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Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives
576
BIOLPSYCHIATRY
Brief Reports
1985;20:570-583
Lack of Efficacy of Estrogen Supplementation to Imipramine in Resistant Female Depressives Baruch Shapira, Gerald Oppenheim, Joseph Zohar, Mark Segal, Danny Malach, and Robert H. Belmaker
Introduction Klaiber et al. (1979) performed a 12-week, double-blind, placebo-controlled study of very high doses of estrogen in a group of 40 pre- and postmenopausal women with severe and resistant depression. A moderate antidepressant effect was seen in the estrogen-treated group compared with the controls. In an open study, the effects of a 4-week treatment with 0.06 rag/day of ethinyl estradiol was investigated in 10 premenopausal and 10 postmenopausal women with endogenous depression (Holsboer et al. 1983). A decrease in the Hamilton depression score of at least 12 points was achieved in seven postmenopausal and four premenopausal patients. Prange (1972) compared 150 mg of imipramine plus ethinyl estradiol to imipramine alone during 3 weeks of antidepressant treatment. The two treatments were equally effective after 3 weeks, but increased toxicity was seen in the combination group, and it was suggested that estrogen may affect antidepressant blood levels. Oppenheim (1984) reported a patient with resistant depression in whom the addition of conjugated estrogen to an antidepressant drug induced the condition of rapid mood cycling, which is a direct complication of various agents with antidepressant activity. From the Jerusalem Mental Health Center-Ezrath Nashim (B.S., J.Z., M.S., R.H.B.), and the Shaare Zed~k Medical Center (G.O., D.M.), Jerusalem, Israel. Address reprint requests to Dr. R. H. Belmaker, Jerusalem Mental Health Center-Ezrath Nashim, P.O.B. 140, Jerusalem, Israel. Received November 2, 1984.
© 1985 Society of Biological Psychiatry
Neurophannacological effects of estrogen have recently been reviewed (Oppenheim 1983). Estrogen has been demonstrated to induce the release of endogenous catecholamines within the hypothalamus (Paul et al. 1979). Long-term antidepressant treatments reduce adrenergic and serotonergic receptor sensitivities. The reduction in serotonin-2 receptor binding in rat cerebral cortex during long-term imipramine administration (Kendall et al. 1981) is estrogen dependent. Thus, decreased receptor binding is abolished by ovariectomy and reestablished by administration of estrogen. The study by Kendall et al. (1981) suggested that some depressed women may fail to respond to antidepressant treatment because of inadequate estrogen levels. We therefore performed a double-blind placebocontrolled, crossover study comparing the effects of imipramine plus estrogen versus imipramine plus placebo in a group of depressed women who had failed to respond to an adequate trial of antidepressant drug treatment. Since Biegun and Samuel (1979) reported that estrogen may affect antidepressant metabolism in rats, we also measured blood levels of imipramine during estrogen and placebo periods. Methods
Patient Selection Eleven female patients suffering from major depression (DSM-III) unresponsive to an adequate trial of antidepressant treatment were the 0006-3223/85/$03.30
Brief Reports
BIOL PSYCHIATRY
577
1985;20:570-583
subjects of the study. Patients were three premenopausal (Patients 3, 5, and 6) and eight postmenopausal women between the ages of 26 and 74, and were admitted to the study only after an illness duration of at least 6 months despite treatment, including two antidepressant drugs given for 6 weeks each at dosages equivalent to 250 mg/day imipramine. Routine pretrial gynecological and medical evaluation was performed, and any patient with breast or endometrial carcinoma, a past history of thromboembolic illness, or active or severe liver disease was excluded. Informed consent was obtained from each patient and her family.
