Prophylactic estrogen in recurrent postpartum affective disorder

Prophylactic Estrogen in Recurrent Postpartum Affective Disorder Deborah A. Sichel, Lee S. Cohen, Laura M. Robertson, Alexandra Ruttenberg, and Jerrold F. Rosenbaum

Seven women with histories of puerperal psychosis and four with histories of puerperal major depression were consecutively treated with high-dose oral estrogen immediately following delivery. None of the women had histories of nonpuerperal affective disorder, and all women were affectively well throughout the current pregnancy and at delivery. Despite the high risk for recurrent illness in this population, only one woman developed relapse of postpartum affective disorder. All others remained entirely well and required no treatment with psychotropic medications during the 1 year follow-up period. This low rate of relapse, 9% compared to an expected 35-60% without prophylaxis, suggests that oral estrogen may stem the rapid rate of change in estrogen following delivery, thereby preventing the potential impact on dopaminergic and serotonergic neuroreceptors. It is hypothesized that the rapid rate of change of estrogen after delivery creates an "estrogen withdrawal state." This may be a critical factor in driving acute puerperal affective psychosis and early-onset puerperal major depression.

Key Words: Puerperal psychosis, relapse, estrogen, prophylaxis, estrogen withdrawal state BIOL PSYCHIATRY

1995;38:814-818

Introduction Postpartum affective disorders occur following approximately 10% of obstetrical deliveries and can be disabling illnesses with considerable impact on family, mammal, and neonatal well-being (Cogill et al 1986; Zuckerman et al 1990). Severe depressive symptoms including confusion, agitation, and disorientation are common (Brockington et al 1981, 1982). Onset of depressive symptoms may be gradual

From the Clinical Psychopharmacology Unit, Massachusetts General Hospital; and Harvard Medical School (DAS, LSC, JPR), Boston, Mass. Address reprint requests to Deborah A. Sicbel, M.D., Perinatal Psychiatry Clinical Research Program, Clinical Psychopharmacology Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114. Received January 10, 1994; revised December 29, 1994.

© 1995 Society of Biological Psychiatry

for some patients, while others experience rapidly escalating symptoms and may require hospitalization. The rate of nonpsychotic postpartum depression has been estimated at 10-12% (Paffenbarger 1982; Kumar and Robson 1984; O'Hara et al 1984; Kendell et al 1987; O'Hara et al 1990). Puerperal psychosis, a less common event, occurs following 0.05-0.1% of births and frequently presents with symptoms resembling mania (Reich and Winokur 1970). This diagnostic overlap, along with recent research indicating an association between history of bipolar disorder and risk for puerperal psychosis (Brockington and Cox-Roper 1988), suggests that these two disorders may share a common diathesis. Puerperal psychosis requires aggressive pharmacologic management so as to minimize risk to mother and infant. Therapeutic 0006-3223/95/$09.50 SSDI 0006-3223(95)00063-M

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interventions frequently include use of mood stabilizers and antipsychotic drugs (Stewart et al 1991). Women with past histories of major depression appear to be at particular risk for puerperal worsening of mood. In addition, patients with previous episodes of postpartum depression or psychosis are at substantial risk for relapse following subsequent pregnancies (Bratfos and Haug 1966; Reich and Winokur 1970; Davidson and Robertson 1985; O'Hara et al 1990). A recent investigation suggests the highest rate of relapse, possibly approaching 100%, if the previous episode of puerperal psychosis occurred during the 24 months prior to delivery (Wieck et al 1992). Given the high risk of relapse in these populations, prophylactic interventions have been advocated including lithium (Stewart et al 1991), neuroleptics (Kris and Carmichael 1957), steroids (Railton 1961), and estrogen (Hamilton and Sichel 1992). Previous studies of estrogen prophylaxis in the treatment of postpartum affective disorders have lacked precise diagnostic information on the subjects (Hamilton and Sichel 1992). However, diagnostic subgroups may have different underlying diatheses and respond to prophylactic agents differently. We hypothesized that estrogen prophylaxis would be most effective in treating women with histories of puerperal illness only, given that their symptoms are linked exclusively with a period of rapid fall in estradiol levels. This report describes an open, pilot trial of intravenous and oral estrogen as a prophylactic agent in a group of 11 women with previous episodes of severe postpartum affective disorder, but no nonpuerperal history of affective instability. Response to prophylaxis with estrogen in this sample of women and its potential use in women identified as being "at risk" for postpartum affective disorder is described.

