physical or psychiatric illnesses. The depressed patients were classified according to the DSM-III (American Psychiatric Association, 1980) into (1) dysthymic disorder (300.40) and adjustment disorder with depressed mood (309.00), hereafter labelled as minor depression, (2) major depression without melancholia (296.X2), and (3) major depression with melancholia (296.X3). A structured interview, i.e. the Structured Clinical Interview for DSM-III-R (Spitzer, Williams, & Gibbon, 1985) was conducted in order to determine the DSM-III diagnosis for depression. Hamilton depression rating scale (HDRS)/(Hamilton, 1960) scores were also obtained on each patient. Any subject with a history of concomitant psychiatric illness, such as substance abuse or schizophrenia, abnormal laboratory findings (urine analysis, chest X-ray, EEG, blood analysis), or with a major medical illness, was excluded. Moreover, we omitted patients who had undergone electroconvulsive therapy during the previous year, and also those who were on lithium, monoamine oxidase inhibitors, anticonvulsants, and antipsychotic dosages of neuroleptics for a similar length of time prior to hospital admission. Table 1 summarizes demographic data for the subjects in our study. Forty-five patients
POSTDEXAMETHASONE PROLACTIN MEASURES
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Table 1
Demographic Data o f the 146 Subjects in this Study Drug state
Category Healthy controls Minor depression Simple major depression Melancholia
Index HC md MD-M MD+M
Ratio Age (years) HDRS c Men/women mean (SEM) mean (SEM) 19/23 11/19 9/36 13/16
38.9 40.5 45.4 56.5
(1.8) (2.4) (1.9) a (2.4) b
-16.2 (0.4) 22.6 (0.3) 27.2 (0.9)
BZ yes/no
DF yes/no
0/42 5/25 17/25 17/12
42/0 17/13 14/28 14/13
HDRS: Hamilton Depression Rating Scale (17-item version). BZ: use of benzodiazepines during the study period; DF: more than one month drug free before hospital admission (yes/no). All results are expressed as mean (+ SEM). aSignificantly different from HC, bSignificantly different from HC, md and MD-M, F = 12, df= 3/142, p < 10-3 (ANOVA), CAllHDRS scores are significantly different from each other, F = 88, df= 2/101, p < 10 - 4 (ANOVA). were d r u g free for at least one m o n t h b e f o r e h o s p i t a l i z a t i o n . B e n z o d i a z e p i n e s , l o w - d o s a g e neuroleptics, a n d a n t i d e p r e s s a n t s were d i s c o n t i n u e d after a d m i s s i o n . T h i r t y - n i n e patients were p l a c e d on b e n z o d i a z e p i n e s ( < 2 5 mg d i p o t a s s i u m - c h l o r a z e p a t e a n d / o r < 2 7 . 5 f l u r a z e p a m ) during the study p e r i o d where sleep disorders or severe agitation were a feature. These benzodiazepines were administered 9 hr before or after 8 a.m. b l o o d sample collection.
Methods O n e m i l l i g r a m o f d e x a m e t h a s o n e was ingested b y all subjects at 11 p . m . B l o o d samples were collected at 8 a . m . for baseline h o r m o n e values, a n d at 8 a . m . the following d a y for p o s t d e x a m e t h a s o n e p r o l a c t i n a n d cortisol assay. In o u r d e p r e s s e d patients, the D S T was c a r r i e d o u t 6 days after h o s p i t a l a d m i s s i o n . The h o r m o n e assays e m p l o y e d are described elsewhere (Maes, V a n d e w o u d e , M a e s , Schotte, & C o s y n s , 1989a,b).
Statistics The independence o f classification systems was checked by means o f contingence analysis (Chi-square test with Yates' correction). N o r m a l i t y o f distribution was ascertained by means o f the test for goodness o f fit (Chi-square test). Relationships between variables were assessed by means o f P e a r s o n ' s p r o d u c t m o m e n t , a n d point-biserial c o r r e l a t i o n coefficients. G r o u p m e a n differences were tested b y m e a n s o f analysis o f v a r i a n c e ( A N O V A ) or analysis o f c o v a r i a n c e ( A N C O V A ) . F a c t o r i a l r e p e a t e d - m e a s u r e A N O V A s were used in o r d e r to c o m p a r e h o r m o n e levels b e f o r e a n d after t r e a t m e n t . T h e level o f significance was set at c~ = 0.05 (two-tailed). Results
Demographic Data Table 1 lists d e m o g r a p h i c d a t a for the 146 subjects in this study. There were no significant differences in sex r a t i o between the 4 s t u d y g r o u p s . P a t i e n t s with simple m a j o r d e p r e s s i o n were o l d e r t h a n h e a l t h y c o n t r o l s , whereas m e l a n c h o l i c s were significantly o l d e r t h a n all
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other subjects. The H D R S score was significantly different between depressive subgroups and increased from: minor depression ---'simple major depression ~ melancholia. We found no significant differences in the ratio of drug free/not drug free subjects between the depressive subgroups. Significantly more major depressives received benzodiazepines compared with minor depressives (x2= 9, d f = 2, p = .01). Pre- and postdexamethasone prolactin distribution curves were not normally distributed (:~2=65, p < 1 0 4; x Z = l l 3 , p < 1 0 --4, respectively, d f = 6 ) . A f t e r l o g a r i t h m i c transformation (natural logarithm), the distribution curves became normal (X2=4, p = 0.67; X 2 = 7.7, p = 0.26, respectively, df = 6). In addition, pre- and postdexamethasone cortisol values approached a normal distribution after logarithmic transformation (see Maes, De Ruyter, Hobin, & Suy, 1986). As a result, the prolactin and cortisol data were processed after logarithmic transformation. Baseline prolactin values were significantly different between men and postmenopausal females on the one hand, and premenopausal females, on the other (mean ± SEM: 202 +25, 199±21 vs. 331±38 #U/ml, respectively; F = 7 . 