BIOL PSYCHIATRY 1990;28:339-348
339
Up-Regulatory Effect of Estrogen on Platelet 3H-Imipramine Binding Sites in Surgically Menopausal Women Barbara B. Sherwin and Barbara E. Suranyi-Cadotte
Although depressive symptoms occur in a considerable number of women following a decrease in circulating estrogen levels, a biological correlate of these mood changes has not been identified, in a prospective, double-blind, cross-over investigation of surgically menopausal women, an increase in the number of tritiated imipramine binding sites on platelets and an improvement of mood occurred with estrogen treatment and were reversed when placebo was admi~istered. In vitro studies indicated that this effect was not due to a direct interaction of the steroid with the imipramine binding site at the same concentrations of esoadiol induced in the in vivo study. Together with other evidence, these findings suggest that pharmacological but not physiological doses of estrogen can enhance the density of tritiated imipramine binding sites on platelets in women.
Introduction Epidemiological studies have consistently found a 2:1 female to male ratio in the prevalence of depressive illness (Cornstock and Helsing 1976; Weissman and Klerman 1977). This gender difference is not due to genetic transmission of the disorder (Merikangas et ai. 1985); nor can it be adequately explained by psychosocial factors (McKinlay et al. 1987). It is also clear that some women are at greater risk for the development of a depressive episode subsequent to reproductive events that are characterized by a decrease in circulating estrogen levels whereas others are seemingly unaffected by the same hormonal changes. For example~ it has been estimated that 3%-5% of women experience severe, depressive symptoms at the time estradioI (E2) and progesterone levels reach a nadir in the late luteal phase of the menstrual cycle (P,e~J and Yen 1981), 10%-20% of women develop a major depressive illr,ess following the 100-fold decrease in estrogen and progesterone levels after childbirth (Kendell et al. 1976), and up to 80% of perimenopausal women develop disturbances in mood (Montgomery et al. 1987). Although these epidemiological statistics compellingly point to an endocrine basis for the developrneat of depressive disorders in these cases, it is clear by now that decreases in sex
From the Department of Psychology, McGill University and Department of Obstetrics and Gynecology, The Sir Mortimer B. Davis-Jewish General Hospital (B.B.S.) and the Douglas Hospital Research Center and Department of Psychiatry (B.E.S.C.), McGill University, Montreal. Canada. Supported by Grant #MA-8707 from the Medical Research Council of Canada awarded to B.B. Sherwin. Address reprint requests to Dr. Barbara B. Sherwin, McGiil University, Department of Psychology, 1205 Docteur Penfield Avenue, Montreal, Quebec, H3A IBI. Received November 7. 1989; revised January 31, 1990. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
340
BIOLPSYCHIATRY 1990:28:339--348
B.B. Sherwin and B.E. Suranyi-Cadotte
steroid levels are not causally related in a simple or direct way to the mood disorders that occur" in a considerable number of women following these reproductive events; Lirculating hormone levels per se have failed to discriminate symptomatic from asymptomatic women (Chakravarti et al. 1977; Gard et al. 1986). A biological index of vulnerability to depressive disorders associated with sex hormone changes has not been identified. By now there are many reports of the antidepressant effects of estrogen both in premenopausal (Klaiber et al. 1979; Price and Giannini 1985) and in postmenopacsal women (Sherwin and Gelfand 1985; Sherwin 1988). Althoutgh estrogenic modifications of serotonergic mechanisms have been demonstrated in rat brain (Fludder et al. 1977), in h,,,,~-._. ~...-...~"'~and. "~°*°~°'e,,,-,-~(Guicheney eta!. 1988), ~ d in human postmortem studies ........ (Stanley et al. 1982), the direct assessment of cen:ral neurochemical mechanisms in living hun-ans is obviously limited. Within the past decade, the presence of tritiated imipramine binding sites in rat brain (Raisman et al. 1979), in human brain (Rehavi et al. 1980), and in human platelets (Paul e~ al. 1980) has been well established. These binding sites are thought to modulate the presynaptic uptake of serotonin in both tissues (Paul et al. 1984). A decrease in the density of tritiated imipramine binding sites in brain and platelets of depressed patients has been reported by many (Raisman et al. 1982; Paul et al. 1984; Suranyi-Cadotte et al. 1983) but not all investigators (Mellerup et al. 1982) and platelettritiated imipramine binding is now widely regarded as a putative biological correlate of depression. That estrogen can influence the number of tfitiated imipramine binding sites has been dr~monstrated in rat platelet and brain. Rehavi et al. (1987) reported a 20%-30% increase in both aH-imipramine biodieg and aH-serotonin uptake in the frontal cortex and hypothalamus of ovariectomizea rats after 12 days of treatment with relatively high doses of 17 fl-estradiol. A simi~.ar increase in imipramine binding was also found in the frontal cortex of male rats heated with E2 benzoate (Ravizza et al. 1985). In vitro studies on human platelets demonstrated that E2 decreased the dissociation rate of aH-imipramine from its binding site, suggesting that the steroid is capable of changing the nature of this binding site (Rehavi et al. 1987). Although possible gender differences in tritiated imipramine binding sites on platelets due to hormonal vafiatic~ns have not been systematically investigated, Roy eta!. (i987) found a decrease in the number of platelet-tritiated imipramine binding sites in depressed women compared with normal controls but no difference in the number of sites in depressed men compared with the control men in their sample. The major goal of the present study was to investigate whether the covariation ,between affect and circulating estrogen levels that we have previously documen*_ed in surgically menopausal women (Sherwin and Gelfand 1985; Sherwin 1988) may have been mediated by an estrogenic effect on tfitiated imipramine binding parameters in platelets. Methods Thirty-one premenopausal women (mean age 47 _+ 4 years) who needed to undergo a total abdominal hysterectomy and bilateral salpingo-oophorectomy for benign uterine fibroids participated in the study. To preclude possible confoundiag effects of preexisting psycLopatho!ogy or physical i!hiess, it was required that the women be ir~ otherwise good general health, not taking any medications, have no history of psychiatric disorders, and were not depressed according to their scores on the Beck Depression Inventory (Beck et
Estrogen, Imipramine Binding, and Affect
elOL PSYCHIATRY 1990;28:339-348
341
al. 1961). Informed, signed consent was obta':ned by means of a form approved by the hospital ethics committee. One month preoperatively, a battery of psychological tests was administered and 40 ml of blood was collected between 8 AM and l0 AM for the measurement of plasma estrone (Et) and E2 and tritiated imipramine binding parameters in platelets. Immediately following surgery, subjects randomly received either an intramuscular injection of 10 mg E2 valerate, or 1 ml sesame oil (placebo) once every 28 days for 3 montl~s (Treatment 1) after which they were crossed over to the other treatment for an additional 3 months (Treatment 2). The use of sesame oil, the vehicle contained in the active drag, rendered the placebo visually indistinguishable from the active preparation and hell~d to ensure double-blindness. Blood sampling and psychometric assessment of mood were. again carried ou~:on the second ).o fourth, day following the third injection in each treatment phase at a time when plasma estrogen levels induced by the dose of the ~ u g we administered have been found to be maximal (Sherwin 1988).
Depression Measures Three instruments with reliable and valid psychometric properties were used to assess mood preoperatively and following each of the 3-month postoperative treatment phases. The Beck Depression Inventory (Beck et al. 196 I) is the most frequently used self-report method of assessing severity of depression. It is a 2 !-item form which requires subjects to indicate the presence and severity of symptoms. A score of 0-9 indicates a normal, nondepressed state whereas v~,iues between 10 and 15 reflect mild depression. The Multiple Affect Adjective Checklist (Zuckerman and Lubin 1965) which measures anxiety, depression, and hostility, is meant for repeated measures designs. Mean scores for a normal, nondepressed population on this measure are 4-9 and scores of 10-13 indicate mild depression. The Profile of Mood States: Bipolar Form (Lorr and McNair i983) measures six bipolar subjective mood states; one pole of each scale represents the positive or desirable aspects of the dimension whereas the other pole refers to the more negative and undesirable aspects. Norms for this measure are not available so that its utility lies in discovering changes in scores in repeated measures study designs.
