Short Time Oestrogen as a Candidate Strategy to Prevent Postpartum Depression in a High-risk Group: a Randomised, Placebo-controlled Trial.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 220
- 试验地点
- 1
- 主要终点
- Number of participants with Major Depression Disorder
研究概览
简要总结
Perinatal depression affects 10-15% of women postpartum and has a recurrence rate of 40%. Women who develop perinatal depression might be particularly susceptible to the rapid and large changes in sex steroid hormones, particularly estradiol, across pregnancy to postpartum. This trial aims 1) to evaluate the preventive effect of transdermal estradiol treatment in the immediate postpartum on depressive episodes in a subgroup of women at high-risk for perinatal depression, and 2) to determine if a set of biomarker gene transcripts can identify this subgroup and thus form the basis for future personalised prevention or treatment.
The MAMA Trial is a double-blind, 1:1 randomised, placebo-controlled trial. The trial involves maternity wards at three university hospitals in the Capital Region of Denmark. Women who are singleton pregnant in the third trimester with a prior history of perinatal depression are eligible to participate. Participants will be randomised to either estradiol patches (200 μg per day) or placebo patches for three weeks starting immediately postpartum.
The primary statistical analysis will be performed based on the intention-to-treat principle. A sample size of 220 will provide the trial with 80% power (alpha 0.05, beta 0.2) to detect a reduction in postpartum depression of 50% and to tolerate a drop-out of around 20%.
详细描述
Major depressive disorder affects twice as many women as men. Women are at increased risk for depression in life phases, where endogenous sex steroid hormone milieu changes; such as in puberty, during late pregnancy to postpartum and across menopausal transition. This includes a subtype of MDD, perinatal depression (PND) that affects 10-15% of mothers postpartum and has a recurrence rate of 40% in subsequent pregnancies. PND is a disabling disorder that affects the entire family, including development and future health of the infant.
The underlying risk and resilience mechanisms in MDD are far from clear, consequently, current treatment strategies are suboptimal. Women who develop PND might be particularly sensitive to the rapid and large changes in sex steroid hormone milieu, seen in the transition from high levels of sex steroid hormones, in particular estradiol, in pregnancy to low levels in the hormone withdrawal phase postpartum. Thus, PND is most likely has a distinct pathophysiology, which may provide a unique opportunity for protecting mental health by targeted short-term prevention in the immediate postpartum period.
Intriguingly, recent human data has provided direct evidence for sex hormone manipulation to provoke subclinical depressive symptoms in about 12% of healthy volunteers. The phenomenon was linked to changes in estradiol, which were induced by the pharmacological manipulation with a Gonadotrophin Releasing Hormone agonist. Estradiol affects critical domains and key brain regions known to be dysfunctional in women with major depressive disorder. Estradiol sensitivity predisposes to PND, which can be demonstrated at the level of gene transcription in clinical cohorts, and is also directly supported by recent research results. Such peripheral markers of estradiol sensitivity may prove useful in identifying individuals at excess risk for PND, also in their first pregnancy, and thus may help direct preventive efforts for the women who can benefit the most.
Transdermal estradiol emerges as a promising preventive treatment option for the postpartum onset of PND supported by epidemiological, preclinical, and clinical research, robust and rapid response to estradiol in some pilot postpartum depression (PPD) trials with few side effects and minimal breastmilk passage to the infant. Further, transdermal estradiol appears to be effective in preventing clinically significant depressive symptoms among perimenopausal women, which is another group of women in hormonal transition phase.
Previously, a double-blind randomized, controlled trial (RCT) showed effect of treatment with transdermal estradiol on manifest PND. A recent pilot RCT with transdermal estradiol as a candidate treatment for postpartum depression failed to achieve its primary outcome, but notably, did reduce depressive symptoms postpartum compared to placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Singleton pregnant
- •Prior history of perinatal depression
- •Age between 18 and 45 years
排除标准
- •Moderate to severe depression with onset during pregnancy
- •Severe psychiatric disorders (e.g. disorders with psychotic symptoms, schizophrenia, bipolar disorders, inpatient eating disorders and inpatient obsessive-compulsive disorders)
- •Previous suicide attempts without having a depressive episode
- •Prior history or ongoing neurological disorders (e.g. migraine or epilepsy)
- •Severe somatic illness
- •Prior history or ongoing cancer
- •Prior history of venous thromboembolism, myocardial infarction, cerebrovascular thromboembolism or thrombophilia, or other risk factors clinically assessed after thrombophilia screening
- •Deep vein thrombosis or pulmonary embolism in current pregnancy
- •Pregnancy-induced hypertension or preeclampsia
- •Pre-existing atherosclerosis or well-known cardiovascular risk factors (e.g. diabetes, hypertension)
- •Other contraindication for oestrogen treatment (e.g. acute liver failure, severe varicose veins)
- •Use of psychotropic pharmacology, except for short-term sleep support treatment
- •Non-fluent in Danish or pronounced vision or hearing loss
- •Body Mass Index (BMI) >35 kg/m2
- •Ongoing alcohol or drug abuse
- •Severe postpartum haemorrhage (>1500 ml)
- •Severe illness in the infant or perinatal death
研究组 & 干预措施
Intervention
Estradiol patches (200 μg per day) 0-3 weeks postpartum.
干预措施: Transdermal patch estradiol (Drug)
Placebo
Placebo patches (Coloplast Comfeel) for 0-3 weeks postpartum
干预措施: Transdermal patch placebo (Drug)
结局指标
主要结局
Number of participants with Major Depression Disorder
时间窗: 0-6 months postpartum
Clinical diagnosis assessed by DSM-V criteria
次要结局
- Maternal anxiety(8-10 weeks postpartum)
- Estradiol level(Baseline time point at third trimester, i.e. week 34-37 of pregnancy)
- EPDS Depressive symptoms(8-10 weeks postpartum)
- Parental competences(8-10 weeks postpartum)
- Epigenetic markers relevant for infant HPA axis(0-1 days postpartum)
- Change in allopregnanolone level(From baseline (third trimester of pregnancy) to 3 weeks postpartum)
- Negative bias in responses to infant vocalisations and video(8-10 weeks)
- HamD6 Depressive symptoms(8-10 weeks postpartum)
- Maternal mental wellbeing(8-10 weeks postpartum)
- Parental stress(8-10 weeks postpartum)
- Predictive value of composite gene transcription and DNA methylation marker for estrogen sensitivity(8-10 weeks postpartum)
- Parental reflective capacity(8-10 weeks postpartum)
- Proportion of women who exclusively breastfeed their infants(8-10 weeks postpartum)
- Maternal sleep quality(8-10 weeks postpartum)
- Maternal attachment to unborn child(Baseline time point at third trimester, i.e. week 34-37 of pregnancy)
- Cold cognitive function(8-10 weeks postpartum)
- Hot cognitive function(8-10 weeks postpartum)
- Socio-emotional infant development(8-10 weeks)
- Infant development (Bayley-III)(8-10 weeks postpartum)
- Cortisol dynamics Cortisol dynamics(3-5 weeks postpartum)
- Hair cortisol level Cortisol dynamics(0-1 days postpartum)
- Cortisol evening Cortisol dynamics(3-5 weeks postpartum)
- Change in estradiol level(From baseline (third trimester of pregnancy) to 3 weeks postpartum)
- Change in progesterone level(From baseline (third trimester of pregnancy) to 3 weeks postpartum)
- Progesterone level(3 weeks postpartum)
- Allopregnanolone level(3 weeks postpartum)
研究者
Vibe G Frøkjær, MD, PhD
Sponsor-investigator
Rigshospitalet, Denmark