2 , d f = 2 / 1 4 3 , p = . 0 0 1 ) . Moreover, postdexamethasone prolactin values were higher in premenopausal females compared with men and postmenopausal females ( m e a n + S E M : 2 1 4 + 2 8 vs. 136+21, 137+ 17 /zU/ml, respectively; F = 3.7, d f = 2/143, p = .03). As a result, we have introduced the sex-hormonal state as a second factor in the statistical tests employed (factorial ANOVAs, ANCOVAs). We found significant and positive correlations between pre- and postdexamethasone prolactin values on the one hand, and age on the other (r= 0.28, p = .0009; r = 0.20, p = .01, respectively). However, age explained only a small part of the variance in pre- and postdexamethasone prolactin values (7% and 4%, respectively). There were no significant relationships between any of the prolactin values and drug state of the depressed patients (i.e. use of benzodiazepines during the study period; length of drug free period before hospital admission, i.e. more than one month: yes, otherwise: no). Consequently, we have no evidence for major effects of the drug state of the subjects on our results. Prolactin Secretion and DSM-III Groups Table 2 presents measurements of pre- and postdexamethasone prolactin values. We found a significant suppressive effect of dexamethasone on prolactin levels. There were no significant group (i.e. diagnostic categories or sex-hormonal state) x treatment interactions. Pre- and postdexamethasone prolactin values were significantly and positively correlated ( r = 0 . 7 3 , p < 10 4). Up to 53°70 of the variance in postdexamethasone prolactin values could be explained by the regression on their basal levels ( F = 162, d f = 1/44, p < 10 4). Therefore, we have used two measures of prolactin responsivity to dexamethasone administration: (1) residual postdexamethasone prolactin values after covarying for baseline prolactin values, and (2) delta p r o l a c t i n = p o s t d e x a m e t h a s o n e prolactin minus basal prolactin. We found no significant differences across diagnostic categories in basal prolactin, postdexamethasone prolactin, and their residual or delta prolactin responses to dexamethasone. Residual and delta prolactin responses were not significantly different between men, pre- and postmenopausal women.
113
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Table 2
Measurements o f pre- and postdexamethasone (DEX) prolactin and cortisol levels in 146 subjects Prolactin levels (#U/mL) Index
Pre-DEX
HC md MD-M MD+M
295 247 251 239
(19) (27) (31) (34)
Post-DEX 203 (15) a 145 (20) a 170 (23) a 174(27) a
A Prolactin -91 -101 -81 -65
(19) (19) (15) (27)
Cortisol (/zg/dL) Residual 9.0 -22.8 0.2 10.2
(14.1) (14.5) (10.5) (21.0)
Pre-DEX
Post-DEX
-22.6 (1.1) 20.5 (0.9) 21.9(1.I)
-2.3 (0.4) 4.4 (0.8) 6.7 ( l . l ) b
H C / m d / M D + M : for explanation see Table 1. All results are expressed as mean ( + SEM). A: Post-DEX--Pre-DEX prolactin levels. Residual: the residual postdexamethasone prolactin values after covarying for basal prolactin. aSignificantly different from baseline levels, F = 101, d f = 1/144, p < 10 4 (repeated ANOVA). bSignificantly different from md and MD-M, F = 8 . 5 , d r = 2 / 1 0 1 , p 0.001 (ANOVA on logarithmic transformation).
Relationships between Prolactin and Cortisol Secretion Table 2 shows pre- and postdexamethasone cortisol values. Patients with melancholia exhibited significantly higher postdexamethasone cortisol levels compared with minor and simple major depressives. The interrelationships between both hormones were investigated in the depressive sample. We found no significant differences between cortisol suppressors and nonsuppressors (defined as 8 a.m. postdexamethasone cortisol /> 3.5 #g/dl; Maes et al., 1986), either in basal prolactin, postdexamethasone prolactin, or in residual or delta prolactin responses. Accordingly, we could not establish a significant relationship either between postdexamethasone cortisol and prolactin values (r= 0.16, p = .09), or between their baseline hormone levels (r= 0.10, p = .30). Discussion In the present study, we were unable to observe any differences in baseline prolactin level between healthy controls and various depression categories. There is, however, a discrepancy in the published data: various studies have reported increased (Horrobin, Mtabaji, Karmali, Manku, & Nasar, 1976; Maeda et al., 1975; Sachar, Frantz, Altman, & Sassin, 1973), decreased (Asnis, Nathan, Halbreich, Halpern, & Sachar, 1980); Mendlewicz et al., 1980), or unchanged (Ehrensing, Kastin, Schalch, Friesen, Vargas, & Schally, 1974; Garfinkel, Brown, Warsh, & Stancer, 1979; Gold, Goodwin, Wehr, Rebar, & Sack, 1976; Gr6goire, Brauman, de Buck, & Corvilain, 1977; Nielsen, 1980; Rubin et al., 1989; Kjellman, Ljunggren, Beck-Friis, & Wetterberg, 1985; Jarrett et al., 1987) baseline prolactin concentrations. The present results are in agreement with other findings that premenopausal females exhibit higher baseline prolactin values compared with postmenopausal females (Maes et al., 1989b) and men (Klein et al., 1984), whilst the actual prolactin responses to dexamethasone were not significantly different between men, pre- and postmenopausal women.