Methods Over 1 1/2 years, 11 pregnant women in their first trimester were consecutively evaluated at the Massachusetts General Hospital, Perinatal Psychiatry Clinical Research Program, a subspecialty service for patients with postpartum psychiatric disorders. All women had histories of at least one episode of postpartum affective disorder, with one woman describing two such episodes following each of her previous pregnancies. All patients had experienced onset of illness within 2 weeks of giving birth and had met Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R) criteria for either nonpsychotic major depression or manic postpartum psychosis at this time. Episodes of affective instability had lasted from 6 to 12 months. All patients recovered from

these severe episodes of postpartum depression and now sought consultation because of concerns regarding risk for recurrence following the current pregnancy. None of the women had histories of affective illness other than puerperally. Demographic data, diagnoses, and treatment received during the index episode of postpartum illness are outlined in Table 1. Data about two previous pregnancies are provided for patient 5. Three patients had received electroconvulsive therapy. All patients were seen during the current pregnancy at 11 weeks, 25 weeks, and 39 weeks of gestation. No symptoms of affective instability were observed at these cross-sections using a structured clinical interview nor were psychotropic medications prescribed during pregnancy. Immediately following delivery, oral Premarin was administered daily in decreasing dosages over 4 weeks as outlined in Table 2. A high dose was chosen in the first few days postpartum to try to approximate term pregnancy estradiol levels before a gradual taper, designed to cushion the usual fall to follicular phase estradiol levels. The doses of oral estrogen used were based on data by James Hamilton indicating successful treatment of 50 high risk women with 10 mg/day of intramuscular Theelin (depot estrogen) (Hamilton, unpublished data). Two patients (10, 11) received intravenous estrogen for 2 days to ensure compliance, when, despite oral Premarin, one patient developed symptoms of relapse. We also considered that intravenous (IV) administration might better approximate high estradiol levels, and enhance treatment response. None of the women in our sample were noted to have a previous history of thrombosis. To prevent thromboembolic events, heparin was administered twice daily in doses of 5000 units subcutaneously, daily for the first week postpartum. Women were evaluated daily for mood and neurovegetative symptoms during the first 5 days postpartum using a DSM-III-R checklist to assess affective instability. Follow-up was performed at 4 weeks and then at 3, 6, and 12 months postpartum via clinical interview.

Results All but one woman remained well during the acute puerperium and for the first postpartum year. In the patients who remained well, there was uniform absence of affecfive and neurovegetative symptoms. Patient lO experienced a relapse during the first postpartum week and was hospitalized for several weeks thereafter. She was noted to have been noncompliant after discharge, taking smaller doses of estrogen than prescribed. No additional women

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Table 1. Treatment and Diagnosis of Index Episode of Postpartum Disorder in 11 Women Patient number 1

Current age

Onset postpartum

23

l week

2

34

3 4

DSM III diagnosis MDD

Nortriptyline 75 mg Clonazepam 2 mg

None

33

1 week

MDD

Nortriptyline 100 mg

None

32

3 days

Psychosis

Alprazolam 3 mg Desipramine 150 nag Trifluoperazine 10 mg

6 weeks

Perphenazine 24 mg Desipramine 150 mg Alprazolam 4 mg

4 weeks

5

33

3 days

1 week

Psychosis

Psychosis

Pregnancy #2

36

32

9

30

10

34

11

Alprazolam 3 mg Desipramine 150 mg Trifluoperazine 15 mg

32

8

8 weeks

MDD

30

7

Fluoxetine 60 mg Imipramine 175 mg ECT

Length of hospitalization

3 weeks

5 Pregnancy #1

6

Treatment (mg/day)

33

3 days

4 days

1 week

3 days

1 week

1 week

Psychosis

Psychosis

Psychosis

Psychosis

Psychosis

MDD

6 weeks

Trifluoperazine 15 mg Lorazepam 3 mg Imipramine 100 mg

5 weeks

Thiothixene 15 mg Imipramine 100 mg Alprazolam 0.5 mg

3 weeks

Thioridazine 500 mg Valproic acid 750 mg Carbemazepine 1000 mg Perphenazine 24 mg Elavil 100 mg

2) 3 weeks

Perphenazine 24 mg Lithium 900 mg Lorazepam 2 mg

4 weeks

Perphenazine 32 mg Lithium 900 mg ECT Imipramine 150 mg ECT

1) 4 weeks

4 weeks

5 weeks

MDD, major depressive disorder; ECT, electroconvulsivetherapy.

demonstrated signs of relapse as determined by clinical interview during the 1 year follow-up period. Thromboembolic events did not complicate therapy in any patients receiving oral or IV estrogen.

