Trial Summary
What is the purpose of this trial?Determine whether postpartum depression is triggered by the abrupt withdrawal of estrogen and progesterone.
The appearance of mood and behavioral symptoms during pregnancy and the postpartum period has been extensively reported. While there has been much speculation about possible biologically based etiologies for postpartum disorders (PPD), none has ever been confirmed. Preliminary results from two related studies (protocols 90-M-0088, 92-M-0174) provide evidence that women with menstrual cycle related mood disorder, but not controls, experience mood disturbances during exogenous replacement of physiologic levels of gonadal steroids. The present protocol is designed to create a "scaled-down" hormonal milieu of pregnancy and the puerperium in order to determine whether women who have had a previous episode of postpartum major effective episode will experience differential mood and behavioral effects compared with controls and to determine whether it is the abrupt withdrawal of gonadal steroids or the prolonged exposure to gonadal steroids that is associated with mood symptoms. Supraphysiologic plasma levels of gonadal steroids will be established, maintained, and then rapidly reduced, simulating the hormonal events that occur during pregnancy and parturition. This will be accomplished by administering estradiol and progesterone to women who are pretreated with a gonadotropin releasing hormone (GnRH) agonist (Lupron). After eight weeks, administration of gonadal steroids will be stopped in one group of patients and controls, and a sudden decline in the plasma hormone levels will be precipitated. Another group will be maintained on supraphysiologic levels of estrogen and progesterone for an additional month. Outcome measures will include mood, behavioral and hormonal parameters (a separate protocol done in collaboration with NICHD).
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Do I have to stop taking my current medications to join the trial?Yes, participants must be medication-free, including birth control pills, to join the trial.
Is the drug Estradiol, Progesterone a promising treatment for postpartum depression?Estradiol, a form of estrogen, shows promise as a treatment for postpartum depression because it addresses hormone changes after childbirth. However, more research is needed to confirm its effectiveness and safety.5681011
What safety data exists for hormone therapy in treating postpartum depression?The safety data for hormone therapy, specifically estradiol, in treating postpartum depression is still being evaluated. Preliminary evidence suggests that transdermal estradiol may be effective, but more research is needed to confirm its efficacy and safety, especially regarding maternal tolerability, long-term safety, and its passage into breast milk. Current studies highlight the need for randomized clinical trials to establish safety and efficacy before routine clinical use. Additionally, the safety of infant exposure during lactation is a concern that requires further investigation.12459
What data supports the idea that Hormone Therapy for Postpartum Depression is an effective treatment?The available research shows mixed results for hormone therapy as a treatment for postpartum depression. Some studies suggest that estrogen therapy might help with severe cases, but these studies have limitations and potential side effects. Progesterone has been reported to help prevent postpartum depression in some uncontrolled studies, but synthetic progesterone might actually cause depression. Compared to standard antidepressants, which are commonly used but have slow effects, hormone therapy could be a natural alternative, especially for breastfeeding mothers. However, more research is needed to confirm its effectiveness and safety. Meanwhile, a new drug called brexanolone has been approved and shows promise in treating postpartum depression more quickly.35789
Eligibility Criteria
This trial is for women aged 18-50 who have experienced major depression or mood disorders within three months after childbirth, are in good health, and have had a stable menstrual cycle for at least three months. They should not be pregnant or breastfeeding and must have been well for at least one year without any history of severe postpartum mental health issues.Treatment Details
The study tests if hormone changes trigger postpartum depression by simulating pregnancy hormones with Estradiol and Progesterone, then suddenly stopping them. Some participants will continue the hormones longer to compare effects on mood and behavior.
2Treatment groups
Active Control
Placebo Group
Group I: Group 2, Continued Replacement GroupActive Control2 Interventions
12 weeks of hormone addback
Group II: Group 1, Hormone and Placebo GroupPlacebo Group3 Interventions
8 weeks of hormonal addback plus 4 weeks of placebo
Estradiol is already approved in European Union, United States, Canada for the following indications:
πͺπΊ Approved in European Union as Estradiol for:
- Menopausal symptoms
- Hypoestrogenism
- Osteoporosis prevention
- Breast cancer palliation
- Prostate cancer palliation
πΊπΈ Approved in United States as Estradiol for:
- Moderate to severe vasomotor symptoms due to menopause
- Vulvar and vaginal atrophy due to menopause
- Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
- Prevention of postmenopausal osteoporosis
- Palliative treatment of breast cancer
- Palliative treatment of prostate cancer
π¨π¦ Approved in Canada as Estradiol for:
- Menopausal symptoms
- Hypoestrogenism
- Osteoporosis prevention
- Breast cancer palliation
- Prostate cancer palliation
Find a clinic near you
Research locations nearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, MD
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Who is running the clinical trial?
National Institute of Mental Health (NIMH)Lead Sponsor
References
Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. [2022]Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women.