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Like other investigators, we have found a highly significant suppressive effect of 1 mg dexamethasone on 8 a.m. prolactin levels (Copinschi et al., 1975; Meltzer et al., 1982; Risch et. al., 1988). Even so, not all authors have observed this dexamethasone-induced suppression of prolactin: Baumgartner et al. (1988), and Wolkowitz et al. (1985), for example, were unable to establish any difference between 4 p . m . pre- and postdexamethasone prolactin levels in healthy controls. It is interesting to note that most authors have established significant suppressive effects of dexamethasone on 8 a.m. and not on 4 p.m. prolactin circulating concentrations. This different time x t r e a t m e n t interaction pattern is further sustained by the findings of Risch et al. (1988) who noted a significant day x time interaction in dexamethasone-induced suppression of prolactin secretion (suppression at 8 a.m., not at 4 p.m.). Accordingly, it is our view that the coined label of " 4 p.m. prolactin nonsuppression" (Klein et al.; 1984; Baumgartner et al., 1988) is irrelevant, as there was no evidence of any suppressive effect by dexamethasone at that time. Moreover, we were unable to establish significant differences in postdexamethasone prolactin levels between healthy controls, minor, simple major and melancholic depressives. These results concur with those of Rubin et al. (1989) who estimated average morning prolactin levels and with those of Baumgartner et al. (1988), who measured 4 p.m. postdexamethasone prolactin. Risch et al. (1988) found a trend towards a significant difference in postdexamethasone prolactin between depressed and control subjects. However, these authors did not adjust their postdexamethasone prolactin data for the differences found in basal prolactin concentrations. As a result, the difference in their postdexamethasone prolactin levels may be ascribed to effects of basal prolactin. Some other groups, on the other hand, found a higher frequency of prolactin nonsuppression in endogenous depressives as opposed to controls (Meltzer et al., 1982; Klein et al., 1984; Rupprecht et al., 1987). Nonetheless, these studies failed to adjust postdexamethasone prolactin levels for baseline prolactin, or to measure morning instead of 4 p.m. prolactin levels, or to adjust their prolactin data for the sex hormonal state. Finally, in agreement with several other authors (Atkinson et al., 1986, Baumgartner et al; 1988; Rubin et al., 1989), we were unable to detect any relationship between postdexamethasone cortisol and prolactin non-suppression. This finding contradicts with those of Meltzer et al. (1982), Klein et al. (1984) and Joyce et al. (1985). We were unable to find any differences in baseline or postdexamethasone prolactin levels between patients who were drug free for at least one month prior to the wash-out period, and those who were not. It is thought that benzodiazepines do not affect prolactin secretion (D'Armiento, Bisignani, & Reda, 1981; L a a k m a n et al., 1982). Similarly, we could not detect differences in prolactin secretion between patients on benzodiazepines and those who were not. Thus, our results suggest that prolactin secretion and response to the suppressive effects of dexamethasone is normal in severely depressed patients. We conclude that the partial glucocorticoid resistance, detected during depression in corticotropic, thyrotropic and immune cells (see Introduction), is unlikely to extend to the lactotropes. References American Psychiatric Association. (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author.
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Asnis, G. M., Nathan, R. S., Halbreich, U., Halpern, F. S., & Sachar, E. J. (1980). Prolactin changes in major depressive disorders. American Journal o f Psychiatry 137, 1117-1118. Atkinson, J. H. Jr., Kremer, E. F., Risch, S. C., & Janowsky, D. S. (1986). Basal and postdexamethasone cortisol and prolactin concentrations in depressed and non-depressed patients with chronic pain syndromes. Pain 25, 23-34. Baumgartner, A., Graf, K.