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Depression, Estrogen, and the Women's Health Initiative
Depression, Estrogen, and the Women’s Health Initiative DONNA E. STEWART, M.D., F.R.C.P.C. DANIELLE E. ROLFE, B.P.H.E. EMMA ROBERTSON, PH.D.
This clinical observation report compares hormone use and clinical presentation in a series of middle-aged depressed women before and after publication of the Women’s Health Initiative. Depressed women over age 40 seen at a general hospital academic women’s affective disorders practice 6 months before and after publication of the Women’s Health Initiative were compared for medication changes, hormone therapy, lifetime depressive episodes, time since last episode, time to depression recurrence after hormone cessation, symptoms, and treatment response. More women stopped hormone therapy and reported onset of depression within 3 weeks of hormone discontinuation after than before publication of the Women’s Health Initiative. Depression in most women responded to reinstitution of estrogen or initiation or increase in antidepressant dose. Discontinuation of hormone therapy appears to be associated with the rapid recurrence of depression in some women with a history of depression. Randomized controlled trials in middleaged depressed women of estrogen or a selective estrogen receptor modulator as monotherapy or as an augmentation agent are urgently needed. (Psychosomatics 2004; 45:445–447)
T
he publication of the Women’s Health Initiative in June 2002, showing increased risks for breast cancer and cardiovascular disease in women in the estrogen/progesterone arm of the trial,1 led to widespread changes in the use of hormone therapy. Not only did physicians change their prescribing habits for hormone therapy, but many menopausal women users abruptly discontinued it themselves.2,3 Within 2 months of the publication of the Women’s Health Initiative, a new phenomenon was observed in an academic general hospital practice of largely middle-aged women with affective disorders. Women with a lengthy history of depression who had been in remission began to have a reemergence of their depressive symptoms shortly after discontinuing hormone therapy. Because the standard intake history taking included two questions salient to this issue, it was possible to compare the clinical presentations of middle-aged women with affective disorders for comparable 6-month periods before and after publication of the Women’s Health Initiative.
Psychosomatics 45:5, September-October 2004
METHOD All women over the age of 40 who came to a woman psychiatrist’s affective disorders practice at a general hospital from July 1 to Dec. 31, 2001, were compared to a similar cohort for the same period in 2002 with regard to their replies to two standard questions: 1. 2.
Have you started, stopped, or changed any medications in the last 6 months? Are you taking any hormones, such as oral contraceptives or menopausal hormones?
Women who reported a hormone therapy change within 6 months of presentation and who had a major deReceived Nov. 11, 2003; revision received March 3, 2004; accepted April 15, 2004. From the University Health Network Women’s Health Program, University of Toronto. Address reprint requests to Dr. Stewart, University Health Network Women’s Health Program, 657 University Ave., ML 2004, Toronto, Ont. M5G 2N2, Canada; [email protected] (e-mail). Copyright 䉷 2004 The Academy of Psychosomatic Medicine.
