Estrogen augments serotonergic activity in postmenopausal women

Estrogen Augments Serotonergic Activity in Postmenopausal Women Uriel Halbreich, Nathan Rojansky, Steven Palter, Henry Tworek, Paul Hissin, and Ke Wang

To investigate the influence of estrogen replacement on serotonergic activity in postmenopausal women, the serotonin agonist meta-chlorophenylpiperazine (m-CPP) (0.5 mg/kg) was given orally to 18 normal postmenopausal women, 11 of whom were also tested following 30 days' treatment with estrogen transdermal patches (estraderm 0.1 mg). Fifteen normal, healthy women of reproductive status served as a control group. Cortisol and prolactin responses to m-CPP were measured. Without estrogen, the prolactin and cortisol responses of postmenopausal women to m-CPP were blunted compared to those of reproductive women. Estrogen replacement increased the hormonal responses. It is suggested that decreased serotonergic activity in postmenopausal women might contribute to their vulnerabili~' to affective disorders. Estrogen replacement therapy might decrease this vulnerability and might add to the efficacy of serotonergic antidepressants when warranted. Key Words: Estrogen, serotonin, postmenopause, cortisol, prolactin

Introduction The serotongergic system has been shown to be involved in the regulation of behavior, especially affective states and disorders (Coppen et al 1972, 1976; Murphy et al 1978; van Praag 1984; van Praag et al 1986; Metlzer and Nash 1988; Meltzer 1990; Murphy 1990). Gonadal hormones have been shown to influence various serotonin (5-HT) functions in humans and animals, including synthesis (Adams et al 1973; Cone et al 1981), uptake (Endersby and Wilson 1974; Wirz-Justice et al 1974), and receptor modulation (Kendall

Department of Psychiatry (UH, HT, KW), Department of Gyn/Ob (NR, SP), and Department of Pathology (PH), State University of New York at Buffalo (SUNYAB), Buffalo, NY. Address reprint requests to Uriel Halbreich, M.D., SUNY-AB Clinical Center BB 170,462 Grider Street, Buffalo, NY 14215. Received January 19, 1993; revised June 24.1994.

© 1995 Society of Biological Psychiatry

et al 1981; Biegon and McEwen 1982; Biegon et al 1982, 1983). In women, the following have been observed to fluctuate during the menstrual cycle, along with fluctuations in levels of gonadal hormones (Halbreich et al 1986): blood monoamine oxidase (Belmaker et al 1974; Poirier et al 1985); 5-HT levels (Ritvo et al 1971); platelet 5-HT2 receptor binding (Biegon 1990); 5-HT uptake (Tam et al 1985); and imipramine (IMI) receptor binding (Rojansky et al 1991). Furthermore, association between plasma levels of estradiol and platelet IMI binding in women of reproductive age has been also reported (Rojansky et al 1991). It has been suggested that postmenopausal women (who have low levels of estrogen) (Mishell 1987), might be more susceptible to the development of depression (Weissman and Klerman 1977; Montgomery et al 1987; Sherwin and Suranyi-Cadotte 1990). The pathophysiology of that increased vulnerability is still unknown. The involvement of

0006-3223/95/$09.5fl SSDI 0006-3223(94)00181 2

Serotonin and E2 in Postmenopausal Women

altered estrogen modulation of monoamine systems including serotonin is plausible (Hatbreich 1990; 1990a,b). The serotonin agonist meta-chlorophenylpiperazine (mCPP) has been used as a 5-HT stimulus in normal subjects (Mueller et al 1985; Charney et al 1987; Murphy et al 1989; Kahn et al 1990a, 1990b) and in patients with a variety of mental disorders (Kahn et al 1988; Zohar et al 1987, 1988; Lawlor et al 1989). In healthy subjects, m-CPP has been shown to induce increases in plasma levels of growth hormone, prolactin, adrenocorticotrophic hormone (ACTH), and cortisol (Mueller et al 1985; Charney et al 1987). The prolactin and cortisol responses are probably due to 5-HT, and not norepinephrine or dopamine stimulation (Stokmeir et al 1985; Mueller et al 1985; Kahn et al 1990c; Halbreich and Tworek 1993). These hormonal responses were shown to be abnormal in patients in whom 5-HT dysregulation has been postulated. Therefore, m-CPP has been suggested as a viable probe to study 5-HT responsivity in normal and abnormal subjects. To elucidate the influence of E 2 o n 5-HT systems, we studied plasma cortisol and prolactin response to m-CPP in postmenopausal women before and after treatment with estradiol (E2). Estrogen replacement therapy is often prescribed for women in their early years of menopause to reduce the risk of osteoporosis and myocardial infarction, or to alleviate urinary tract or vasomotor symptoms as well as vaginal irritation (Mishell 1987). The rather constant E2 replacement in postmenopausal women appears to provide an advantageous model for investigating the hormone's effects on responsive systems (Whitehead 1983; Backstrom et al 1989; Halbreich 1990a). Although levels of circulating hormones have not discriminated between oophorectomized and postmenopausal women with and without mood disorders (Chakravarti et al 1977; Gard et al 1986), antidepressant effects of added estrogen have been suggested in premenopausal (Klaiber et al 1979; Price and Giannini 1985) and postmenopausal women (Sherwin and Gelfand 1985; Sherwin 1988; Sherwin and Suranyi-Cadotte 1990). The findings of this report suggest a positive effect of estrogen replacement therapy on the serotonergic system of postmenopausal women.