Preclinical profiles of progestins used in formulations of oral contraceptives and hormone replacement therapy. [2019]Progestins used in oral contraceptive formulations available in the United States include norgestimate, desogestrel, norethindrone, norethindrone acetate, and levonorgestrel. Progestins used in the United States in continuous and intermittent formulations of hormone replacement therapy are norgestimate, medroxyprogesterone acetate, and norethindrone acetate. The chemical structure of a progestin determines its relative binding affinity for the progesterone and androgen receptors, as well as the sex hormone binding globulin in human serum, and determines its clinical profile. Overall, the properties of levonorgestrel or norethindrone acetate in this regard differ from norgestimate and are more conducive to androgenic stimulation. Estrogen replacement offers cardioprotective effects in postmenopausal women. Progestins are added to hormone replacement therapy to counteract the well-known increased risk of endometrial hyperplasia associated with the use of unopposed estrogen. Animal models show that for some parameters, including improvement of lipid profiles, progestins can diminish the cardioprotective effect of estrogen. Initial animal studies of norgestimate combined with estrogen do not show an attenuation of estrogenic effects.
The benefit of oestrogens and progestogens in postnatal depression. [2013]Postnatal depression, with a prevalence of at least 10%, is a common complication of the puerperium. The aetiology is unclear, specific diagnostic criteria cannot be drawn and the treatment options are limited. As hormones are thought to contribute to its pathophysiology, the supplementation with either progesterone or oestrogen might be of prophylactic and/or therapeutic value in postnatal depression. Research into hormonal prophylaxis and treatment of postnatal depression (PND) is limited. This review article is aimed at exploring the evidence available regarding the use of oestrogen and progesterone in postnatal depression. A search of electronic databases Medline, Psychinfo, Embase and published books from 1970 to 2002 was carried out. The search strategy was limited to the English language. Of 193 articles, 30 were chosen and all 30 copies were identified and analysed critically. Prophylactic and treatment value were separately analysed for both oestrogen and progesterone. Some uncontrolled studies by Dalton (1982, 1985) report the benefit of progesterone in preventing postnatal depression. The value of oestrogen in preventing and treating this disorder is suggested by some articles but the methodological shortcomings in these studies make the study results unreliable. In addition, the use of oestrogen in the postnatal period may have significant side effects. Use of synthetic progesterone is associated with depression in the postnatal period and should be used with caution. Oestrogen therapy may be of modest value in severe postnatal depression.
New products and regimens (since 2003). [2015]The downturn in the use of hormone replacement therapy since the original publication of the Women's Health Initiative (2002) and Million Women studies (2003) has now stabilized. New products are now being developed which maintain benefits and minimise risks. However, some useful products have been withdrawn by Pharma companies through profitability decisions; other products will regrettably not be launched despite favorable data. New low- and ultra-low-dose oral preparations (containing 0.3 mg conjugated equine estrogens and 0.5 mg estradiol, respectively) appear to maintain benefits for symptom relief and osteoporosis whilst minimizing side-effects and risks. A 14 microg transdermal system appears to maintain bone protection without the need for endometrial protection. New progestogens can minimize progestogenic side-effects through antiandrogenic and antimineralocorticoid effects, e.g. drospirenone, bioidentical progesterone and selective progesterone receptor modulators. A new female androgen patch has been licensed in Europe for treatment of low libido causing distress (hypoactive sexual desire disorder) in surgically menopaused women on estrogen therapy. A non-hormonal option, desvenlafaxine succinate (a serotonin and noradrenaline reuptake inhibitor), for vasomotor symptoms is currently in phase-III clinical trial stage and should be launched in the next year. Additionally, a selective estrogen receptor modulator/conjugated equine estrogen preparation combination currently in phase-III clinical trials is showing encouraging data for efficacy/risks and should provide a further option for women using hormone therapy in the future.
Transdermal estradiol for postpartum depression: a promising treatment option. [2021]Postpartum depression (PPD) is the most common unrecognized complication of childbirth and affects 1 out of 7 childbearing women. Although conventional pharmacologic and psychotherapeutic antidepressant treatments are effective for PPD, a natural alternative may be preferred by postpartum women, especially those who breastfeed their infants. The treatment of PPD with synthetic forms of naturally occurring estrogen is mechanistically appealing because PPD occurs in the context of estrogen withdrawal at parturition. Preliminary evidence suggests that PPD is a disorder of hormone-related mood dysregulation (similar to perimenopausal depression) that can be effectively treated with estrogen. This review provides the basic science and clinical background as well as safety considerations to support the application of transdermal estradiol as a treatment for PPD. We conclude that estradiol treatment for PPD requires confirmation of efficacy in a randomized clinical trial before routine clinical use as monotherapy. Additional data regarding maternal tolerability of cyclic progestins, long-term safety of estradiol treatment, estradiol passage into breast milk and infants, and interdisciplinary collaboration among psychiatrists and gynecologists is also needed before estradiol is used in women who decline or fail to respond to first-line antidepressant treatments, or as an augmentation of conventional antidepressant treatment.