-J., & Kurten, I. (1988). Prolactin in patients with major depressive disorder and in healthy subjects. I. Cross-sectional study of basal and post-TRH and postdexamethasone prolactin levels. Biological Psychiatry, 24, 249-267. Carroll, B. J. (1982). The dexamethasone suppression test for melancholia. British Journal of Psychiatry, 140, 292-304. Copinschi, G., L'Hermite, M., Leclercq, R., Golstein, J., Vanhaelst, L., Virasoro, E., & Robyn, C. (1975). Effects of glucocorticoids on pituitary hormonal responses to hypoglycemia. Inhibition of prolactin release. Journal of Clinical Endocrinology and Metabolism, 40, 442-449. D'Armiento, M., Bisignani, G., & Reda, G. (1981). Effect of bromazepam on growth hormone and prolactin secretion in man. Hormone Research, 16, 224-227. De la Fuente, J. R., and Rosenbaum, A. H. (1981). Prolactin in psychiatry. American Journal of Psychiatry, 138, 1154-1160. Ehrensing, R. H., Kastin, A. J., Schalch, D. S., Friesen, H. G., Vargas, J. R., & Schally, A. V. (1974). Affective state and thyrotropin and prolactin responses after repeated injections of thyrotropin-releasing hormone in depressed patients. American Journal of Psychiatry, 131, 714-718. Feinberg, M., & Carroll, B. J. (1984). Biological markers for endogenous depression. Archives of General Psychiatry, 41, 1080-1085. Garbutt, J. C., Loosen, P. T., Blacharsh, J., & Prange, A. J. (1986). The prolactin response to thyrotropin releasing hormone in depressed patients and normal subjects. Psychoneuroendocrinology, 11, 213-219. Garfinkel, P. E., Brown, G. M., Warsh, J. J., & Stancer, H. C. (1979). Neuroendocrine responses to carbidopa in primary affective disorders. Psychoneuroendocrinology, 4, 13-20. Gold, P. W., Goodwin, F. K., Wehr, T., Rebar, R., & Sack, R. (1976). Growth hormone and prolactin response to levodopa in affective illness. Lancet, 2, 1308-1309. Gr6goire, F., Brauman, H., de Buck, R., & Corvilain, J. (1977). Hormone release in depressed patients before and after recovery. Psychoneuroendocrinology, 2, 303-312. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56-62. Horrobin, D. F., Mtabaji, J. P., Karmali, R. A., Manku, M. S., & Nasar, B. A. (1976). Prolactin and mental illness. Postgraduate Medical Journal, 52, 79-85. Jarrett, D. B., Miewald, J. M., Fedorka, I. B., Coble, P., 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. Joyce, P. R., Donald, R. A., & Livesey, J. H. (1985). A relationship between prolactin levels and dexamethasone suppression test results in major depressive disorder. Journal of Affective Disorders, 8, 191-195. Kjellman, B. F., Ljunggren J.-G., Beck-Friis, 1., & Wetterberg, L. (1985). Effect of TRH on TSH and prolactin levels in affective disorders. Psychiatry Research, 14, 353-363. Klein, H. E., Seibold, B., Bender, W., Nedopil, N., Albus, M., & Schmauss, M. (1984). Postdexamethasone prolactin and cortisol: a biological state variable in depression. Acta Psychiatrica Scandinavica, 70, 239-247. Laakman, G., Treusch, J., Eichmeier, A., Schmuss, M., Treusch, U., & Wahlster, V. (1982). Inhibitory effect of phentolamine on diazepam-induced growth hormone secretion and lack of effect of diazepam on prolactin secretion in man. Psychoneuroendocrinology, 7, 135-139. Lowy, M. T., Reder, A. T., Gormley, G. J., & Meltzer, H. Y. (1988). Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test. Biological Psychiatry, 24, 619-630. Maeda, K., Kato, Y., Ongo, S., Chihara, K., Yoshimoto, Y., Yamaguchi, N., Kuromaru, S., & Imura, H. (1975). Growth hormone and prolactin release after injection of thyrotropin-releasing hormone in patients with depression. Journal of Clinical Endocrinology and Metabolism, 40, 501-503. Maes, M., De Ruyter, M., Hobin, P., & Suy, E. (1986). The dexamethasone suppression test, the Hamilton Depression Rating Scale and the DSM-III depressive categories. Journal of Affective Disorders, 10, 207-214. Maes, M., De Ruyter, M., & Suy, E. (1987). Prediction of subtype and severity of depression by means of dexamethasone suppression test, L-trytophan/competing amino acid ratio, and MHPG flow. Biological Psychiatry, 22, 177-188. Maes, M., Vandewoude, M., Maes, L., Schotte, C., & Cosyns, P. (1989a). A revised interpretation of the TRH test results in female depressed patients. Part I: TRH responses. Effects of severity of illness, thyroid hormones, monoamines, age, sex hormonal, corticosteroid and nutritional state. Journal of Affective Disorders, 16, 203-213.