Medication Procedure All patients received imipramine, 200 mg/day, throughout the study. Night sedation was allowed if needed (nitrazepam, 10 mg), but other medication was avoided. All patients had been on 200 mg of imipramine for at least 2 weeks before entering the double-blind period of the study. Conjugated estrogen (Premarin) was added to the imipramine beginning at 1.25 mg/day (one capsule) for 2 days, 2.5 mg/day on days 3 and 4, and reaching the full dose of 3.75 mg/day on day 5. This gradual dose increase was aimed at minimizing any side effects, including breast tenderness. This full dose was then continued for 16 days, followed by a similar gradual decrease over 5 days to zero. The exact same procedure was carried out with identical placebo capsules. Patients were randomly assigned to begin with the active agent or placebo. On the day of estrogen or placebo cessation (day 26), norethisterone acetate (Pfimolut-Nor), 10 mg/day, was begun for a 5-day period in order to induce menses in the three premenopausal women. In premenopausal women, the estrogen or placebo was begun with the onset of menses. The Hamilton Depression Rating Scale (Hamilton 1960) was administered once weekly to all patients throughout the study by a rater (B.S.) who was blind to the nature of the ongoing treatment. Blood was drawn in the morning during the last week of full-dose estrogen administration and during the corresponding period of placebo.
Serum was separated and stored at -20°C and assayed as a single batch using the Wien Laboratories (Succasunna, NJ) radioimmunoassay. Duplicate correlation was excellent (r = 0.97). The antibody used in this kit has higher affinity for imipramine than desmethylimipramine; but differential extraction of the metabolite was found to leave residue that interfered with antibody binding. Results were therefore estimated based on a mean imipramine : desmethylimipramine ratio of 2 : 3. Results No overall improvement in depression score was seen with estrogen or placebo (Table 1). In one patient (No. 11), a striking improvement was seen after 1 week of estrogen, and after 2 weeks, she was no longer depressed, a remission that continued for 3 months. Another striking response was the mania that began 9 days after the addition of estrogen in a 33-year-old woman (No. 3) previously resistant to treatment. This premenopausal bipolar patient had been depressed for 2 years. After the mania subsided, she remained hypomanic for 6 months and then entered another depression that responded partially to estrogen on an open basis. In Patient 2, an 11-point improvement in depression score followed placebo administration. Two patients suffered temporary breast tenderness that needed no change in treatment. Two others had uterine bleeding (beginning on days 4 and 6 of estrogen), which ceased after temporary dosage lowering. The toxic side effects previously reported from a combination of 150 mg imipramine and 0.05 mg ethinyl estradiol (Prange 1972) were not seen with the antidepressant-conjugated estrogen combination used in our study. There was no significant change in blood levels of imipramine during the period of estrogen treatment compared with placebo. Discussion This study represents the first investigation in resistant depression of an antidepressant-estrogen combination rather than estrogen alone. In
578
BIOL PSYCHIATRY 1985;20:570-583
Brief Reports
Table 1. Effects on Depression Score of Addition of Estrogen or Placebo to Failed Antidepressant Drug Hamilton Depression Rating Scale scores Estrogen Subject
Age/diagnosis
Pre
Post
1 2 3 4 5 6 7 8 9 10 11
59/UP 62/UP 33/BP 55/BP 26/BP 38/BP 74/UP 60/UP 57/BP 59/UP 62/UP
33 22 28 31 33 36 30 30 31 23 28
32 22 28 30 48 31 30 27 29 4
Blood level°
Placebo Pre
Post
Blood level~
220 32 36 140 33 22 Florid mania on day 9 and trial discontinued 400 30 31 51 30 19 290 39 36 430 31 32 280 29 30 470 27 29 250 23 23 250 4 12
230 180 500 50 160 420 360 450 100 320
*Level(ng/ml)of imipramineplus desmethylimipramin¢,basedon a calculationdescribedin Methods.Imipramin¢dose was 200 rag/day,constantthroughoutthe study.
the group of patients studied here, no significant improvement was seen following the addition
ramine, would have been missed by the assay method.