Pharmacotherapy of Postpartum Depression: Current Approaches and Novel Drug Development. [2023]Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of the mother and child, negatively impacting child cognitive, behavioral, and emotional development with lasting consequences. There are a number of therapeutic interventions for postpartum depression including pharmacotherapy, psychotherapy, neuromodulation, and hormonal therapy among others, most of which have been adapted from the treatment of major depressive disorder outside of the peripartum period. Current evidence of antidepressant treatment for postpartum depression is limited by the small number of randomized clinical trials, underpowered samples, and the lack of long-term follow-up. The peripartum period is characterized by rapid and significant physiological change in plasma levels of endocrine hormones, peptides, and neuroactive steroids. Evidence supporting the role of neuroactive steroids and Ξ³-aminobutyric acid (GABA) in the pathophysiology of postpartum depression led to the investigation of synthetic neuroactive steroids and their analogs as potential treatment for postpartum depression. Brexanolone, a soluble proprietary intravenous preparation of synthetic allopregnanolone, has been developed. A recent series of open-label and placebo-controlled randomized clinical trials of brexanolone in postpartum depression demonstrated a rapid reduction in depressive symptoms, and has led to the submission for regulatory approval to the US Food and Drug Administration (decision due in March 2019). SAGE-217, an allopregnanolone analog, with oral bioavailability, was recently tested in a randomized, double-blind, placebo-controlled phase III study in severe postpartum depression, with reportedly positive results. Finally, a 3Ξ²-methylated synthetic analog of allopregnanolone, ganaxolone, is being tested in both intravenous and oral forms, in randomized, double-blind, placebo-controlled phase II studies in severe postpartum depression.
Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used? [2020]Postpartum depression is considered to be a subtype of major depressive disorder that occurs in approximately 10-20% of mothers worldwide. However, in actuality, these numbers are likely underreported due to minimization and the stigma of mental illness. Until recently, there were no approved medications for the treatment of postpartum depression. Allopregnanolone is a naturally occurring neuroactive steroid whose serum levels decline precipitously following childbirth. This hormonal fluctuation has been postulated as playing a role in the pathophysiology of postpartum depression. Brexanolone is the first medication approved by the US Food and Drug Administration for the treatment of postpartum depression. Brexanolone is an intravenous proprietary formulation of allopregnanolone that can be administered to produce stable serum levels comparable with third-trimester concentrations in postpartum mothers. It is hypothesized to modulate neuronal excitability by functioning as an allosteric modulator of Ξ³-aminobutyric acid-A receptors and is administered under monitoring as a 60 h continuous infusion. In this review, we will highlight the results of the clinical trial program, including efficacy and tolerability data. Practical and logistical considerations of brexanolone will be reviewed, as will its potential place in therapy for the treatment of postpartum depression.
Oestrogen therapy for postpartum depression: efficacy and adverse effects. A double-blind, randomized, placebo-controlled pilot study. [2022]Postpartum depression (PPD) is detrimental to the mother and the family as a whole. Early initiation of appropriate treatment is important. The aim of this pilot study was to evaluate the efficacy and adverse effects of oestradiol treatment.
Advances in pharmacotherapy for postpartum depression: a structured review of standard-of-care antidepressants and novel neuroactive steroid antidepressants. [2022]Postpartum depression is one of the most common morbidities of childbearing, yet it is underdiagnosed and undertreated with negative consequences for mother and offspring. Despite the widespread use of standard-of-care antidepressants as the mainstay of treatment for postpartum depression, there is limited evidence on their safety and efficacy due to their slow onset of action and suboptimal outcomes. The emergence of gamma-aminobutyric acidergic neuroactive steroids may offer faster response and remission times and improved patient outcomes. This article reviews the evidence base for the efficacy of standard-of-care antidepressants, hormonal therapeutics including progestins and estradiol, and gamma-aminobutyric acidergic neuroactive steroids in the treatment of postpartum depression, as well as the safety of infant exposure to these agents during lactation.
Neuroendocrine insights into neurosteroid therapy for postpartum depression. [2023]Postpartum depression (PPD) is associated with a decline in progesterone-derived anxiolytic-antidepressant neurosteroids after delivery. Neurosteroid replacement therapy (NRT) with GABA-A receptor-modulating allopregnanolone (brexanolone) shows promise as the first drug treatment for PPD. Here we describe the molecular insights of the neurosteroid approach for rapid relief of PPD symptoms compared with traditional antidepressants.
Current pharmacotherapy approaches and novel GABAergic antidepressant development in postpartum depression. [2023]Postpartum depression has deleterious effects on childbearing persons globally. Existing treatments have been largely extrapolated from those for other forms of depression and have included pharmacotherapy, psychotherapy, and neuromodulation. Hormonal treatments with oestrogen and progestogens, thought to be a rational approach to treatment in response to an emerging literature on the pathophysiology of postpartum depression, have only limited evidence for efficacy to date. Novel antidepressant development with allopregnanolone analogues, in contrast, has proven a promising avenue for the development of rationally designed and efficacious treatments. This state-of-the-art review presents the evidence for the current standard-of-care pharmacotherapy, hormonal treatment, and emerging allopregnanolone analogues for the treatment of postpartum depression along with a discussion of the current understanding of its neuroactive steroid-driven pathophysiology.