Discussion

The puerperium has been increasingly identified as a period of risk for affective instability, particularly in women with a history (or family history) of affective disorder (O'Hara et al 1991). Women with histories of postpartum depression may be at even greater risk for illness following subsequent pregnancies. Relapse rates in

women with histories of nonpsychotic postpartum depression have been estimated at 25-40% (Davidson and Robertson 1985). In women with bipolar disorders, relapse rates appear to be higher, with estimates ranging from 40 to 60% (Bratfos and Haug 1966; Reich and Winokur 1970). Patients with histories of puerperal psychosis are most vulnerable to relapse. At least one recent investigation has described relapse rates greater than 90% if the index episode of puerperal psychosis occurred during the 24 months prior to delivery (Wieck et al 1992). The recurrent nature of postpartum depressive illness has prompted investigation of prophylactic measures in an effort to stem morbidity associated with these disorders. Stewart has reported successful use of prophylactic lith-

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Table 2. Prophylactic Use of Estrogen (Premarin) in 11 Women with Histories of Postpartum Affective Illness

Oral estrogen

Intravenous estrogen

Dosage

Days Postpartum

5 mg twice daily 2.5 mg three times daily 2.5 mg twice daily 1.25 mg twice daily 0.9 mg daily 0.625 mg daily, then discontinue 25 mg every 8 h, then switched to oral, as above

0-3 4-7 8-12 13-15 16-21 21-28 1-2

ium in an open trial when instituted immediately after delivery in women with histories of puerperal psychosis (Stewart et al 1991). Efficacy of this intervention in patients with nonpsychotic postpartum depression has not been demonstrated. In another open trial, Kris and Carmichael (1957) proposed use of antipsychotic drugs during pregnancy, extending through the puerperium in schizophrenic patients. Although successful for that population, antipsychotics have not been shown to be effective for prophylaxis against postpartum depression in patients with bipolar affective disorder. Hamilton has reported the successful use of estrogen administered as a bolus intramuscular dose in an open trial of 50 women with histories of postpartum depressive illness; however, precise diagnostic information regarding those women is not available (Hamilton and Sichel 1992). Anecdotal reports regarding prophylactic treatment of puerperal affective episodes have included the use of pyridoxine (Riley 1982), prednisone (Railton 1961), and progesterone (Dalton 1989). Thus far, no compelling clinical or neurochemical data support the efficacy of these agents in the treatment of postpartum depression. Few studies have investigated the role of estrogen as a potential treatment for depressive symptoms. One report of a series of depressed inpatients with resistant depression suggested that estrogen was effective in ameliorating mood disturbance (Klaiber et al 1979). Another study has shown estrogen to be helpful for vasomotor symptoms, although of unclear value for depressive symptoms associated with menopause (Foldes 1971). In the current sample, nine patients had been hospitalized for periods ranging from 3 to 8 weeks for one or more previous episodes of postpartum illness. Although they were affectively well and off medication during the current pregnancy, by virtue of their histories of severe postpartum illness these patients were at great risk for recurrence following delivery. Despite the small sample size, it is noteworthy that none of the 10 women who complied with treatment experienced relapse of postpartum affective disorder. One would expect three or four

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patients to relapse given available data on the risk in this population. One hypothesis explaining lower relapse rates in patients treated with high-dose oral estrogen during the acute puerperium is that estrogen supplementation stems the rapid fall in plasma estrogen concentration, from elevated term pregnancy levels to nearly follicular phase levels within 48h following delivery. Previous studies have failed to establish a clear relationship between postpartum affective symptoms and puerperal level of estradiol (O'Hara et al 1991). However, a critical factor driving clinical puerperal relapse may be the rapid change in estradiol level and not a specific level of this agent per se. It is possible that this acute "estrogen withdrawal state" in women with a vulnerable diathesis for affective disorder may be sufficient to kindle puerperal affective illness. Pending larger controlled studies, we can only hypothesize as to the neurochemical mechanism preventing affective relapse in these high-risk patients. Several studies suggest estrogen modulation of dopamine and serotonin in striatum, hippocampus, substantia nigra, and hypothalamus in the rat brain (Ehrenkranz 1976; Chiodo and Caggiula 1980; Hruska and Silbergeld 1980; Kendall et al 1981; Biegon et al 1983; Kow and Pfaff 1985; Meakin et al 1992). Although precise mechanisms of estrogen modification of the monoaminergic receptor are still unclear, some studies suggest alteration in numbers of binding sites, effects on pre- and postsynaptic receptors, activation of breakdown enzymes, and direct effects on neuronal firing (Luine et al 1977; Luine and Rhodes 1983; Pfaff 1983; Kow and Pfaff 1985; Clarke and Maayani 1990). One explanation may be that high-dose estrogen stemmed the rapid puerperal drop in estradiol levels, thereby cushioning the negative impact of the "estrogen withdrawal state" on serotonergic and dopaminergic transmission. More recent work demonstrates decreased sensitivity of central nervous system (CNS) dopamine receptors in women who have developed postpartum psychosis (Wieck et al 1992), suggesting that the acute fall of estrogen at delivery in vulnerable women may catalyze dopaminergic receptor dysfunction sufficiently to produce affective symptoms. Attenuation of this "estrogen withdrawal state" via administration of high-dose estrogen may protect against affective decompensation in at least some patients. Extreme caution regarding selection of patients for this type of prophylaxis is advised. This particular group represents a very small subset of women at risk for postpartum depression who manifest only puerperal disorder, and do not demonstrate pathology outside of this period. Prophylactic recommendations for women who may demonstrate nonpuerperal pathology, as well as symptoms during pregnancy, should include the appropriate psychotropic drugs. Future research is needed to clarify

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the role risk for parallel noted to

of prophylactic agents in women considered at postpartum illness. This work must be done in with studies clarifying relapse rates in women be at greatest risk for puerperal decompensation.