of conjugated estrogen to the patient's antidepressant drug treatment. One patient developed a mania after a long depression, and another patient appeared to make a marked improvement, suggesting that occasional patients do have psychoactive responses to estrogen. However, given the wealth o f powerful neurochemical effects that have been reported for estrogen, it is
surprising that more potent psychoactive effects are not found. The present group o f patients was selected for resistance to conventional psychopharmacological treatment; however, seven showed clinical amelioration or hypomanic responses to other treatments later in their hospitalization. There was no overlap with the group of resistant depressives previously studied with salbutamol (Belmaker et al. 1982). The absence o f effects o f estrogen on blood levels of imipramine contradicts previous indirect animal studies of Biegun and Samuel (1979). The present assay did not measure imipramine and desmethylimipramine separately, and because o f the differing affinities o f these compounds for the antibody, it is possible that an estrogen-induced decline in total blood levels, with a simultaneous shift in ratio toward imip-
References Belmaker RH, Lerer B, Zohar J (1982): Salbutamol treatment of depression. In Costa E, Raeagni G (eds), Typical and Atypical Antidepressants. New York: Raven, pp 181-193. Biegun A, Samuel D (1979): In vivo distribution of an antidepressant drug (DMI) in male and female rats. Psychopharmacology 65:254-263. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56--62. Holsboer F, Benkert O, Demisch L (1983): Changes in MAO activity during estrogen treatment of females with endogenous depression. Mod Probl Pharmacopsychiatry 19:321-326. Kendall DA, Stancel GM, Enna SJ (1981): Imipramines: Effect of ovarian steroids on modifications in serotonin receptor binding. Science 211:1183-1185. Klalber EL, Broverman DM, Vogel W, Kobayashi T (1979): Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 36:550-554. Oppenheim G (1983): Estrogen in the treatment of depression: Neuropharmaeologieal mechanisms. Biol Psychiatry 18:721-725. Oppenheim G (1984): A case of rapid mood cycling
Brief Reports
BIOLPSYCHIATRY
579
1985;20:570-583
with estrogen: Implications for therapy. J Clin Psychiatry 45:34--35.
Paul SM, Axelrod J, SaavedraJIM, SkolnickP (1979): Estrogen-induced efflux of endogenous catechol-
amines from the hypothalamus in vitro. Brain Res 178:499-505. Prange AJ (1972): Estrogen may well affect response to antidepressant. JAMA 219:143-144.
Factor Analytic Derivation of the MHPG/NM Ratio: Implications for Studying the Link Between Physical Fitness and Depression Mark S. Sothmann and A. H. Ismail
Introduction It has been suggested that 20%--60% of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) is derived from central nervous system (CNS) noradrenergic activity (Maas et al. 1979; Bloombery et al. 1980; Maas and Leckman 1983). However, considerable variation may occur in association with heightened peripheral catecholamine (CA) activity. Several approaches have been employed to analyze urinary MHPG relative to peripheral CA involvement. They include multivariate discriminant function analysis (Schildkraut et al. 1978; Schatzberg et al. 1980) and the MHPG/NM ratio (Shekim et al. 1978). We utilized factor analysis to determine the multivariate structural associations involving urinary MHPG and selected amines known to be precursors in its formation. This procedure clarified the combination of variables most as-
From the Department of Human Kinetics, School of Allied Health, University of Wisconsin-Milwaukee (M.S.S.), Milwaukee, WI and the PhysicalEducationDepartment, Purdue University(A.H.I.), West Lafayette. IN. Address reprint requests to Dr. Mark S+ Sothmann, Department of Human Kinetics, School of Allied Health, Universityof Wisconsin-Milawukee, Milwaukee, WI 53201. Received August 30, 1984; revised November 16, 1984.