Methods

Subjects Eighteen postmenopausal women ages 33-57 years (x ± SD = 49.1 + 6.7 years) were enrolled in the study. Their eligibility was determined by the following criteria: They had not had any menstrual cycles for at least 2 years; no serum progesterone was detected on at least two occasions; they were at least 1 year after cessation of menopausal symptoms (including hot flashes, night sweats, and irrita-

BIOLPSYCHIATRY 1995;37:434-441

435

tion by vaginal dryness) but were not older than 60 years of age; they weighed within 20% of ideal body weight; they met Research Diagnostic Criteria (RDC) (Spitzer et al 1978) for "not currently mentally ill" for a period of at least 2 years prior to the studies; and they were candidates for estrogen replacement therapy (ERT) and had no medical contraindications to ERT. Women were excluded if estrogen was contraindicated or if they had any physical illness or disorder necessitating any chemical or other somatic treatment; met criteria for any axis I diagnosis of the DSMIII-R (APA 1987) at the time of testing, or used any psychotropic drugs. Subjects were compared with 15 women of reproductive status (age 32-46 years, x ± SD = 37.8 + 3.6 years) who had regular menstrual cycles and otherwise met the same inclusion and exclusion criteria. Subjects monitored their mood and behavior with Daily Rating Forms (DRF) (Endicott et al 1986) and were symptom-free at time of tests. The studies were approved by the Institutional Review Board, and all subjects signed consent forms prior to the studies.

Procedures Prior to enrollment in the studies, all women underwent a structured clinical interview with the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer 1978) and RDC were derived (Spitzer et al 1978). Women of reproductive age also filled out the Premenstrual Assessment Form (PAF) (Halbreich et al 1982) and Daily Rating Forms (DRF) (Endicott et a11986) to exclude women with dysphoric symptoms during the midfollicular phase. On days of tests, the SADS Current Version (SADS-C) (Endicott et al 1981) were assessed to ensure no change in mental status. Postmenopausal women were tested before and 30 days after initiation of estrogen replacement. Estrogen replacement therapy was administered with Estraderm ® (estradiol transdermal system) patches (0.1 rag). Women arrived at the laboratory at 0830 after an overnight fast. An indwelling catheter was inserted into a forearm vein and kept patent with a heparin lock. Subjects stayed in comfortable recliners in a semirecumbent position until the end of the study and were not allowed to sleep, eat, or smoke. At 0900, blood pressure, pulse, oral temperature, and blood samples were taken. At 0930, following another blood draw for baseline hormone measures, 0.5 mg/kg mCPP was orally administered. Blood samples were taken at 30-minute intervals thereafter for 4 hours. Following the pretreatment tests, patches of Estraderm 0.1 (with a release rate of 0.1 mg EJday) were applied twice weekly at rotated application sites. After 30 days, the m-CPP (0.5 mg/kg PO) test was repeated in 11 women who complied with this treatment (seven women dropped out due to noncompliance or sensitivity to treatment). Women of reproductive age

436

BIOLPSYCHIATRY

U. Halbreich et al

1995;37:434--441

were all tested during days 7 - 1 0 of the follicular phase of their menstrual cycles. Hormonal levels were determined by radioimmunoassay (RIA) with commercially available kits. 17-Beta estradiol (E2) (Diagnostic Products, Los Angeles, CA) was assayed with 100 Ixl aliquots of plasma which were incubated at room temperature for 3 hours in an antibody-coated tube with ~25I-free estradiol. Bound estradiol was counted after decantation of the supernatant. Intra- and interassay coefficients of variation ranged from 4.0%-8.1%; the sensitivity limit was 8 pg/ml. Plasma progesterone determinations (Diagnostic Products, Los Angeles, CA) followed procedures similar to those used for estradiol. Intra- and interassay coefficients of variation ranged from 5.8%-10%; the sensitivity limit was 0.05 ng/ml. Plasma prolactin was determined using Clinical Assays G a m m a Dab ]25I. In this double antibody competitive binding assay, precipitating equine antirabbit serum was used to separate antibody-bound from unbound tracer. Plasma cortisol was determined with Gammacoat 125I-labeled tracer bound to rabbit anticortisol sera, which was coated on the tube surface.