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Maes, M., Vandewoude, M., Maes, L., Schotte, C., & Cosyns, P. (1989b). A revised interpretation of the TRHtest results in female depressed patients. Part II: Prolactin responses. Relationships with sex hormones, corticosteroid state, age, monoamines and amino acid levels. Journal o f Affective Disorders, 16, 215-221. Maes, M., Vandewoude, M., Schotte, C., Maes, L., Martin, M., & Blockx, P. (1990a). A revised interpretation of the postdexamethasone ACTH and cortisol values in unipolar depressed females. Psychiatry Research (in press). Maes, M., Vandewoude, M., Schotte, C., Martin, M., & Blockx, P. (1990c). Suppressive effects of dexamethasone on hypothalmic-pituitary-thyroid-axis function in depressed patients. Journal o f Affective Disorders. Maes, M., Jacobs, M.-P., Suy, E., Leclercq, C., Christiaens, F., & Raus, J. (1990b). An augmented escape of {3-endorphins to suppression by dexamethasone in severely depressed patients. Journal o f Affective Disorders, 18, 149-156. Maes, M., Bosmans, E., Suy, E., Vandervorst, C., De Jonckheere, C., & Raus, J. (1991). Depression-related disturbances in mitogen-induced lymphocyte responses, interleukin-l/3, and soluble interleukin-2 receptor production. Acta Psychiatrica Scandinavica (in press). Meltzer, H. Y., Fang, V. S., Tricou, B. J., Robertson, A., & Piyaka, S. K. (1982). Effect of dexamethasone on plasma prolactin and cortisol levels in psychiatric patients. American Journal o f Psychiatry, 139, 763-768. Mendlewicz, J., Linkowski, P., & Brauman, H. (1980). Reduced prolactin release after thyrotropin-releasing hormone in manic depression. New England Journal o f Medicine, 302, 1091-1092. Nielsen, J. L. (1980). Plasma prolactin during treatment with nortriptyline. Neuropsychobiology, 6, 52-55. Risch, S. C., Janowsky, D. S., Judd, L., Gillin, J. C., Mott, M. A., Rausch, J. L., & Huey, L. (1988). Multiendocrine analysis in depression. In A. F. Schatzberg, & C. B. Nemeroff (Eds.). The hypothalmic-pituitaryadrenal-axis: physiology, pathophysiology, and psychiatric implications (pp. 171-186). New York: Raven Press. Rubin, R. T., Poland, R. E., Lesser, I. M., & Martin, D. J. (1989). Neuroendocrine aspects of primary endogenous depression. V. Serum prolactin measures in patients and matched control subjects. BiologicalPsychiatry, 25, 4-21. Rupprecht, R., Barocka, A., Jecht, E., Noder, M., Pichl, J., & Schwartz, W. (1987). Prolactin response to dexamethasone: A study on normal controls and depressed patients. Acta Psychiatrica Scandinavica, 76, 139-143. Rupprecht, R., Rupprecht, C., Rupprecht, M., Noder, M., & Mahlstedt, J. (1989). Triiodothyronine, thyroxine and TSH response to dexamethasone in depressed patients and normal controls. Biological Psychiatry, 25, 22-32. Sachar, E. J., Frantz, A. B., Altman, N., & Sassin, J. (1973). Growth hormone and prolactin in unipolar and bipolar depressed patients: Responses to hypoglycemia and L-dopa. American Journal o f Psychiatry, 130, 1362-1367. Spitzer, R. L., Williams, J. B. W., & Gibbon, M. (1985). Structured Clinical Interview for DSM-III Patient Version. Biometrics Research Department, New York State Psychiatric Institute 722 West 168th Street, New York, 10032. Wolkowitz, O. M., Sutton, M. E., Doran, A. R., Labarca, R., Roy, A., Thomas, J. W., Pickar, D., & Paul, S. (1985). Dexamethasone increases plasma HVA but not MHPG in normal humans. Psychiatry Research, 16, 101-109.
0022-3956/91 $3.00 + .00 Pergamon Press plc
Printed in Great Britain.
SERUM POSTDEXAMETHASONE
PROLACTIN
DEPRESSIVE PATIENTS AND CONTROL M.
M A E S , 1,3 C .
SCHOTTE, 1
D. PEETERS, 1 P.
D'HONDT, l
M.
MEASURES
IN
SUBJECTS MARTIN, 2
P.
BLOCKX, 2
B. MINNER, 3 E. SuY 3 and P. CosYys 1 1Department of Psychiatry, 2Department of Nuclear Medicine, University Hospital of Antwerp and 3psychiatric Centre, Munsterbilzen ( R e c e i v e d 23 N o v e m b e r 1990; revised 17 M a r c h 1991)
S u m m a r y - - R e c e n t l y , some researchers noted significant positive relationships between postdexamethasone serum cortisol and prolactin levels, whilst endogenous depressives exhibited a significantly lower suppression of prolactin by dexamethasone than non-endogenous patients or normal controls. To ascertain the extent of prolactin responses to dexamethasone in severely depressed patients, we measured 8 a.m. pre- and postdexamethasone prolactin levels in 104 depressed and 42 normal subjects. Serum cortisol levels were also determined in depressed patients before and after dexamethasone administration. We found a significant suppressive effect of dexamethasone on prolactin levels. There were no significant differences either in pre- or postdexamethasone prolactin, or in actual dexamethasone-induced decrements in prolactin between normal controls, melancholics, simple major or minor depressed subjects. We have not found any significant relationships between cortisol and prolactin, either under baseline or postdexamethasone conditions.