© 1985 Society of Biological Psychiatry
sociated with MHPG during periods of low and high peripheral CA activity. We then examined whether or not subjects classified according to physical fitness condition differed in urinary MHPG excretion and selfreported depression. There is evidence that highfit individuals report less depression than their low-fit counterparts (Gondola and Tuckman 1982; Lobstein et al. 1983) and that an exercise program is effective in alleviating depression in clinical subjects (Greist et al. 1979). More research is needed to clarify the findings in terms of the cognitive and biochemical processes involved. Along this line, the findings from three rat studies indicate that exercise conditioning results in increased resting levels of the brain biogenic amines (Brown and Van Hus 1973; Brown et al. 1979; Lamb et al. 1979). These findings may be applicable to humans in that reduced self-reported depression with exercise may occur in conjunction with adaptations of the biogenic amines in brain areas mediating emotionality. Given the research identifying urinary MHPG as a sensitive indicator of severe depression (Maas 1983), we considered it of interest to determine whether or not high and low physically fit groups differed in their urinary 0006-3223/85/$03.30
BIOLPSYCHIATRY
Brief Reports
1985;20:570-583
Lack of Efficacy of Estrogen Supplementation to Imipramine in Resistant Female Depressives Baruch Shapira, Gerald Oppenheim, Joseph Zohar, Mark Segal, Danny Malach, and Robert H. Belmaker
Introduction Klaiber et al. (1979) performed a 12-week, double-blind, placebo-controlled study of very high doses of estrogen in a group of 40 pre- and postmenopausal women with severe and resistant depression. A moderate antidepressant effect was seen in the estrogen-treated group compared with the controls. In an open study, the effects of a 4-week treatment with 0.06 rag/day of ethinyl estradiol was investigated in 10 premenopausal and 10 postmenopausal women with endogenous depression (Holsboer et al. 1983). A decrease in the Hamilton depression score of at least 12 points was achieved in seven postmenopausal and four premenopausal patients. Prange (1972) compared 150 mg of imipramine plus ethinyl estradiol to imipramine alone during 3 weeks of antidepressant treatment. The two treatments were equally effective after 3 weeks, but increased toxicity was seen in the combination group, and it was suggested that estrogen may affect antidepressant blood levels. Oppenheim (1984) reported a patient with resistant depression in whom the addition of conjugated estrogen to an antidepressant drug induced the condition of rapid mood cycling, which is a direct complication of various agents with antidepressant activity. From the Jerusalem Mental Health Center-Ezrath Nashim (B.S., J.Z., M.S., R.H.B.), and the Shaare Zed~k Medical Center (G.O., D.M.), Jerusalem, Israel. Address reprint requests to Dr. R. H. Belmaker, Jerusalem Mental Health Center-Ezrath Nashim, P.O.B. 140, Jerusalem, Israel. Received November 2, 1984.
© 1985 Society of Biological Psychiatry
Neurophannacological effects of estrogen have recently been reviewed (Oppenheim 1983). Estrogen has been demonstrated to induce the release of endogenous catecholamines within the hypothalamus (Paul et al. 1979). Long-term antidepressant treatments reduce adrenergic and serotonergic receptor sensitivities. The reduction in serotonin-2 receptor binding in rat cerebral cortex during long-term imipramine administration (Kendall et al. 1981) is estrogen dependent. Thus, decreased receptor binding is abolished by ovariectomy and reestablished by administration of estrogen. The study by Kendall et al. (1981) suggested that some depressed women may fail to respond to antidepressant treatment because of inadequate estrogen levels. We therefore performed a double-blind placebocontrolled, crossover study comparing the effects of imipramine plus estrogen versus imipramine plus placebo in a group of depressed women who had failed to respond to an adequate trial of antidepressant drug treatment. Since Biegun and Samuel (1979) reported that estrogen may affect antidepressant metabolism in rats, we also measured blood levels of imipramine during estrogen and placebo periods. Methods
Patient Selection Eleven female patients suffering from major depression (DSM-III) unresponsive to an adequate trial of antidepressant treatment were the 0006-3223/85/$03.30
Brief Reports
BIOL PSYCHIATRY
577
1985;20:570-583
subjects of the study. Patients were three premenopausal (Patients 3, 5, and 6) and eight postmenopausal women between the ages of 26 and 74, and were admitted to the study only after an illness duration of at least 6 months despite treatment, including two antidepressant drugs given for 6 weeks each at dosages equivalent to 250 mg/day imipramine. Routine pretrial gynecological and medical evaluation was performed, and any patient with breast or endometrial carcinoma, a past history of thromboembolic illness, or active or severe liver disease was excluded. Informed consent was obtained from each patient and her family.