Statistical Analysis

variability, the pre- and post-treatment PRL Amax were not significantly different from each other (5.4 + 3.8 vs. 8.8 +-_ 8.1 ng/ml, t = 1.69, p = .12), even though the mean PRL response increased by about 50% post-treatment (Figure 2). The post-treatment cortisol response to m-CPP (Amax) was correlated with post-treatment baseline E2 levels (r = .7152, p < .05), but the absolute peak values' association with Ez did not reach significance (r = 0.4913). PRL responses to m-CPP were not correlated with E2 levels (Amax: r = 0.1843; peak: r = 0.2703). Pretreatment hromonal response was not correlated with baseline E2 levels (r = .086 - . 3 0 2 ) . It is of note that the individual post-treatment responses were significantly correlated with the pretreatment responses. (PRL: Amax r = .6523, p < .05, PRL peak: r = .7289, p < .01; cortisol Amax: r = .8966, p < .01, cortisol peak: r = .9301,p < .01, n = 11). Repeated measures M A N O V A for within-subjects effects indicated significant effect o f time ( F = 10.99; df= 90, 9; p < .0001) and near-significant effect o f treatment ( F = 4.72; df= 101; p = .055) on prolactin response to m-CPP. F o r p l a s m a cortisol response, time ( F = 6.45; dr= 90,9; p < .0001) but not treatment effects were statistically significant.

All hormone values are reported as mean + standard deviation. Associations between the variables were evaluated with Pearson's product-moment correlations. Treatment and time effects on hormonal levels were assessed by repeated measures multivariate analysis of variance (MANOVA). Paired Student's t tests were used to compare preand post-treatment variable means. Unpaired tests were applied for the comparison between pre- and postmenopausal women.

24

20

18

Results Pretreatment serum levels of E 2 confirmed the postmenopausal status of these subjects (mean E 2 --- 12.9 -+ 8.9 pg/ml) (n = 18). Following treatment, they were increased to 83.7 + 47.9 pg/ml, t = 4.45, p = .002) (n = 11). As expected, serum progesterone levels were very low before as well as following treatment (0.2 -+ 0.1 and 0.2 -+ 0.1, respectively). Estraderm treatment was associated with an increase in peak cortisol levels (pretreatment: 20.2 +_ 7.3 Ixg/dl, posttreatment: 22.9 + 5,9 b~g/dl, t = 2.34, p = .039). The treatment effect was more apparent when the Amax (actual response: peak values minus baseline) was measured (due to lower post-treatment baseline levels of cortisol) (Amax pretreatment: 9.2 _+ 6.9 txg/dl, post-treatment 13.0 +_ 5.0 txg/dl, t = 3.76, p = .004) (Figure 1). Peak levels of prolactin (PRL) were significantly increased after treatment with E 2 (pretreatment: 11.2 _+ 4.2 ng/ml, post4reatment: 15.1 _+ 7.9 ng/ml, t = 2.36, p = .038). Due to the large intersubject

¢/.._

22

14 13_

12

il i

!fr

lo 8

o-- - o pretreatment ~, : post treatment J,....A (reproductive)

......

n 6 4

I

I

l

-30 0

t

I

60

t

I

t

[

I

J

120 180 240 Pre PostRepr. Pre Post Repr.

Time (minutes)

Peak

Amax

Figure l. Cortisol response to m-chlorophenylpiperazine (m-CPP) in postmenopausal women with (n = 11) and without (n = 18) estrogen replacement therapy. Error bars indicate standard deviations.

Serotonin and E: in Postmenopausal Women

BIOLPSYCHIATRY

437

1995;37:434~4A 1

o-- - o pretreatment •~. post t r e a t m e n t A . . . . . t (reproductive)

26 24

..,...

22

-

2O 18

~

14

, .

12

T

h--

,

"1]

: 1

I

v

-30 0

60

I

i

i

b

~I

I

120 180 240 Pre Post Repr. Pre Post Repr.

Time (minutes)

Peak

Amax

Figure 2. Prolactin (PRL) response to m-chlorophenylpiperazine (m-CPP) in postmenopausal women with (n = 11) and without (n = 18) estrogen replacement therapy. Error bars indicate standard deviations.

Compared with women of reproductive status, postmenopausal women had blunted PRL (peak: 11.2 + 4.2 vs. 21.2 + 12.1 ng/ml, t = 2 . 8 0 p = .006; Amax: 5.4 _+ 3.8 vs. 13.9 -+ 13.1 ng/ml, t = 1.96, p = .038) and only nonsignificant lesser cortisol responses (peak: 20.2 _+ 7.3 vs. 23.8 +_ 7.0 i,cg/dl t = 0.94;p = .179, Amax 9.2 _+ 6.9 vs. 13.7 _+ 7.8 txg/dl, t = 1.50, p -- .079). These differences almost disappeared following ERT. PRL peak: t = 1.35; p = .095; PRL &max: t = .84, p = .205; cortisol peak: t = 0.34, p = .37; &max: t = .27, p = .39. The pretreatment hormonal responses of the 11 women who were also studied following ERT did not differ from those of the initial group of 18.