445
Depression and Estrogen pressive episode according to DSM-IV criteria were then described by age, number of lifetime depressive episodes, time since last episode, time between discontinuing hormones and onset of depressive symptoms, symptoms, and treatment response. RESULTS Similar numbers of middle-aged women were seen in 2001 (N⳱78) and 2002 (N⳱72). Sixty-eight women in each year were diagnosed as suffering from major depressive disorder with DSM-IV criteria, and among these women, there was no difference in age (mean⳱55 years, SD⳱6) or the number of lifetime episodes of depression (mean⳱5, SD⳱3). With respect to the question concerning starting, stopping, or changing any medication in the last 6 months, 28 women responded affirmatively in 2001, with changes primarily involving antidepressants, osteoporosis treatments, vitamins, herbal products, antibiotics, and antihypertensives. In 2002, 39 women changed medications, primarily antidepressants, hormones, osteoporosis treatments, vitamins, antibiotics, and antihypertensives. With regard to the question about taking any hormones, there was a significant difference between years; 34 women in 2001 reported the use of hormone therapy compared to 18 in 2002 (v2⳱5.72, df⳱1, p⬍0.02). With regard to changes in hormone therapy within 6 months, three women (9%) in 2001 reported a change in hormone therapy (initiation of a progestin) preceding the onset of depression. In 2002, 11 women (61%) reported abruptly discontinuing estrogen or estrogen and progestins within 6 months of the relapse of depression (v2⳱7.67, df⳱1, p⬍0.05). These women had a mean age of 59 years (SD⳱8), a mean of seven (SD⳱5) lifetime depressive episodes, a mean of 4 years (SD⳱5) since their last episode of depression, and a mean time to onset of depressive symptoms of 3 weeks (SD⳱2) after discontinuing hormone therapy. One woman was perimenopausal (amenorrhea for 7 months), and 10 were menopausal (amenorrhea for at least 12 months). Depression severity was clinically assessed as severe in two women, moderate in eight, and mild in one. Symptoms were reported as depression (N⳱ 11), anxiety (N⳱10), agitation (N⳱9), vasomotor (N⳱7), early morning wakening (N⳱6), irritability (N⳱5), and panic (N⳱2). The perimenopausal woman had an agitated, melancholic type of depression with psychotic features. Eight of the 11 patients had been taking selective serotonin reuptake inhibitor (SSRI) antidepressants and estrogen 446
with (N⳱6) or without (N⳱5) progestins before the onset of their depressive symptoms. After consultation, the depressive symptoms in four of the 11 women responded to reinstitution of estrogen (in two women) and estrogen/progestin (in two women) without changing the SSRI dose. Four women who refused to reinstitute hormone therapy responded to an increase in, or initiation of, SSRI antidepressants. Three women remain depressed at the time of this writing despite reinstitution of estrogen (one woman) or estrogen and progesterone (two women) and SSRIs at higher doses. Three women had had reproductive-related depressive episodes only; the other eight had suffered from intermittent episodes that had sometimes occurred independently of reproductive events. DISCUSSION In this small clinical series, more patients had changed their medication after the publication of the Women’s Health Initiative than before, and these changes were overwhelmingly the cessation of hormone therapy. Women with a recurrence of depression after discontinuing hormone therapy reported becoming rapidly depressed (within a mean of 3 weeks), despite having been well for several years. It is unclear whether the depression resulted from abrupt estrogen withdrawal effects rather than its absolute absence. It is increasingly clear that the rates of hormone change may be important, as well as its levels. The symptoms reported were typical of those seen in women with depression in the perimenopausal period: agitated, anxious, irritable depression with early morning wakening and vasomotor symptoms. Although the depression in most women responded to reinstitution of estrogen and progesterone or initiation or an increase in an SSRI, three women remained depressed despite reinstitution of continued estrogen and progesterone and an increase in an SSRI to the maximum recommended dose. We were unable to identify other published reports of the effects of acute hormone therapy withdrawal on mood. However, there are reports of increased depressive symptoms after childbirth, during perimenopause,4,5 and after surgically induced menopause.6 What is known about the role of hormones and depression in women that might begin to explain these findings? The incidence of depression in women mirrors estrogen shifts in the life cycle at puberty and in the premenstrual, postpartum, and perimenopausal periods.7 Moreover, some women may be especially vulnerable to depression at the Psychosomatics 45:5, September-October 2004