Medication Procedure All patients received imipramine, 200 mg/day, throughout the study. Night sedation was allowed if needed (nitrazepam, 10 mg), but other medication was avoided. All patients had been on 200 mg of imipramine for at least 2 weeks before entering the double-blind period of the study. Conjugated estrogen (Premarin) was added to the imipramine beginning at 1.25 mg/day (one capsule) for 2 days, 2.5 mg/day on days 3 and 4, and reaching the full dose of 3.75 mg/day on day 5. This gradual dose increase was aimed at minimizing any side effects, including breast tenderness. This full dose was then continued for 16 days, followed by a similar gradual decrease over 5 days to zero. The exact same procedure was carried out with identical placebo capsules. Patients were randomly assigned to begin with the active agent or placebo. On the day of estrogen or placebo cessation (day 26), norethisterone acetate (Pfimolut-Nor), 10 mg/day, was begun for a 5-day period in order to induce menses in the three premenopausal women. In premenopausal women, the estrogen or placebo was begun with the onset of menses. The Hamilton Depression Rating Scale (Hamilton 1960) was administered once weekly to all patients throughout the study by a rater (B.S.) who was blind to the nature of the ongoing treatment. Blood was drawn in the morning during the last week of full-dose estrogen administration and during the corresponding period of placebo.
Serum was separated and stored at -20°C and assayed as a single batch using the Wien Laboratories (Succasunna, NJ) radioimmunoassay. Duplicate correlation was excellent (r = 0.97). The antibody used in this kit has higher affinity for imipramine than desmethylimipramine; but differential extraction of the metabolite was found to leave residue that interfered with antibody binding. Results were therefore estimated based on a mean imipramine : desmethylimipramine ratio of 2 : 3. Results No overall improvement in depression score was seen with estrogen or placebo (Table 1). In one patient (No. 11), a striking improvement was seen after 1 week of estrogen, and after 2 weeks, she was no longer depressed, a remission that continued for 3 months. Another striking response was the mania that began 9 days after the addition of estrogen in a 33-year-old woman (No. 3) previously resistant to treatment. This premenopausal bipolar patient had been depressed for 2 years. After the mania subsided, she remained hypomanic for 6 months and then entered another depression that responded partially to estrogen on an open basis. In Patient 2, an 11-point improvement in depression score followed placebo administration. Two patients suffered temporary breast tenderness that needed no change in treatment. Two others had uterine bleeding (beginning on days 4 and 6 of estrogen), which ceased after temporary dosage lowering. The toxic side effects previously reported from a combination of 150 mg imipramine and 0.05 mg ethinyl estradiol (Prange 1972) were not seen with the antidepressant-conjugated estrogen combination used in our study. There was no significant change in blood levels of imipramine during the period of estrogen treatment compared with placebo. Discussion This study represents the first investigation in resistant depression of an antidepressant-estrogen combination rather than estrogen alone. In
578
BIOL PSYCHIATRY 1985;20:570-583
Brief Reports
Table 1. Effects on Depression Score of Addition of Estrogen or Placebo to Failed Antidepressant Drug Hamilton Depression Rating Scale scores Estrogen Subject
Age/diagnosis
Pre
Post
1 2 3 4 5 6 7 8 9 10 11
59/UP 62/UP 33/BP 55/BP 26/BP 38/BP 74/UP 60/UP 57/BP 59/UP 62/UP
33 22 28 31 33 36 30 30 31 23 28
32 22 28 30 48 31 30 27 29 4
Blood level°
Placebo Pre
Post
Blood level~
220 32 36 140 33 22 Florid mania on day 9 and trial discontinued 400 30 31 51 30 19 290 39 36 430 31 32 280 29 30 470 27 29 250 23 23 250 4 12
230 180 500 50 160 420 360 450 100 320
*Level(ng/ml)of imipramineplus desmethylimipramin¢,basedon a calculationdescribedin Methods.Imipramin¢dose was 200 rag/day,constantthroughoutthe study.
the group of patients studied here, no significant improvement was seen following the addition
ramine, would have been missed by the assay method.