Discussion The main results reported here are, that in postmenopausal women, estrogen replacement therapy (ERT) augments the cortisol and prolactin responses to the serotonergic agonist m-CPP. The prolactin responses to m-CPP are blunted in postmenopausal women compared to women of reproductive status. Blunted hormonal response to m-CPP is considered to be an indication of decreased serotonergic responsivity (Mueller et al 1985; Murphy 1990). There was a

positive correlation between levels of E2 after treatment and increases in plasma cortisol responses, which further indicates augmentation of serotonergic activity by estradiol therapy. This finding is in accordance with our previous reports that platelets' IMI binding is higher in women of reproductive age than in postmenopausal women (Halbreich et al 1991), and that platelets' IMI binding (but not 5-HT uptake) in premenopausal women is positively correlated with plasma levels of estradiol (Halbreich et al 1991; Rojansky et al 1991). It is still not completely clear if the difference in the serotonergic activity of postmenopausal women compared to that of women of reproductive age is due to the influence of estrogen or whether it is related to other ovulation- or menstrual cycle-related processes. Estrogen replacement is commonly prescribed for postmenopausal women (about 15%-20% are maintained on ERT) and has been used as protection from osteoporosis, coronary heart disease, and other abnormalities (Mishell 1987). It has also been suggested by some to be beneficial for treatment of depression (Campbell et al 1975; Klaiber et al 1979; Sherwin and Gelfand 1985; Sherwin 1988). In animals and humans, estrogen has been shown to differentially influence several 5-HT systems. Various exogenous treatments clearly indicate that estrogen effects on 5-HT are species and site specific as well as dose and regimen dependent. (Ehrenkranz 1976; Crowley et al 1979; Cone et al 1981; Biegon et al 1983; DiPaolo et al 1983; Guicheney and Marcel 1984; Guicheney et a11988; Ravizza et al 1985; Stockert and Derobertis 1985; Rehavi et al 1987). In addition, platelets' 5-HT uptake and total IMI binding sites have been correlated with central serotonergic activity. Several studies have demonstrated alterations in 5-HT uptake and IMI binding with physiologic or pharmacologic alterations in estrogen; however, others have failed to demonstrate such relationships (for review, see Halbreich and Tworek 1993). Our data are in accord with some previous studies. In normal males and females, m-CPP (0.5 mg/kg PO) produced significant augmentation of plasma levels of PRL and cortisol (Mueller et al 1985) which are comparable to the values obtained in our younger women' s and postmenopausal posttreatment studies. In some studies, baseline levels in females have been reported to be more diversified and somewhat higher for PRL and somewhat lower for cortisol compared to men (Murphy et al 1989; Kahn et al 1990c). In our study, baseline values of PRL were lower and those of cortisol were higher before treatment with E2, which might indicate that the sex difference might be due to estrogen. Divergence of PRL and cortisol baseline levels and response to m-CPP by gender has been observed by several groups. Baseline PRL levels and response to m-CPP were significantly reduced in females with obsessive-compulsive

438

BIOLPSYCHIATRY

U. Halbreich et al

1995:37:434-441

disorder (OCD) compared with healthy women, but were not different in men (Charney et al 1988). PRL responses to m-CPP were reported to be higher in healthy women than in men (Mueller et al 1985; Chamey et al 1987, 1988; Zohar et al 1987; Murphy et al 1989); they were also reported to be higher in females with panic disorder (PD) and OCD patients than in their male counterparts (Charney et al 1987; Zohar et al 1987, 1988). Increases in cortisol after m-CPP were reported to be somewhat higher in healthy women than in men, or not significantly different (Mueller et al 1985; Charney et al 1987, 1988; Murphy et al 1989; Kahn et al 1990a). Blunted plasma cortisol response to m-CPP has been reported in patients with depression, OCD, (Zohar et al 1987) and in women with dysphoric premenstrual changes during the luteal phase of the menstrual cycle (Halbreich 1990b). Vulnerability of postmenopausal women to depression might be associated with low 5-HT responsivity. Low levels of serum E2 (Kendell et al 1976; Price and Giannini 1985; Sherwin and Ge|fand 1985; Sherwinn and Suranyi-Cadotte 1990) or diminished 5-HT activity (Coppen et al 1972, 1976; Murphy et al 1974; Takahashi 1976; Raisman et al 1982; Suranyi-Cadotte et al 1982, 1983; Paul et al 1984; Le Quan-Bui 1984; Roy et al 1987) have all been associated with depressed mood (in patients who met or did not meet full criteria for Major Depressive Disorder (MDD). In addition, affective symptoms in women have been reported to be treated effectively with estrogens (Schneider et al 1977; Klaiber et al 1979) even though this issue is still conventional. The use of 5-HT receptor agonists and antagonists has implicated altered 5-HT activity in a variety of disorders and syndromes (Glennon 1990; Murphy 1990), including obsessive-compulsive disorder (Zohar et al 1987), anxiety and panic disorders (Charney et al 1987; Kahn et al 1988), aggression (Linnoila et al 1983), increased sensitivity to pain (Roberts 1984), and premenstrual syndromes (Rapkin et al 1987; Ashby et al 1988; Rojansky et al 1991). All these are in addition to depression. Comparability of experimen-