Introduction SEVERE depression (melancholia) is frequently accompanied by dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis. The best-documented abnormalities are the resistance of HPA-axis hormones, such as adrenocorticotropic hormone, ¢3-endorphin and cortisol, to the suppressive effects of dexamethasone (Carroll, 1982; Feinberg & Carroll, 1984; Maes, De Ruyter, & Suy, 1987; Maes et al., 1990a; Maes et al., 1990b). Recently, a significant suppressive effect of dexamethasone on baseline levels of thyroid secreting hormone (TSH) was observed (Rupprecht, Rupprecht, Rupprecht, Noder, & Mahlstedt, 1989; Maes, Vandewoude, Schotte, Martin, & Blockx, 1990c). In addition, we noted less suppression of TSH by dexamethasone in cortisol nonsuppressors compared with suppressors (Maes et al., 1990c). We (Maes et al., in press), and others (Lowy, Reder, Gormley, & Meltzer, 1988) also reported a partial resistance of immune cell function in depressive patients to the suppressive effects of glucocorticoids. All these findings lend support to the existence of more generalized, partial glucocorticoid resistance in some severely depressed patients (Maes et al., 1990c). Previous work has revealed that severe depression may be associated with abnormalities in another pituitary hormone, i.e. prolactin. These abnormalities include, amongst others, * Address for correspondence: Dr. M. Maes, University Hospital of Antwerp, UZA, Wilrijkstraat, 10, B-2650 Edegem, Belgium. 109
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alterations in baseline prolactin secretion (Mendlewicz, Linkowski, & Brauman, 1980; De la Fuente, & Rosenbaum, 1981 ; Garbutt, Loosen, Blacharsh, & Prange, 1986). In addition, some groups have reported a higher degree of prolactin nonsuppression in endogenously depressed patients compared with controls (Meltzer, Fang, Tricou, Robertson, & Piyaka, 1982; Klein et al., 1984; Rupprecht, Barocka, Jecht, Noder, Pichl, & Schwartz, 1987; Risch et al., 1987). Atkinson, Kremer, Risch, and Janowsky (1986) observed a significant positive correlation between postdexamethasone prolactin values and severity of depression in pain patients. Baumgartner, Graf, and Kurten (1988) and Rubin, Poland, Lesser, and Martin (1989), on the other hand, were unable to find prolactin nonsuppression in endogenous depressed subjects. In cortisol nonsuppressors, dexamethasone administration had a less pronounced suppressant effect, no effect, or even an enhancing effect upon prolactin secretion (Meltzer et al., 1982; Klein et al., 1984; Joyce, Donald, & Livesey, 1985). Joyce et al. (1985) described a positive correlation between postdexamethasone cortisol and prolactin values. Others failed to detect any relationship between cortisol and prolactin nonsuppression (Atkinson et al., 1986; Baumgartner et al., 1988; Rubin et al., 1989). This prospective study has been conducted in order to determine whether (1) melancholia is characterized by less prolactin suppression by dexamethasone, compared with the healthy state or minor depression and (2) cortisol nonsuppression is related to prolactin responses to dexamethasone. Subjects and Methods
Subjects One hundred and forty-six subjects participated in this study. The depressed patients (n = 104) were evaluated in the Psychiatric Ward of the University Hospital of Antwerp. They were consecutively admitted to Hospital from January 1988 to July 1990. Forty-two normal control subjects, staff or their family members, were also examined. None were regular drinkers and all had been free from medication for at least one month before the dexamethasone suppression test (DST). They were free of significant physical or psychiatric illnesses. The depressed patients were classified according to the DSM-III (American Psychiatric Association, 1980) into (1) dysthymic disorder (300.40) and adjustment disorder with depressed mood (309.00), hereafter labelled as minor depression, (2) major depression without melancholia (296.X2), and (3) major depression with melancholia (296.X3). A structured interview, i.e. the Structured Clinical Interview for DSM-III-R (Spitzer, Williams, & Gibbon, 1985) was conducted in order to determine the DSM-III diagnosis for depression. Hamilton depression rating scale (HDRS)/(Hamilton, 1960) scores were also obtained on each patient. Any subject with a history of concomitant psychiatric illness, such as substance abuse or schizophrenia, abnormal laboratory findings (urine analysis, chest X-ray, EEG, blood analysis), or with a major medical illness, was excluded. Moreover, we omitted patients who had undergone electroconvulsive therapy during the previous year, and also those who were on lithium, monoamine oxidase inhibitors, anticonvulsants, and antipsychotic dosages of neuroleptics for a similar length of time prior to hospital admission. Table 1 summarizes demographic data for the subjects in our study. Forty-five patients
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Table 1
Demographic Data o f the 146 Subjects in this Study Drug state
Category Healthy controls Minor depression Simple major depression Melancholia
Index HC md MD-M MD+M
Ratio Age (years) HDRS c Men/women mean (SEM) mean (SEM) 19/23 11/19 9/36 13/16
38.9 40.5 45.4 56.5
(1.8) (2.4) (1.9) a (2.4) b
-16.2 (0.4) 22.6 (0.3) 27.2 (0.9)
BZ yes/no
DF yes/no
0/42 5/25 17/25 17/12
42/0 17/13 14/28 14/13
HDRS: Hamilton Depression Rating Scale (17-item version). BZ: use of benzodiazepines during the study period; DF: more than one month drug free before hospital admission (yes/no). All results are expressed as mean (+ SEM). aSignificantly different from HC, bSignificantly different from HC, md and MD-M, F = 12, df= 3/142, p < 10-3 (ANOVA), CAllHDRS scores are significantly different from each other, F = 88, df= 2/101, p < 10 - 4 (ANOVA). were d r u g free for at least one m o n t h b e f o r e h o s p i t a l i z a t i o n . B e n z o d i a z e p i n e s , l o w - d o s a g e neuroleptics, a n d a n t i d e p r e s s a n t s were d i s c o n t i n u e d after a d m i s s i o n . T h i r t y - n i n e patients were p l a c e d on b e n z o d i a z e p i n e s ( < 2 5 mg d i p o t a s s i u m - c h l o r a z e p a t e a n d / o r < 2 7 . 5 f l u r a z e p a m ) during the study p e r i o d where sleep disorders or severe agitation were a feature. These benzodiazepines were administered 9 hr before or after 8 a.m. b l o o d sample collection.
Methods O n e m i l l i g r a m o f d e x a m e t h a s o n e was ingested b y all subjects at 11 p . m . B l o o d samples were collected at 8 a . m . for baseline h o r m o n e values, a n d at 8 a . m . the following d a y for p o s t d e x a m e t h a s o n e p r o l a c t i n a n d cortisol assay. In o u r d e p r e s s e d patients, the D S T was c a r r i e d o u t 6 days after h o s p i t a l a d m i s s i o n . The h o r m o n e assays e m p l o y e d are described elsewhere (Maes, V a n d e w o u d e , M a e s , Schotte, & C o s y n s , 1989a,b).