Stewart et al. times of hormonal changes.5 Estrogen is a modulator of cell growth, differentiation, maturation, and aging in the brain. It acts throughout the brain affecting learning, shortterm verbal memory, coordination, fine motor skills, and spatial abilities, as well as mood and cognition. Estrogen has effects on the serotonergic, noradrenergic, dopaminergic, and cholinergic systems and stimulates electrical brain activity.8 It can exert profound cyclical influences upon synapses in certain neurons, with synapses being erected in the early menstrual cycle and withdrawn and dismantled in the late cycle.8 It also influences glial cells and their protein expression.9 Estrogen has important actions in the CNS through its actions on unique nuclear receptors that can lead to the production of hormonal growth factors as well as enzymes and receptors that facilitate monoaminergic neurotransmission. Recent work has shown that receptors for neurotransmitters are located on neuronal membranes and that these include neurotransmitter transporters and G-protein-linked receptors that are the targets of many psychotropic drugs. The G receptors are also the targets of many hormones and the co-participation of some neurotransmitters with certain hormones may be critical for normal functioning.10 In contrast, progesterone has sedative and negative mood effects in many women.11
Recent studies have shown that estradiol alone can result in the remission of depression in some depressed perimenopausal women.12–14 In addition, estrogen as an augmentation agent for antidepressants in women with treatment-resistant depression has been discussed for over two decades.15 More recently, several investigators have reported the use of estrogen as an effective augmentation agent with SSRI antidepressants,16,17 resulting in renewed interest. This clinical series of patients is limited by its size, the lack of standardized depression rating scales, and the absence of estradiol measures. However, considering current knowledge about the effects of estrogen on depression, clinical anecdotes, and this report, there is a need for clinicians to be aware of the possible recurrence of depression in vulnerable women who suddenly discontinue estrogen and to observe them carefully for recurrent depression. There is also a need for an adequately powered, randomized, controlled trial of the efficacy of estrogen (or newer selective estrogen receptor modulators) in the treatment of depression in middle-aged and older women as monotherapy or an augmentation agent with SSRIs. In light of previous errors in estrogen use resulting from relying on uncontrolled clinical reports, it is essential that such a trial be conducted in the near future to inform the optimal treatment of depression in middle-aged and older women.
References
1. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333 2. Rymer J, Wilson R, Ballard B: Making decisions about hormone replacement therapy. Br Med J 2003; 326:322–326 3. Breslau ES, Davis WW, Doner L, Eisner EJ, Goodman NR, Meissner HI, Rimer BK, Rossouw JE: The hormone therapy dilemma: women respond. J Am Med Womens Assoc 2003; 58:33–43 4. Avis NE: Depression during the menopausal transition. Psychol Women Q 2003; 27:91–100 5. Stewart DE, Boydell KM: Psychologic distress during menopause: associations across the reproductive life cycle. Int J Psychiatry Med 1993; 23:157–162 6. Sherwin BB, Gelfand MM: Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985; 10:325–335 7. Stahl SM: Effects of estrogen on the central nervous system. J Clin Psychiatry 2001; 62:317–318 8. Stahl SM: Estrogen makes the brain a sex organ. J Clin Psychiatry 1997; 58:421–422 9. McEwan B: Estrogens on the brain. ORGYN 2001; 2:28–31 10. Stahl SM: Why drugs and hormones may interact in psychiatric disorders. J Clin Psychiatry 2001; 62:225–226 11. Klaiber EL, Broverman DM, Vogel W, Peterson LG, Snyder MB:
Psychosomatics 45:5, September-October 2004
Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology 1996; 21:575–592 12. Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, Rubinow DR: Estrogen replacement in perimenopause related depression: a preliminary report. Am J Obstet Gynecol 2000; 183:414–420 13. Soares CN, Almeida OP, Joffe H, Cohen LS: Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001; 58:529–534 14. Cohen LS, Soares CN, Poitras JR, Prouty JR, Alexander AB, Shifren JL: Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry 2003; 160:1519–1522 15. Shapira B, Oppenheim G, Zohar J, Segal M, Malach D, Belmaker RH: Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry 1985; 20:576–579 16. Joffe H, Cohen LS: Estrogen, serotonin, and mood disturbance: Where is the therapeutic bridge? Biol Psychiatry 1998; 44:798– 811 17. Rasgon NL, Altshuler LL, Fairbanks LA, Dunkin JJ, Davtyan C, Elman S, Rapkin A: Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry 2002; 63:S45–S48
447
This clinical observation report compares hormone use and clinical presentation in a series of middle-aged depressed women before and after publication of the Women’s Health Initiative. Depressed women over age 40 seen at a general hospital academic women’s affective disorders practice 6 months before and after publication of the Women’s Health Initiative were compared for medication changes, hormone therapy, lifetime depressive episodes, time since last episode, time to depression recurrence after hormone cessation, symptoms, and treatment response. More women stopped hormone therapy and reported onset of depression within 3 weeks of hormone discontinuation after than before publication of the Women’s Health Initiative. Depression in most women responded to reinstitution of estrogen or initiation or increase in antidepressant dose. Discontinuation of hormone therapy appears to be associated with the rapid recurrence of depression in some women with a history of depression. Randomized controlled trials in middleaged depressed women of estrogen or a selective estrogen receptor modulator as monotherapy or as an augmentation agent are urgently needed. (Psychosomatics 2004; 45:445–447)
T
he publication of the Women’s Health Initiative in June 2002, showing increased risks for breast cancer and cardiovascular disease in women in the estrogen/progesterone arm of the trial,1 led to widespread changes in the use of hormone therapy. Not only did physicians change their prescribing habits for hormone therapy, but many menopausal women users abruptly discontinued it themselves.2,3 Within 2 months of the publication of the Women’s Health Initiative, a new phenomenon was observed in an academic general hospital practice of largely middle-aged women with affective disorders. Women with a lengthy history of depression who had been in remission began to have a reemergence of their depressive symptoms shortly after discontinuing hormone therapy. Because the standard intake history taking included two questions salient to this issue, it was possible to compare the clinical presentations of middle-aged women with affective disorders for comparable 6-month periods before and after publication of the Women’s Health Initiative.
Psychosomatics 45:5, September-October 2004
METHOD All women over the age of 40 who came to a woman psychiatrist’s affective disorders practice at a general hospital from July 1 to Dec. 31, 2001, were compared to a similar cohort for the same period in 2002 with regard to their replies to two standard questions: 1. 2.
Have you started, stopped, or changed any medications in the last 6 months? Are you taking any hormones, such as oral contraceptives or menopausal hormones?
Women who reported a hormone therapy change within 6 months of presentation and who had a major deReceived Nov. 11, 2003; revision received March 3, 2004; accepted April 15, 2004. From the University Health Network Women’s Health Program, University of Toronto. Address reprint requests to Dr. Stewart, University Health Network Women’s Health Program, 657 University Ave., ML 2004, Toronto, Ont. M5G 2N2, Canada; [email protected] (e-mail). Copyright 䉷 2004 The Academy of Psychosomatic Medicine.