tal variables between studies and contribution of uncontrolled secondary factors to a specific set of data is still an unsettled issue (Kanof et al 1987). It is still unsettled whether 5-HT dysregulation is different in different clinical situations. It is plausible, that in any particular state, one or more 5-HT functions might be altered while others are intact. In the same way, probably not all 5-HT functions are altered during menopause, and not all functions are affected by estrogen in the same way. This might explain the differential responses of PRL and cortisol to m-CPP in baseline and following ERT. These two hormonal responses are probably differentially related to 5HTm/5-HT2 and 5-HTIA receptors (Seibyl et al 1991; Lesch et al 1990; Stahl 1992). The influence of estradiol on the various 5-HT receptors is probably also diversified. Further human studies are needed to clarify this issue. None the less, if a decrease in some serotonergic activities is involved in the pathophysiology of some dysphoric states, then our findings suggest that estrogen replacement therapy may be beneficial for prevention of these states. Addition of estrogen as an adjunct therapy for depression in some postmenopausal women may also be advised. It is still uncertain whether estrogen might also improve mood in women who are not clinically depressed (Schneider et al 1977; Montgomery et al 1987; Halbreich 1990a; Sherwin and Suranyi-Cadotte 1990).

The authors are grateful to Lorrain Howard, R.N. for her diagnostic and clinical assistance and to Joan Golhelf, B.S. for her expert technical assistance in performingthe hormonaldeterminations. We gratefullyacknowledge the generous supply of First Response Ovulation Predictor Test and First ResponsePregnancyTest Kits by Tambrands. The preparation of the manuscript was partially supported by grants RO1-45242and RO 1-46901 fromthe National institute of Mental Health. At time of the studyDr. Rojanskywas a ResearchFellow in the Department of Ob/Gynand also a recipientof fellowshipfrom the AmericanPhysicians Fellowship.

References Adams PW, Wynn V, Rose DP, Seed M, Folkard J, Strong R (1973): Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraception. Lancet 1:897. American Psychiatric Association ( 1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Press. Ashby CR, Cart AI, Cooke LC, Steptoe MM, Franks DD (1988): Alteration of platelet serotonergic mechanisms and monoamine oxidase activity in premenstrual syndrome. Biol Psychiatry 4:225-233. Backstrom T, Hammerback S, Johansson UB (1989); Etiological aspects of menstrual cycle linked mood changes. In van Hall EV, Everaerd W (eds), The Free Woman. Lancaster and Park Ridge, NJ: Parthenon Pub, pp 625-632.

Belmaker RH, Wyatt DL, Louiaux DL (1974): Human platelet monoamine oxidase changes during the menstrual cycle. Arch Gen PsychiatO, 31:553-556. Biegon A ( 1990): Effects of steroid hormones on the serotonergic system. Ann NY Acad Sci 600:427-434. Biegon A, McEwen BS ( 1982): Modulation by estradiol of serotonin receptors in brain. J Neurosci 2:199-205. Biegon A, Fischette CT, Rainbow TC, McEwen BS (1982): Serotonin receptor modulation by estrogen in discrete brain nuclei. Neuroendocrinology 35:287-291. Biegon A, Reches A, Snyder L, McEwen BS (1983): Serotonergic and noradrenergic receptors in the rat brain: modulation by chronic exposure to ovarian hormones. Life Sci 32:2015-2021. Campbell S (1975): Psychometric studies on the effect of natural