of conjugated estrogen to the patient's antidepressant drug treatment. One patient developed a mania after a long depression, and another patient appeared to make a marked improvement, suggesting that occasional patients do have psychoactive responses to estrogen. However, given the wealth o f powerful neurochemical effects that have been reported for estrogen, it is
surprising that more potent psychoactive effects are not found. The present group o f patients was selected for resistance to conventional psychopharmacological treatment; however, seven showed clinical amelioration or hypomanic responses to other treatments later in their hospitalization. There was no overlap with the group of resistant depressives previously studied with salbutamol (Belmaker et al. 1982). The absence o f effects o f estrogen on blood levels of imipramine contradicts previous indirect animal studies of Biegun and Samuel (1979). The present assay did not measure imipramine and desmethylimipramine separately, and because o f the differing affinities o f these compounds for the antibody, it is possible that an estrogen-induced decline in total blood levels, with a simultaneous shift in ratio toward imip-
References Belmaker RH, Lerer B, Zohar J (1982): Salbutamol treatment of depression. In Costa E, Raeagni G (eds), Typical and Atypical Antidepressants. New York: Raven, pp 181-193. Biegun A, Samuel D (1979): In vivo distribution of an antidepressant drug (DMI) in male and female rats. Psychopharmacology 65:254-263. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56--62. Holsboer F, Benkert O, Demisch L (1983): Changes in MAO activity during estrogen treatment of females with endogenous depression. Mod Probl Pharmacopsychiatry 19:321-326. Kendall DA, Stancel GM, Enna SJ (1981): Imipramines: Effect of ovarian steroids on modifications in serotonin receptor binding. Science 211:1183-1185. Klalber EL, Broverman DM, Vogel W, Kobayashi T (1979): Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 36:550-554. Oppenheim G (1983): Estrogen in the treatment of depression: Neuropharmaeologieal mechanisms. Biol Psychiatry 18:721-725. Oppenheim G (1984): A case of rapid mood cycling
Brief Reports
BIOLPSYCHIATRY
579
1985;20:570-583
with estrogen: Implications for therapy. J Clin Psychiatry 45:34--35.
Paul SM, Axelrod J, SaavedraJIM, SkolnickP (1979): Estrogen-induced efflux of endogenous catechol-
amines from the hypothalamus in vitro. Brain Res 178:499-505. Prange AJ (1972): Estrogen may well affect response to antidepressant. JAMA 219:143-144.
Factor Analytic Derivation of the MHPG/NM Ratio: Implications for Studying the Link Between Physical Fitness and Depression Mark S. Sothmann and A. H. Ismail
Introduction It has been suggested that 20%--60% of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) is derived from central nervous system (CNS) noradrenergic activity (Maas et al. 1979; Bloombery et al. 1980; Maas and Leckman 1983). However, considerable variation may occur in association with heightened peripheral catecholamine (CA) activity. Several approaches have been employed to analyze urinary MHPG relative to peripheral CA involvement. They include multivariate discriminant function analysis (Schildkraut et al. 1978; Schatzberg et al. 1980) and the MHPG/NM ratio (Shekim et al. 1978). We utilized factor analysis to determine the multivariate structural associations involving urinary MHPG and selected amines known to be precursors in its formation. This procedure clarified the combination of variables most as-
From the Department of Human Kinetics, School of Allied Health, University of Wisconsin-Milwaukee (M.S.S.), Milwaukee, WI and the PhysicalEducationDepartment, Purdue University(A.H.I.), West Lafayette. IN. Address reprint requests to Dr. Mark S+ Sothmann, Department of Human Kinetics, School of Allied Health, Universityof Wisconsin-Milawukee, Milwaukee, WI 53201. Received August 30, 1984; revised November 16, 1984.
© 1985 Society of Biological Psychiatry
sociated with MHPG during periods of low and high peripheral CA activity. We then examined whether or not subjects classified according to physical fitness condition differed in urinary MHPG excretion and selfreported depression. There is evidence that highfit individuals report less depression than their low-fit counterparts (Gondola and Tuckman 1982; Lobstein et al. 1983) and that an exercise program is effective in alleviating depression in clinical subjects (Greist et al. 1979). More research is needed to clarify the findings in terms of the cognitive and biochemical processes involved. Along this line, the findings from three rat studies indicate that exercise conditioning results in increased resting levels of the brain biogenic amines (Brown and Van Hus 1973; Brown et al. 1979; Lamb et al. 1979). These findings may be applicable to humans in that reduced self-reported depression with exercise may occur in conjunction with adaptations of the biogenic amines in brain areas mediating emotionality. Given the research identifying urinary MHPG as a sensitive indicator of severe depression (Maas 1983), we considered it of interest to determine whether or not high and low physically fit groups differed in their urinary 0006-3223/85/$03.30