Statistics The independence o f classification systems was checked by means o f contingence analysis (Chi-square test with Yates' correction). N o r m a l i t y o f distribution was ascertained by means o f the test for goodness o f fit (Chi-square test). Relationships between variables were assessed by means o f P e a r s o n ' s p r o d u c t m o m e n t , a n d point-biserial c o r r e l a t i o n coefficients. G r o u p m e a n differences were tested b y m e a n s o f analysis o f v a r i a n c e ( A N O V A ) or analysis o f c o v a r i a n c e ( A N C O V A ) . F a c t o r i a l r e p e a t e d - m e a s u r e A N O V A s were used in o r d e r to c o m p a r e h o r m o n e levels b e f o r e a n d after t r e a t m e n t . T h e level o f significance was set at c~ = 0.05 (two-tailed). Results
Demographic Data Table 1 lists d e m o g r a p h i c d a t a for the 146 subjects in this study. There were no significant differences in sex r a t i o between the 4 s t u d y g r o u p s . P a t i e n t s with simple m a j o r d e p r e s s i o n were o l d e r t h a n h e a l t h y c o n t r o l s , whereas m e l a n c h o l i c s were significantly o l d e r t h a n all
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other subjects. The H D R S score was significantly different between depressive subgroups and increased from: minor depression ---'simple major depression ~ melancholia. We found no significant differences in the ratio of drug free/not drug free subjects between the depressive subgroups. Significantly more major depressives received benzodiazepines compared with minor depressives (x2= 9, d f = 2, p = .01). Pre- and postdexamethasone prolactin distribution curves were not normally distributed (:~2=65, p < 1 0 4; x Z = l l 3 , p < 1 0 --4, respectively, d f = 6 ) . A f t e r l o g a r i t h m i c transformation (natural logarithm), the distribution curves became normal (X2=4, p = 0.67; X 2 = 7.7, p = 0.26, respectively, df = 6). In addition, pre- and postdexamethasone cortisol values approached a normal distribution after logarithmic transformation (see Maes, De Ruyter, Hobin, & Suy, 1986). As a result, the prolactin and cortisol data were processed after logarithmic transformation. Baseline prolactin values were significantly different between men and postmenopausal females on the one hand, and premenopausal females, on the other (mean ± SEM: 202 +25, 199±21 vs. 331±38 #U/ml, respectively; F = 7 . 2 , d f = 2 / 1 4 3 , p = . 0 0 1 ) . Moreover, postdexamethasone prolactin values were higher in premenopausal females compared with men and postmenopausal females ( m e a n + S E M : 2 1 4 + 2 8 vs. 136+21, 137+ 17 /zU/ml, respectively; F = 3.7, d f = 2/143, p = .03). As a result, we have introduced the sex-hormonal state as a second factor in the statistical tests employed (factorial ANOVAs, ANCOVAs). We found significant and positive correlations between pre- and postdexamethasone prolactin values on the one hand, and age on the other (r= 0.28, p = .0009; r = 0.20, p = .01, respectively). However, age explained only a small part of the variance in pre- and postdexamethasone prolactin values (7% and 4%, respectively). There were no significant relationships between any of the prolactin values and drug state of the depressed patients (i.e. use of benzodiazepines during the study period; length of drug free period before hospital admission, i.e. more than one month: yes, otherwise: no). Consequently, we have no evidence for major effects of the drug state of the subjects on our results. Prolactin Secretion and DSM-III Groups Table 2 presents measurements of pre- and postdexamethasone prolactin values. We found a significant suppressive effect of dexamethasone on prolactin levels. There were no significant group (i.e. diagnostic categories or sex-hormonal state) x treatment interactions. Pre- and postdexamethasone prolactin values were significantly and positively correlated ( r = 0 . 7 3 , p < 10 4). Up to 53°70 of the variance in postdexamethasone prolactin values could be explained by the regression on their basal levels ( F = 162, d f = 1/44, p < 10 4). Therefore, we have used two measures of prolactin responsivity to dexamethasone administration: (1) residual postdexamethasone prolactin values after covarying for baseline prolactin values, and (2) delta p r o l a c t i n = p o s t d e x a m e t h a s o n e prolactin minus basal prolactin. We found no significant differences across diagnostic categories in basal prolactin, postdexamethasone prolactin, and their residual or delta prolactin responses to dexamethasone. Residual and delta prolactin responses were not significantly different between men, pre- and postmenopausal women.
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Table 2
Measurements o f pre- and postdexamethasone (DEX) prolactin and cortisol levels in 146 subjects Prolactin levels (#U/mL) Index
Pre-DEX
HC md MD-M MD+M
295 247 251 239
(19) (27) (31) (34)
Post-DEX 203 (15) a 145 (20) a 170 (23) a 174(27) a
A Prolactin -91 -101 -81 -65
(19) (19) (15) (27)
Cortisol (/zg/dL) Residual 9.0 -22.8 0.2 10.2
(14.1) (14.5) (10.5) (21.0)
Pre-DEX
Post-DEX
-22.6 (1.1) 20.5 (0.9) 21.9(1.I)
-2.3 (0.4) 4.4 (0.8) 6.7 ( l . l ) b
H C / m d / M D + M : for explanation see Table 1. All results are expressed as mean ( + SEM). A: Post-DEX--Pre-DEX prolactin levels. Residual: the residual postdexamethasone prolactin values after covarying for basal prolactin. aSignificantly different from baseline levels, F = 101, d f = 1/144, p < 10 4 (repeated ANOVA). bSignificantly different from md and MD-M, F = 8 . 5 , d r = 2 / 1 0 1 , p 0.001 (ANOVA on logarithmic transformation).