Plasma E~ and E2 Levels Ten milliliters of blood was immediately centrifuged and the plasma stored at -70°C until the completion of the study. Plasma E~ and E2 were measured in duplicate by radioimmunoassay u:;ing an antibody raised to F~-17~-succinyl bovine serum alb~men (BSA) after extraction into et.hyl ether; charcoal was used as an adsorbent. Laboratory ~.grms for El are 3-10 ng/dl and 9-18 ng/dl in the follicular and luteal phases, respectively, and
339
Up-Regulatory Effect of Estrogen on Platelet 3H-Imipramine Binding Sites in Surgically Menopausal Women Barbara B. Sherwin and Barbara E. Suranyi-Cadotte
Although depressive symptoms occur in a considerable number of women following a decrease in circulating estrogen levels, a biological correlate of these mood changes has not been identified, in a prospective, double-blind, cross-over investigation of surgically menopausal women, an increase in the number of tritiated imipramine binding sites on platelets and an improvement of mood occurred with estrogen treatment and were reversed when placebo was admi~istered. In vitro studies indicated that this effect was not due to a direct interaction of the steroid with the imipramine binding site at the same concentrations of esoadiol induced in the in vivo study. Together with other evidence, these findings suggest that pharmacological but not physiological doses of estrogen can enhance the density of tritiated imipramine binding sites on platelets in women.
Introduction Epidemiological studies have consistently found a 2:1 female to male ratio in the prevalence of depressive illness (Cornstock and Helsing 1976; Weissman and Klerman 1977). This gender difference is not due to genetic transmission of the disorder (Merikangas et ai. 1985); nor can it be adequately explained by psychosocial factors (McKinlay et al. 1987). It is also clear that some women are at greater risk for the development of a depressive episode subsequent to reproductive events that are characterized by a decrease in circulating estrogen levels whereas others are seemingly unaffected by the same hormonal changes. For example~ it has been estimated that 3%-5% of women experience severe, depressive symptoms at the time estradioI (E2) and progesterone levels reach a nadir in the late luteal phase of the menstrual cycle (P,e~J and Yen 1981), 10%-20% of women develop a major depressive illr,ess following the 100-fold decrease in estrogen and progesterone levels after childbirth (Kendell et al. 1976), and up to 80% of perimenopausal women develop disturbances in mood (Montgomery et al. 1987). Although these epidemiological statistics compellingly point to an endocrine basis for the developrneat of depressive disorders in these cases, it is clear by now that decreases in sex
From the Department of Psychology, McGill University and Department of Obstetrics and Gynecology, The Sir Mortimer B. Davis-Jewish General Hospital (B.B.S.) and the Douglas Hospital Research Center and Department of Psychiatry (B.E.S.C.), McGill University, Montreal. Canada. Supported by Grant #MA-8707 from the Medical Research Council of Canada awarded to B.B. Sherwin. Address reprint requests to Dr. Barbara B. Sherwin, McGiil University, Department of Psychology, 1205 Docteur Penfield Avenue, Montreal, Quebec, H3A IBI. Received November 7. 1989; revised January 31, 1990. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
340
BIOLPSYCHIATRY 1990:28:339--348
B.B. Sherwin and B.E. Suranyi-Cadotte
steroid levels are not causally related in a simple or direct way to the mood disorders that occur" in a considerable number of women following these reproductive events; Lirculating hormone levels per se have failed to discriminate symptomatic from asymptomatic women (Chakravarti et al. 1977; Gard et al. 1986). A biological index of vulnerability to depressive disorders associated with sex hormone changes has not been identified. By now there are many reports of the antidepressant effects of estrogen both in premenopausal (Klaiber et al. 1979; Price and Giannini 1985) and in postmenopacsal women (Sherwin and Gelfand 1985; Sherwin 1988). Althoutgh estrogenic modifications of serotonergic mechanisms have been demonstrated in rat brain (Fludder et al. 1977), in h,,,,~-._. ~...-...~"'~and. "~°*°~°'e,,,-,-~(Guicheney eta!. 1988), ~ d in human postmortem studies ........ (Stanley et al. 1982), the direct assessment of cen:ral neurochemical mechanisms in living hun-ans is obviously limited. Within the past decade, the presence of tritiated imipramine binding sites in rat brain (Raisman et al. 1979), in human brain (Rehavi et al. 1980), and in human platelets (Paul e~ al. 1980) has been well established. These binding sites are thought to modulate the presynaptic uptake of serotonin in both tissues (Paul et al. 1984). A decrease in the density of tritiated imipramine binding sites in brain and platelets of depressed patients has been reported by many (Raisman et al. 1982; Paul et al. 1984; Suranyi-Cadotte et al. 1983) but not all investigators (Mellerup et al. 1982) and platelettritiated imipramine binding is now widely regarded as a putative biological correlate of depression. That estrogen can influence the number of tfitiated imipramine binding sites has been dr~monstrated in rat platelet and brain. Rehavi et al. (1987) reported a 20%-30% increase in both aH-imipramine biodieg and aH-serotonin uptake in the frontal cortex and hypothalamus of ovariectomizea rats after 12 days of treatment with relatively high doses of 17 fl-estradiol. A simi~.ar increase in imipramine binding was also found in the frontal cortex of male rats heated with E2 benzoate (Ravizza et al. 1985). In vitro studies on human platelets demonstrated that E2 decreased the dissociation rate of aH-imipramine from its binding site, suggesting that the steroid is capable of changing the nature of this binding site (Rehavi et al. 1987). Although possible gender differences in tritiated imipramine binding sites on platelets due to hormonal vafiatic~ns have not been systematically investigated, Roy eta!. (i987) found a decrease in the number of platelet-tritiated imipramine binding sites in depressed women compared with normal controls but no difference in the number of sites in depressed men compared with the control men in their sample. The major goal of the present study was to investigate whether the covariation ,between affect and circulating estrogen levels that we have previously documen*_ed in surgically menopausal women (Sherwin and Gelfand 1985; Sherwin 1988) may have been mediated by an estrogenic effect on tfitiated imipramine binding parameters in platelets. Methods Thirty-one premenopausal women (mean age 47 _+ 4 years) who needed to undergo a total abdominal hysterectomy and bilateral salpingo-oophorectomy for benign uterine fibroids participated in the study. To preclude possible confoundiag effects of preexisting psycLopatho!ogy or physical i!hiess, it was required that the women be ir~ otherwise good general health, not taking any medications, have no history of psychiatric disorders, and were not depressed according to their scores on the Beck Depression Inventory (Beck et
Estrogen, Imipramine Binding, and Affect
elOL PSYCHIATRY 1990;28:339-348
341
al. 1961). Informed, signed consent was obta':ned by means of a form approved by the hospital ethics committee. One month preoperatively, a battery of psychological tests was administered and 40 ml of blood was collected between 8 AM and l0 AM for the measurement of plasma estrone (Et) and E2 and tritiated imipramine binding parameters in platelets. Immediately following surgery, subjects randomly received either an intramuscular injection of 10 mg E2 valerate, or 1 ml sesame oil (placebo) once every 28 days for 3 montl~s (Treatment 1) after which they were crossed over to the other treatment for an additional 3 months (Treatment 2). The use of sesame oil, the vehicle contained in the active drag, rendered the placebo visually indistinguishable from the active preparation and hell~d to ensure double-blindness. Blood sampling and psychometric assessment of mood were. again carried ou~:on the second ).o fourth, day following the third injection in each treatment phase at a time when plasma estrogen levels induced by the dose of the ~ u g we administered have been found to be maximal (Sherwin 1988).
Depression Measures Three instruments with reliable and valid psychometric properties were used to assess mood preoperatively and following each of the 3-month postoperative treatment phases. The Beck Depression Inventory (Beck et al. 196 I) is the most frequently used self-report method of assessing severity of depression. It is a 2 !-item form which requires subjects to indicate the presence and severity of symptoms. A score of 0-9 indicates a normal, nondepressed state whereas v~,iues between 10 and 15 reflect mild depression. The Multiple Affect Adjective Checklist (Zuckerman and Lubin 1965) which measures anxiety, depression, and hostility, is meant for repeated measures designs. Mean scores for a normal, nondepressed population on this measure are 4-9 and scores of 10-13 indicate mild depression. The Profile of Mood States: Bipolar Form (Lorr and McNair i983) measures six bipolar subjective mood states; one pole of each scale represents the positive or desirable aspects of the dimension whereas the other pole refers to the more negative and undesirable aspects. Norms for this measure are not available so that its utility lies in discovering changes in scores in repeated measures study designs.
Plasma E~ and E2 Levels Ten milliliters of blood was immediately centrifuged and the plasma stored at -70°C until the completion of the study. Plasma E~ and E2 were measured in duplicate by radioimmunoassay u:;ing an antibody raised to F~-17~-succinyl bovine serum alb~men (BSA) after extraction into et.hyl ether; charcoal was used as an adsorbent. Laboratory ~.grms for El are 3-10 ng/dl and 9-18 ng/dl in the follicular and luteal phases, respectively, and