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We wish to acknowledge the continued support of James Hamilton, whose pioneering work in this area catalyzed the current investigation of estrogen as a preventive agent for women at risk.

References Biegon A, Reches A, Snyder L (1983): Serotonergic and noradrenergic hormones. Life Sci 32:2015-2021. Bratfos O, Hang JO (1966): Puerperal mental disorders in manic depressive females. Acta Psychiatr Scand 42:285-294. Brockington IF, Cernik KF, Schofield EM, et al (1981): Puerperal psychosis: Phenomena and diagnosis. Psychiatry 38: 829. Chiodo LA, Caggiula AR (1980): Alterations in the basal fn'ing of rate and autoreceptor sensitivity of dopamine neurones in the substantia nigra following acute and extended exposure to estrogen. Eur J Pharmacol 67:165-166. Clarke WP, Maayani S (1990): Estrogen effects on 5-HT 1A receptors in hippocampal membranes from ovariectomized rats: Functional and binding studies. Brain Res 518:287-291. Cogill SR, Caplan HL, Alexandra H, Robson KM, Kumar R (1986): Impact of maternal depression on cognitive development of young children. Br Meal J 292:1165-1167. Dalton K (1989): Depression after Childbirth. Oxford: Oxford University Press. Davidson J, Robertson E (1985): A follow-up study of postpartum illness. Acta Psychiatr Scand 71:451-457. Ehrenkranz JRL (1976): Effects of sex steroids on serotonin uptake in blood platelets. Acta Endocrinol 83:420-428. Hruska RE, Silbergeld EK (1980): Estrogen treatment enhances dopamine receptor sensitivity in rat striatum. Eur J Pharmacol 61:397-400. Kendall DA, Stancel GM, Enna SJ (1981): Effect of ovarian steroids on modifications in serotonin receptor binding. Science 211:1183-1185. Kendell RE, Chalmers JC, Platz C (1987): Epidemiology of puerperal psychoses. Br J Psychiatry 150:662-673. Klaiber E, Broverman DM, Vogel W, Kobayashi Y (1979): Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 36:550-554. Kow LM, Pfaff D (1985): Estrogen effects on neuronal responsiveness to electrical and neurotransmitter stimulation: An in

vitro study on the ventromedial nucleus of the hypothalamus. Brain Res 347:1-10. Kris EB, Cannichael DM (1957): Chlorpromazine maintenance therapy during pregnancy and confinement. Psychiatr Q 31:690-695. Kumar R, Robson KM (1984): A prospective study of emotional disorders in childbearing women. Br J Psychiatry 144:35-47. Luine VN, McEwen S, Black IB (1977): Effect of 17-betaestradiol on hypothalamic tyrosine hydroxylase activity. Brain Res 120:188-192. Luine VN, Rhodes JC (1983): Gonadal hormonal regulation of MAO and other enzymes in hypothalamic areas. Neuroendocrinology 36:235-241. O'Hara MW, Neunaber DJ, Zekoski EM (1984): Prospective study of postpartum depression: Prevalence, course, and predictive factors. J Abnorm Psychol 93:158-171. O'Hara MW, Schlechte JA, Lewis DA, et al (1991): A controlled prospective study of postpartum mood disorders: Psychological, environmental and hormonal factors. J Abnorm Psychol 100:63-73. O'Hara MW, Zekoski EM, Phillips LH, Wright EJ (1990): A controlled prospective study of postpartum mood disorders: Comparison of childbearing and nonchildbearing women. J Abnorm Psychol 99:3-15. Pfaff DW (1983): Impact of estrogens on hypothalamic nerve cells: Ultrastructural, chemical, and electrical effects. Recent Prog Hormone Res 39:127-79. Railton IE (1961): The use of corticoids in postpartum depression. J Am Womens Med Assoc 17:450-452. Reich T, Winokur G (1970): Postpartum psychosis in patients with manic depressive disease. J Nerv Merit Dis 151:60-68. Stewart DE, Klompenhouwer JL, Kendall RE, Van Hurst AM (1991): Prophylactic lithium in puerperal psychosis: The experience of three centers. Br J Psychiatry 158:393-397. Zuckerman B, Bauchner H, Parker S, Cabral H (1990): Maternal depressive symptoms during pregnancy, and newborn irritability. J Dev Behav Pediatr 11:190-194.