Serotonin and Ez in Postmenopausal Women

oestrogens on postmenopausal women. In: Campbell S (ed), Management of the menopause and postmenopausal years. Lancaster, PA: MTP Press, pp 149-158. Chakravarti S, Collins WP, Newton JR, Oram DH, Studd JWW (l 977): Endocrine changes and symptomatology after oophorectomy in premenopausal women. Br J Obstet Gynecol 84:769-775. Charney DS, Woods SW, Goodman WK, Heninger GR (1987): Serotonin function in anxiety, II. Effects of the serotonin agonist m-CPP in panic disorder and healthy subjects. Psychopharmacology 92:14-24. Charney DS, Goodman WK, Price LH, Woods SW, Rasmussen SA, Heninger GR (1988): Serotonin function in obsessivecompulsive disorder: A comparison of the effects of tryptophan and m-chlorophenyl-piperazine in patients and healthy subjects. Arch Gen Psychiato' 45:177-185. Cone RI, Davis GA, Goy RW (1981): Effects of ovarian steroids on serotonin metabolism within grossly dissected and microdissected brain regions of the ovariectomized rat. Brain Res Bull 7:639-644. Coppen A, Prange AJ, Hill C, Whybrow PC, Noguera R (1972): Abnormalities of indoleamines in affective disorders. Arch Gen Psychiatry 26:474-478. Coppen A, Turner P, Rowsell AR, Padgham C ( 1976): 5-hydroxytryptamine (5-HT) in the whole blood of patients with depressive illness. PostgradMedJ 52:156-158. Crowley WR, O'Donohue TL, Muth EA, Jacobowitz DM (1979): Effects of ovarian hormones on levels of luteinizing hormone in plasma and on serotonin concentrations in discrete brain nuclei. Brain Res Bull 4:571-574. DiPaolo T, Daigle M, Picard V, Barden N ( 1983): Effects of acute and chronic-estradiol treatment on serotonin and 5-hydroxyindole acetic acid content of discrete brain nuclei of ovariectomized rat. Exp Brain Res 51:73-76. Ehrenkranz JRL (1976): Effects of sex steroids on serotonin uptake in blood platelets. Acta Endocrino183:420-428. Endersby CA, Wilson CA (1974): The effect of ovarian steroids on the accumulation of 3H-labelled monoamines by hypothalamic tissue in vitro. Brain Res 73:321-331. Endicott J, Nee J, Cohen J, Halbreich U (1986): Premenstrual changes: Patterns and correlates of daily ratings. J Affect Dis 10:127-135. Endicott J, Nee J, Cohen J, Fleiss JL, Sarantakos S (1981 ): Hamilton Depression Rating Scale extracted from Schedule for Affective Disorders and Schiophrenia and SADS-C. Arch Gen Psychiatry 38: 98-103. Endicott J, Spitzer RL (1978): A diagnostic interview: The schedule for affective disorders and schizophrenia (SADS). Arch Gen Psychiatry 35:837-844. Gard PR, Handley SL, Parsons AD, Waldron G (1986): A multivariate investigation of postpartum mood disturbance. Br J Psychiatry 148:567-575. Glennon RA (1990): Serotonin receptors: clinical implications. Neurosci Biobehav Rev 14:35--47. Guicheney P, Marcel D (1984): Decrease of platelet serotonin content in ovariectomized female rats. Endocrinology 114:2412-2414.

BIOLPSYCHIATRY 1995;37:434--441

439

Guicheney P, Leger D, Barrat J, et al (1988): Plasma serotonin content and plasma tryptophan in peri- and postmenopausal women: variations with plasma oestrogen levels and depressive symptoms. Eur J Clin Invest 18:297-304. Halbreich U (1990): Estrogen replacement in postmenopausal disorders. Biol Psychiatry 28:369-371. Halbreich U (1990): Gonadal hormones and antihormones, serotonin and mood. Psychopharm Bull 26:291-295. Halbreich U, Endicott J, Goldstein S, Nee J (1986): Premenstrual changes and changes in gonadal hormones. Acta Psychiatry Scand 74:576-586. Halbreich U, Endicott J, Schacht S, Nee J (1982): The diversity of premenstrual changes as reflected in the Premenstrual Assessment Form. Acta Psychiatr Scand 65:46-65. Halbreich U, Tworek H (1993): The serotonergic activity in women with premenstrual syndrome, lnt J Psychiato' Med 23:1-27. Halbreich U, Tworek HA, Rojansky N, Suckow RF, Cooper TB (1993): m-CPP in humans does not stimulate noradrenergic or dopaminergic systems. NeuroendocrinoI Lett 15:425-430. Halbreich U, Rojansky N, Zander KJ, Barkai A (1991): Influence of age, sex and diurnal variability on i mipramine receptor binding and serotonin uptake in platelets of normal subjects. J Psychiatric Res 25:7-18. lnnis RB, Charney DS, Heninger GR (1987): Differential 3H-imipramine platelet binding in patients with panic disorder and depression. Psychiatry Res 21:33-41. Kahn RS, Wetzler S, Van Praag HM, Asnis GM (1988): Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder. Psychopharmacology 96:360-364. Kahn RS, Wetzler S, Asnis GM, Kling MA, Suckow RF, Van Praag HM (1990a): Effects of m-chlorophenylpiperazine in normal subjects: a dose-response study. Psychopharmacology 100:339-344. Kahn RS, Kalus O, Wetzler S, Cahn W, Asnis GM, Van Praag HM (1990b): Effects of serotonin antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects. Psychiatry Res 33:189-198. Kahn RS, Wetzler S, Asnis GM, Papolos D, Van Praag HM (1990c): Serotonin receptor sensitivity in major depression. Biol Psychiatry 28:358-362. Kanof PD, Coccaro EF, Johns CA, Siever LJ, Davis KL (1987): Platelet {3H } imipramine binding in psychiatric disorders. Biol Psychiatry 22:278-286. Katona CLE, Theodorou AE, Missouris CG, et al (1984): Platelet ~H-imipramine binding and mood in pregnancy and the puerperium. Abstracts 14th CINP Congress, Florence, Italy, p 202. Kendall D, Stancel GH, Enna SJ (1981): Imipramine effect of ovarian steroids on modification in serotonin receptor binding sites. Science 211 : 1183-1185. Kendell RE, Wainwright S, Halley A, Shannon B (1976): The influence of childbirth on psychiatric morbidity. Psychol Med 6:297-302. Klaiber EL, Broverman DM, Vogel W, Kobayashi Y (1979): Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 36:550-554. Lawlor BA, Sunderland T, Mellow AM, Hill JL, Molehan SE,