Relationships between Prolactin and Cortisol Secretion Table 2 shows pre- and postdexamethasone cortisol values. Patients with melancholia exhibited significantly higher postdexamethasone cortisol levels compared with minor and simple major depressives. The interrelationships between both hormones were investigated in the depressive sample. We found no significant differences between cortisol suppressors and nonsuppressors (defined as 8 a.m. postdexamethasone cortisol /> 3.5 #g/dl; Maes et al., 1986), either in basal prolactin, postdexamethasone prolactin, or in residual or delta prolactin responses. Accordingly, we could not establish a significant relationship either between postdexamethasone cortisol and prolactin values (r= 0.16, p = .09), or between their baseline hormone levels (r= 0.10, p = .30). Discussion In the present study, we were unable to observe any differences in baseline prolactin level between healthy controls and various depression categories. There is, however, a discrepancy in the published data: various studies have reported increased (Horrobin, Mtabaji, Karmali, Manku, & Nasar, 1976; Maeda et al., 1975; Sachar, Frantz, Altman, & Sassin, 1973), decreased (Asnis, Nathan, Halbreich, Halpern, & Sachar, 1980); Mendlewicz et al., 1980), or unchanged (Ehrensing, Kastin, Schalch, Friesen, Vargas, & Schally, 1974; Garfinkel, Brown, Warsh, & Stancer, 1979; Gold, Goodwin, Wehr, Rebar, & Sack, 1976; Gr6goire, Brauman, de Buck, & Corvilain, 1977; Nielsen, 1980; Rubin et al., 1989; Kjellman, Ljunggren, Beck-Friis, & Wetterberg, 1985; Jarrett et al., 1987) baseline prolactin concentrations. The present results are in agreement with other findings that premenopausal females exhibit higher baseline prolactin values compared with postmenopausal females (Maes et al., 1989b) and men (Klein et al., 1984), whilst the actual prolactin responses to dexamethasone were not significantly different between men, pre- and postmenopausal women.
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Like other investigators, we have found a highly significant suppressive effect of 1 mg dexamethasone on 8 a.m. prolactin levels (Copinschi et al., 1975; Meltzer et al., 1982; Risch et. al., 1988). Even so, not all authors have observed this dexamethasone-induced suppression of prolactin: Baumgartner et al. (1988), and Wolkowitz et al. (1985), for example, were unable to establish any difference between 4 p . m . pre- and postdexamethasone prolactin levels in healthy controls. It is interesting to note that most authors have established significant suppressive effects of dexamethasone on 8 a.m. and not on 4 p.m. prolactin circulating concentrations. This different time x t r e a t m e n t interaction pattern is further sustained by the findings of Risch et al. (1988) who noted a significant day x time interaction in dexamethasone-induced suppression of prolactin secretion (suppression at 8 a.m., not at 4 p.m.). Accordingly, it is our view that the coined label of " 4 p.m. prolactin nonsuppression" (Klein et al.; 1984; Baumgartner et al., 1988) is irrelevant, as there was no evidence of any suppressive effect by dexamethasone at that time. Moreover, we were unable to establish significant differences in postdexamethasone prolactin levels between healthy controls, minor, simple major and melancholic depressives. These results concur with those of Rubin et al. (1989) who estimated average morning prolactin levels and with those of Baumgartner et al. (1988), who measured 4 p.m. postdexamethasone prolactin. Risch et al. (1988) found a trend towards a significant difference in postdexamethasone prolactin between depressed and control subjects. However, these authors did not adjust their postdexamethasone prolactin data for the differences found in basal prolactin concentrations. As a result, the difference in their postdexamethasone prolactin levels may be ascribed to effects of basal prolactin. Some other groups, on the other hand, found a higher frequency of prolactin nonsuppression in endogenous depressives as opposed to controls (Meltzer et al., 1982; Klein et al., 1984; Rupprecht et al., 1987). Nonetheless, these studies failed to adjust postdexamethasone prolactin levels for baseline prolactin, or to measure morning instead of 4 p.m. prolactin levels, or to adjust their prolactin data for the sex hormonal state. Finally, in agreement with several other authors (Atkinson et al., 1986, Baumgartner et al; 1988; Rubin et al., 1989), we were unable to detect any relationship between postdexamethasone cortisol and prolactin non-suppression. This finding contradicts with those of Meltzer et al. (1982), Klein et al. (1984) and Joyce et al. (1985). We were unable to find any differences in baseline or postdexamethasone prolactin levels between patients who were drug free for at least one month prior to the wash-out period, and those who were not. It is thought that benzodiazepines do not affect prolactin secretion (D'Armiento, Bisignani, & Reda, 1981; L a a k m a n et al., 1982). Similarly, we could not detect differences in prolactin secretion between patients on benzodiazepines and those who were not. Thus, our results suggest that prolactin secretion and response to the suppressive effects of dexamethasone is normal in severely depressed patients. We conclude that the partial glucocorticoid resistance, detected during depression in corticotropic, thyrotropic and immune cells (see Introduction), is unlikely to extend to the lactotropes. References American Psychiatric Association. (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author.
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