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Abstract
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BACKGROUND: High rates of postpartum relapse occur in women with histories of bipolar or schizoaffective disorder. These relapses may be triggered by the postdelivery fall in circulating estrogen through alteration of central neurotransmitter (especially dopaminergic) systems. This study tested the hypothesis that estrogen administration after childbirth would prevent postpartum relapse and would alter dopamine receptor sensitivity.
METHOD: Twenty-nine pregnant women with a Research Diagnostic Criteria diagnosis of hypomania (bipolar II), mania (bipolar I), or schizo-affective disorder participated in an open clinical trial. Three transdermal dose regimens of estrogen (17β-estradiol) were tested. Starting doses were 200 (N = 13), 400 (N = 3), and 800 (N = 13) μg/day, beginning within 48 hours after delivery and reduced by one half every 4 days for a total of 12 days. On the fourth day after starting estradiol therapy (before relapse occurred), subjects participated in a neuroendocrine challenge test that measured the sensitivity of the central nervous system (tubero-infundibular) dopaminergic system (plasma prolactin and growth hormone responses to apomorphine).
RESULTS: Estradiol at all dose regimens did not reduce the rate of relapse. However, of the 12 women who relapsed, those who had taken the highest dose of estradiol (800 μg/day) needed less subsequent psychotropic medication (fewer chlorpromazine equivalents) and were discharged sooner than those who had taken either of the 2 lower doses. No differences in neuroendocrine responses to apomorphine were detected between women receiving the high-dose and the lower-dose regimens.
CONCLUSION: The results do not support the hypothesis that a fall in circulating concentrations of estrogens precipitates relapse in subjects at risk of postpartum affective psychosis. The use of prophylactic estrogen in such circumstances is therefore highly questionable.; Indications:Prevention of relapse of hypomania (bipolar II), mania (bipolar I), or schizoaffective disorder after childbirth in 29 women.; Patients:29 female inpatients. Estraderm TTS 200 mcg daily group: n=13. Estraderm TTS 400 mcg daily group: n=3. Estraderm TTS 800 mcg daily group: n=13. Follow-up was 1 year.; TypeofStudy:An open study evaluating whether Estraderm TTS administration soon after childbirth would mitigate, in a dose-related manner, the impact of the precipitous falls in circulating estrogen levels and thus prevent relapse in subjects with histories of bipolar and schizoaffective disorders, and whether Estraderm TTS would exert its prophylactic effects by antagonizing dopamine receptor hypersensitivity.; DosageDuration:Initially 200, 400, or 800 mcg daily as transdermal patches, that was later reduced by half every 4 days for a total of 12 days.; Results:Twelve of 29 women experienced an episode of illness according to Research Diagnostic Criteria in the 90 days following childbirth. No difference was observed in age, weight, parity, number of previous episodes of illness, or time (months) elapsed since last episode between patients who relapsed and remained well. No differences were observed between dose groups in these variables. 3 of 13 women who received the lowest-dose regimen of Estraderm TTS (200 mcg daily) relapsed, 3/3 who received 400 mcg daily relapsed, and 6/13 who received 800 mcg daily relapsed. The diagnoses attached to the women who relapsed in the 2 lower-dose groups were manic disorder (N = 3), schizoaffective disorder (N = 2), and depression (N = 1); in the high-dose group, they were manic disorder (N = 5) and depression (N = 1). Onsets of illness were all between 7 and 14 days after delivery, with 2 exceptions: 1 case of depression in which illness began 77 days postpartum (subject 8800 mcg daily) and 1 case of manic relapse in which illness began 75 days postpartum (subject 3200 mcg daily). None of the women in the high-dose group suffered a recurrence of illness during the follow-up from 90 days to 1 year postpartum. 1 subject, who received a starting dose of 200 mcg daily, had a further relapse 4 months after leaving the hospital and committed suicide before she could be readmitted. There were no other recurrences of illness in the 2 lower-dose groups. None of the 17 women who had remained well during the first 3 months after delivery experienced a recurrence in the subsequent 9 months. An unexpected difference was observed between the women in terms of their responses to pharmacotherapy. The speed of recovery (time to final discharge) of the relapsing subjects was significantly faster in the women receiving the highest-dose regimen of Estraderm TTS (median number of days admitted = 29) compared with those receiving the 2 lower starting doses (400 mcg daily, median = 93 days; 200 mcg daily, median = 63 days; p =.015). Chlorpromazine and haloperidol were prescribed for 11 of the 12 women who relapsed; 2 women in the lower-dose groups received droperidol and clopixol as well, and subjects in both groups also received mood stabilizers. Women in the high-dose group received fewer chlorpromazine equivalents (median = 3.5) compared with women in the lower-dose groups (400 mcg daily, median = 14.4; 200 mcg/ day, median = 36.7), but these differences were not significant (p =.21). Postpartum concentrations of plasma estradiol differed according to the treatment dose. There appeared to be a dose-response relationship, but with only 3 subjects at the intermediate dose (plasma estradiol mean = 2478 pmol/L), the conclusive difference is between the subjects who received 200 mcg daily and those who received 800 mcg daily (plasma estradiol mean = 1049 pmol/L and 3788 pmol/L, respectively; p <.0001). 200 mcg of Estraderm TTS daily for 4 days did not elevate plasma levels above those reported in untreated subjects. There were no increases in progesterone concentrations to parallel the rise in estradiol. Subjects who subsequently relapsed and those who stayed well did not differ in terms of postnatal plasma estradiol or progesterone Levels. In all patients, baseline (pre-apomorphine) GH concentration after 4 days of treatment with Estraderm TTS, 800 mcg daily, was elevated compared with the concentrations found following treatment with 200 and 400 mcg daily (p <.02). At the 2 lower doses of Estraderm TTS, there were no differences between well and relapsing subjects in baseline GH or prolactin level or in the responses of these markers to apomorphine. At the highest Estraderm TTS dose, subjects who remained well had significantly greater baseline plasma GH concentrations than those who relapsed, but the GH response to apomorphine (AUC), the baseline prolactin values, and the inhibition of prolactin secretion by apomorphine (AOC) did not differ significantly between subjects who remained well and those who relapsed. A comparison of baseline prolactin values across all subjects showed that the 800-mcg daily dose of Estraderm TTS elevated prolactin level to a greater extent than did the 2 lower doses (p <.05).; AdverseEffects:No adverse events were mentioned.; AuthorsConclusions:This study shows that estrogen administration in the immediate postpartum period reduces the rate of fall in circulating estrogen, but does not reduce the rate of relapse. These findings question its use as a prophylactic compound in women at risk of postpartum psychosis and do not support hypotheses which propose that the postpartum fall in estrogen is etiologically important in postpartum psychosis. However, the data showing that, in women who relapsed, the high dose of estrogen enhanced the effectiveness of antipsychotic drugs warrant further systematic investigation. These data are of particular interest because estrogen was administered only for a maximum of 12 days immediately postpartum, and, thus, its relationship to the longer-term treatment with psychotropic drugs is unclear.; FreeText:Estraderm TTS treatment was started on the first day after delivery and, by the latest, within 48 hours of delivery. All subjects received heparin at reducing doses (2500-5000 units daily subcutaneously for 12 days) for prophylaxis of thromboembolism. The protocol was such that the lowest dose (200 mcg daily) was used in the first subjects. The first 13 subjects recruited were thus treated with the lowest dose, and 3 relapsed. Because the relapse rate was approaching those reported in untreated samples, the next 3 subjects recruited were treated with the intermediate dose (400 mcg daily). All 3 subjects receiving this intermediate dose relapsed, and thus all subsequent subjects were given the highest dose (800 mcg daily). Psychiatric assessments were carried using a semistructured interview (the Schedule for Affective Disorders and Schizophrenia-Lifetime Version). Psychiatric history up to the time of interview was assessed in pregnancy at the time of recruitment to the trial, and postnatal psychiatric outcome was assessed at 3 months postpartum. A postpartum relapse was defined as an episode of illness according to Research Diagnostic Criteria that occurred within 90 days following delivery. On the 4th day of Estraderm TTS treatment, neuroendocrine measures were taken. Estradiol, progesterone, growth hormone (GH), and prolactin were assayed, and baseline plasma concentrations of GH and prolactin and the response of these hormonal markers to apomorphine were measured. Responses to the agonist (apomorphine HCl 0.005 mg/kg subcutaneously) were expressed as the mean of the 6 measures (15-90 minutes) calculated as changes from the baseline (area under the curve [AUC] for GH and area over the curve [AOC] for prolactin).
Language: en |