440

BIOLPSYCHIATRY 1995;37:434-441

Murphy DL (1989): Hyperresponsivity to the serotonin agonist m-chlorophenylpiperazine in Alzheimer's disease. Arch Gen Psychiatr?, 46:542-549. Le Quan-Bui KH, Plaisant O, Leboyer M, et al (1984): Reduced platelet serotonin in depression. Psychiatry Res 13:129-139. Lesch KP, Sohule K, Poten B, Schoellnhammer G, Rapprecht R, Schulte HM (1990): Corticotropin and cortisol secretion after central 5-hydroxytryptamine-1A (5-HT~A) receptor activation: Effects of 5-HT receptor and [~-adrenoceptor antagonist. J Clin Endocrinol Metab 70:670-674. Linnoila M, Virkhunen M, Scheinin M, Nuuttia A, Rimon R, Goodwin FK (1983): Low cerebral fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sci 33:2609-2614. Meltzer,HY (1990): Role of serotonin in depression. Ann NYAcad Sci 600:486-500. Meltzer HY, Nash JF (1988): Neuroendocrine studies of 5-HT and mood. In Ganten D, PfaffD (eds), Current Topics in Neuroendocrinology, vol 8. Berlin: Springer-Verlag, pp 181-210. Mishell DR (ed) ( 1987): Menopause: Physiology and Pharmacology. Chicago: Yearbook Med Publishers. Montgomery JC, Brincat M, Tapp A, et al (1987): Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet 1:297-299. Mueller EA, Murphy DL, Sunderland T (1985): Neuroendocrine effects of m-chlorophenylpiperazine, a serotonin agonist, in humans. JCMEM 61 : 1179-1184. Murphy DE (1990): Neuropsychiatric disorders and the multiple human brain serotonin receptor subtypes and subsystems. Neuropsychopharmacology 3:457-47 I. Murphy DL, Baker M, Goodwin FK, Miller H, Kotin J, Bunney WE (1974): L-Tryptophan in affective disorders: indoleamine changes and differential clinical effects. Psychopharmacology 34:11-20. Murphy DE, Campbell I, Costa ( 1978): Current status of the indoleamine hypothesis of the affective disorders. In Lipton MA, Dimascio A, Killam KF (eds), Psychopharmacology: A Generation of Progress. New York: Raven Press, pp 1235-1247. Murphy DL, Mueller EA, Hill JL, Tolliver TJ, Jacobsen FM (1989): Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. P.~3,chopharmacology 98:275-282. Paul SM, Rehavi M, Skolnick P, Goodwin FK (1984): High affinity binding antidepressants to biogenic amine transport in human brain and platelet: studies in depression: In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins, pp 846-853. Poirier MF, Lop H, Scatton B, Le Fur G (1985): Platelet monoamine oxidase activity and 3,4-dihydroxyphenylethyleneglycol levels during the menstrual cycle. Neuropsychobiology 14:165-169. Price WA, Giannini AJ ( 1985): Antidepressant effects of estrogen. J Clin Psychiat~, 46:506. Raisman R, Briley MS, Bouchami F, Sechter D, Zarifian E, Langer SZ (1982): 3H-imipramine binding and serotonin uptake in