445
Depression and Estrogen pressive episode according to DSM-IV criteria were then described by age, number of lifetime depressive episodes, time since last episode, time between discontinuing hormones and onset of depressive symptoms, symptoms, and treatment response. RESULTS Similar numbers of middle-aged women were seen in 2001 (N⳱78) and 2002 (N⳱72). Sixty-eight women in each year were diagnosed as suffering from major depressive disorder with DSM-IV criteria, and among these women, there was no difference in age (mean⳱55 years, SD⳱6) or the number of lifetime episodes of depression (mean⳱5, SD⳱3). With respect to the question concerning starting, stopping, or changing any medication in the last 6 months, 28 women responded affirmatively in 2001, with changes primarily involving antidepressants, osteoporosis treatments, vitamins, herbal products, antibiotics, and antihypertensives. In 2002, 39 women changed medications, primarily antidepressants, hormones, osteoporosis treatments, vitamins, antibiotics, and antihypertensives. With regard to the question about taking any hormones, there was a significant difference between years; 34 women in 2001 reported the use of hormone therapy compared to 18 in 2002 (v2⳱5.72, df⳱1, p⬍0.02). With regard to changes in hormone therapy within 6 months, three women (9%) in 2001 reported a change in hormone therapy (initiation of a progestin) preceding the onset of depression. In 2002, 11 women (61%) reported abruptly discontinuing estrogen or estrogen and progestins within 6 months of the relapse of depression (v2⳱7.67, df⳱1, p⬍0.05). These women had a mean age of 59 years (SD⳱8), a mean of seven (SD⳱5) lifetime depressive episodes, a mean of 4 years (SD⳱5) since their last episode of depression, and a mean time to onset of depressive symptoms of 3 weeks (SD⳱2) after discontinuing hormone therapy. One woman was perimenopausal (amenorrhea for 7 months), and 10 were menopausal (amenorrhea for at least 12 months). Depression severity was clinically assessed as severe in two women, moderate in eight, and mild in one. Symptoms were reported as depression (N⳱ 11), anxiety (N⳱10), agitation (N⳱9), vasomotor (N⳱7), early morning wakening (N⳱6), irritability (N⳱5), and panic (N⳱2). The perimenopausal woman had an agitated, melancholic type of depression with psychotic features. Eight of the 11 patients had been taking selective serotonin reuptake inhibitor (SSRI) antidepressants and estrogen 446
with (N⳱6) or without (N⳱5) progestins before the onset of their depressive symptoms. After consultation, the depressive symptoms in four of the 11 women responded to reinstitution of estrogen (in two women) and estrogen/progestin (in two women) without changing the SSRI dose. Four women who refused to reinstitute hormone therapy responded to an increase in, or initiation of, SSRI antidepressants. Three women remain depressed at the time of this writing despite reinstitution of estrogen (one woman) or estrogen and progesterone (two women) and SSRIs at higher doses. Three women had had reproductive-related depressive episodes only; the other eight had suffered from intermittent episodes that had sometimes occurred independently of reproductive events. DISCUSSION In this small clinical series, more patients had changed their medication after the publication of the Women’s Health Initiative than before, and these changes were overwhelmingly the cessation of hormone therapy. Women with a recurrence of depression after discontinuing hormone therapy reported becoming rapidly depressed (within a mean of 3 weeks), despite having been well for several years. It is unclear whether the depression resulted from abrupt estrogen withdrawal effects rather than its absolute absence. It is increasingly clear that the rates of hormone change may be important, as well as its levels. The symptoms reported were typical of those seen in women with depression in the perimenopausal period: agitated, anxious, irritable depression with early morning wakening and vasomotor symptoms. Although the depression in most women responded to reinstitution of estrogen and progesterone or initiation or an increase in an SSRI, three women remained depressed despite reinstitution of continued estrogen and progesterone and an increase in an SSRI to the maximum recommended dose. We were unable to identify other published reports of the effects of acute hormone therapy withdrawal on mood. However, there are reports of increased depressive symptoms after childbirth, during perimenopause,4,5 and after surgically induced menopause.6 What is known about the role of hormones and depression in women that might begin to explain these findings? The incidence of depression in women mirrors estrogen shifts in the life cycle at puberty and in the premenstrual, postpartum, and perimenopausal periods.7 Moreover, some women may be especially vulnerable to depression at the Psychosomatics 45:5, September-October 2004