U. Halbreich et al

platelets from untreated depressed patients and control volunteers. Psychopharmacology 77:332-335. Rapkin AJ, Edelmuth E, Chang LC, Reading AE, McGuire M, Su TP (1987): Whole-blood serotonin in premenstrual syndrome. Obstet Gyneco170:533-537. Ravizza L, Nicoletti F, Pozzi O, Barbaccia ML (1985): Repeated daily treatments with estradiol increase the {3H} imipramine binding in male rat frontal cortex. EurJPharmacol 107:395-396. Rehavi M, Sepcuti H, Weizman A (1987): Upregulation of imipramine binding and serotonin uptake by estradiol in female rat brain. Brain Res 410:135-139. Ritvo E, Yawiler A, Geller E, Plotkin S, Mason A, Saeger K (1971): Maturational changes in blood serotonin levels and platelet counts. Biochem Med 5:90-96. Roberts MHT (1984): 5-hydroxytryptamine and antinociception. Neuropharmacology 23:1529-1536. Rojansky N, Halbreich U, Zander K, Barkai A, Goldstein S (1991): Imipramine receptor binding and serotonin uptake in platelets of women with premenstrual changes. Gynecol Obstet Invest 31 : 146-152. Roy A, Everett D, Pickar D, Paul SM (1987): Platelet tritiated imipramine binding and serotonin uptake in depressed patients and controls. Arch Gen Psychiatry 33:320-327. Schneider MA, Brotherton PL, Hailes J (1977): The effect of exogenous oestrogens on depression in menopausal women. Med J Austr 2:162-163. Seibyl JP, Krystal JH, Price JH, et al (1991): Effects of ritanserin on the behavioral, neuroendocrine and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects. Psychiatry Res 38:227-236. Sherwin BB (1988): Affective changes with estrogen and androgen therapy in surgically menopausal women. J Affect Disord 14:177-187. Sherwin BB, Gelfand MM (1985): Sex steroids and affect in the surgical menopause: a double-blind cross-over study. Psychoneuroendocrinology 10:325-335. Sherwin BB, Suranyi-Cadotte BE (1990): Up-regulatory effect of estrogen on platelet 3H-imipramine binding sites in surgically menopausal women. Biol Psychiatry 28:339-348. Spitzer RL, Endicott J, Robins E (1978): Research diagnostic criteria: Rationale and reliability. Arch Gen Psychiatry 35:733-782. Stahl SM (1992): Neuroendocrine markers of serotonin responsivity in deprSession. Prog Neuropsychopharmacol Biol Psychiatr), 16:655-659. Stockert M, De Robertis E (1985): Effect of ovariectomy and estrogen on {3H } imipramine binding to different regions of rat brain. Eur J Pharmacology 119:255-257. Stockmeier CA, Martino AM, Kellar KJ (1985): A strong influence of serotonin axons on [3-adrenergic receptors in rat brain. Science 230:323-325. Suranyi-Cadotte BE, Wood PL, Nair NVP, Schwartz G (1982): Normalization of 3H-imipramine binding in depressed patients during remission. Eur J Pharmaco185:357-359. Suranyi-Cadotte BE, Wood PL, Schwartz G, Nair NVP (1983):

Serotonin and E~ in Postmenopausal Women

BIOLPSYCHIATRY

441

1995;37:434M-41

Altered platelet 3H-imipramine binding in schizo-affective and depressive disorders. Biol Psychiatr3, 18:923-927. Takahashi S ( 1976): Reduction of blood platelet serotonin levels in manic and depressed patients. Folia Psychiatr Neurol Jpn 30:475-586. Tam WYK, Chan MY, Lee PHK (1985): The menstrual cycle and platelets 5-HT uptake. Psychosomatic Med 47:352-362. van Praag HM (1984): Depression, suicide, and serotonin metabolism in the brain. In Post RM, Ballenger, JC eds), Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins, pp 601-618. van Praag HM, Plutchick R, Conte H (1986): The serotonin hypothesis of (auto) aggression. Critical appraisal of the evidence. Ann NY Acad Sci 487:150-167. Weissman MM, Klerman GL (1977): Sex differences and the epidemiology of depression. A reh Gen Psychiatry' 34:98-1 I 1.

Whitehead MI ( 1983): The menopause. Part A: Hormone replacement therapy--the controversies. In Dennerstein L, Burrow G (eds), Handbook of Psychosomatic Obstetrics and Gynecology. Amsterdam: Elsevier Biomedical Press, pp 445-48l. Wirz-Justice A, Hackman E, Lichsteiner M (1974): The effect of oestradiol dipropionate and progesterone on monoamine uptake in rat brain. JNeurochem 22:187-189. Zohar J, Mueller EA, lnse] TR, Zohar-Kadouch RC, Murphy DL (1987): Serotonergic responsivity in obsessive-compulsive disorder: comparison of patients and healthy controls. Arch Gen Psychiat~ 44:946-951. Zohar J, Insel TR, Zohar-Kadouch RC, Hill JL, Murphy DL (1988): Serotonergic responsivity in obsessive-compulsive disorder: effects of chronic clomipramine treatment. Arch Gen Psychiatry 45:167-172.