Stewart et al. times of hormonal changes.5 Estrogen is a modulator of cell growth, differentiation, maturation, and aging in the brain. It acts throughout the brain affecting learning, shortterm verbal memory, coordination, fine motor skills, and spatial abilities, as well as mood and cognition. Estrogen has effects on the serotonergic, noradrenergic, dopaminergic, and cholinergic systems and stimulates electrical brain activity.8 It can exert profound cyclical influences upon synapses in certain neurons, with synapses being erected in the early menstrual cycle and withdrawn and dismantled in the late cycle.8 It also influences glial cells and their protein expression.9 Estrogen has important actions in the CNS through its actions on unique nuclear receptors that can lead to the production of hormonal growth factors as well as enzymes and receptors that facilitate monoaminergic neurotransmission. Recent work has shown that receptors for neurotransmitters are located on neuronal membranes and that these include neurotransmitter transporters and G-protein-linked receptors that are the targets of many psychotropic drugs. The G receptors are also the targets of many hormones and the co-participation of some neurotransmitters with certain hormones may be critical for normal functioning.10 In contrast, progesterone has sedative and negative mood effects in many women.11
Recent studies have shown that estradiol alone can result in the remission of depression in some depressed perimenopausal women.12–14 In addition, estrogen as an augmentation agent for antidepressants in women with treatment-resistant depression has been discussed for over two decades.15 More recently, several investigators have reported the use of estrogen as an effective augmentation agent with SSRI antidepressants,16,17 resulting in renewed interest. This clinical series of patients is limited by its size, the lack of standardized depression rating scales, and the absence of estradiol measures. However, considering current knowledge about the effects of estrogen on depression, clinical anecdotes, and this report, there is a need for clinicians to be aware of the possible recurrence of depression in vulnerable women who suddenly discontinue estrogen and to observe them carefully for recurrent depression. There is also a need for an adequately powered, randomized, controlled trial of the efficacy of estrogen (or newer selective estrogen receptor modulators) in the treatment of depression in middle-aged and older women as monotherapy or an augmentation agent with SSRIs. In light of previous errors in estrogen use resulting from relying on uncontrolled clinical reports, it is essential that such a trial be conducted in the near future to inform the optimal treatment of depression in middle-aged and older women.
References
1. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333 2. Rymer J, Wilson R, Ballard B: Making decisions about hormone replacement therapy. Br Med J 2003; 326:322–326 3. Breslau ES, Davis WW, Doner L, Eisner EJ, Goodman NR, Meissner HI, Rimer BK, Rossouw JE: The hormone therapy dilemma: women respond. J Am Med Womens Assoc 2003; 58:33–43 4. Avis NE: Depression during the menopausal transition. Psychol Women Q 2003; 27:91–100 5. Stewart DE, Boydell KM: Psychologic distress during menopause: associations across the reproductive life cycle. Int J Psychiatry Med 1993; 23:157–162 6. Sherwin BB, Gelfand MM: Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985; 10:325–335 7. Stahl SM: Effects of estrogen on the central nervous system. J Clin Psychiatry 2001; 62:317–318 8. Stahl SM: Estrogen makes the brain a sex organ. J Clin Psychiatry 1997; 58:421–422 9. McEwan B: Estrogens on the brain. ORGYN 2001; 2:28–31 10. Stahl SM: Why drugs and hormones may interact in psychiatric disorders. J Clin Psychiatry 2001; 62:225–226 11. Klaiber EL, Broverman DM, Vogel W, Peterson LG, Snyder MB:
Psychosomatics 45:5, September-October 2004
Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology 1996; 21:575–592 12. Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, Rubinow DR: Estrogen replacement in perimenopause related depression: a preliminary report. Am J Obstet Gynecol 2000; 183:414–420 13. Soares CN, Almeida OP, Joffe H, Cohen LS: Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001; 58:529–534 14. Cohen LS, Soares CN, Poitras JR, Prouty JR, Alexander AB, Shifren JL: Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry 2003; 160:1519–1522 15. Shapira B, Oppenheim G, Zohar J, Segal M, Malach D, Belmaker RH: Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry 1985; 20:576–579 16. Joffe H, Cohen LS: Estrogen, serotonin, and mood disturbance: Where is the therapeutic bridge? Biol Psychiatry 1998; 44:798– 811 17. Rasgon NL, Altshuler LL, Fairbanks LA, Dunkin JJ, Davtyan C, Elman S, Rapkin A: Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry 2002; 63:S45–S48
447