The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Cortisol awakening response
研究概览
简要总结
Hormonal transitions such as across pregnancy and postpartum may trigger depressive episodes in some women. It is not known why, but estrogen sensitivity may play a critical role. A preclinical human risk model showed that depressive symptoms induced by pharmacological sex-hormone manipulation is linked to increases in serotonin transporter (SERT) brain binding, which lowers serotonergic brain tone. It is currently unknown if these findings translates to women across pre- to postpartum transitions.
This longitudinal project studies a group of women who will deliver by planned caesarian, thus permitting the collection of cerebrospinal fluid (csf) containing central markers of serotonergic signaling, at the latest point in pregnancy. The women are followed across late pregnancy, delivery and 6 months postpartum to illuminate relations between sex-hormones, stress-regulation, estradiol sensitivity, csf markers of neurotransmission, serotonin transporter genotype variance, and potential development of subclinical or manifest depressive symptoms. Further, markers of relevance for the infant brain development and stress-regulation will be obtained from placenta tissue and umbilical cord blood. A subgroup of 70 women will participate in a brain imaging program early postpartum (week 3-5), which includes an evaluation of brain activity and structure and in vivo molecular brain imaging serotonergic markers. Thus, serotonergic markers in csf can be combined with postpartum molecular brain imaging of key features of serotonin signaling. Women in the imaging program are selected based on variation in their level of mental distress immediately postpartum (day 2-5).
The study's main hypothesis is that women with high-expressing SERT genotypes are more sensitive to peripartum hormonal transition in terms of changes in serotonergic tone and emergence of depressive symptoms and that such an association will be stronger in the presence of candidate gene transcript biomarkers of oestrogen sensitivity. A further hypothesis is that in vivo molecular brain imaging and csf based serotonergic markers will be associated with depressive symptoms both early and later postpartum.
Ideally, this project will provide a rationale for future targeted prevention and/or treatment of perinatal depression in women at high risk, which holds grand potential to protect not only mother but also infant brain health long-term.
详细描述
Motivation:
Major depressive disorder (MDD) affects twice as many women as men and women are at an increased risk during hormonal transition phases such as pregnancy and birth. A highly relevant subpopulation within the mixed MDD diagnostic category comprises women who develop perinatal depression (PND). PND is defined as a depressive episode with onset during pregnancy or up to 4 weeks postpartum, however epidemiological studies show that the risk of developing depression is heightened for 6 months postpartum. PND affects 10-15% of mothers postpartum. Why certain women are at high risk of developing perinatal depression (PND) remains unclear but recent studies suggest that these women might be particularly sensitive to the transition from high levels of placenta-produced sex-steroids in pregnancy to the hormone withdrawal phase postpartum. Further, pharmacologically induced changes in ovarian sex-hormones can produce depressive symptoms in a subgroup of otherwise healthy women and that the emergence of depressive symptoms is linked to both estrogen fluctuations and increases in serotonin transporter (SERT) brain binding (which putatively lowers serotonergic brain tone). Intriguingly, common gene variants that index SERT expression levels show "gene BY environment" associations with risk for depression, such that high-expressing SERT genotypes render women more vulnerable to depressive symptoms early - but not late - postpartum in a "gene-dose" dependent manner. Further, DNA methylation and gene expression markers of estradiol sensitivity predispose to PND and are linked to the estradiol stimulation phase in the pharmacological manipulation of sex-steroids risk model, thus constituting a candidate biomarker for PND.
It is currently unknown if estradiol sensitivity during pregnancy confers to PND risk through mechanism that (transiently) affect serotonergic tone in susceptible women. Changes in brain function late in pregnancy may extend to the early postpartum and shape how the brain integrates additional neurobiological changes that are associated with the postpartum hormonal withdrawal phase. This study will examine these mechanisms in a group of pregnant women that are followed from late pregnancy across early to late postpartum up to 6 month.
Natural variation in SERT-genotypes provides a unique opportunity to specifically address the interaction between SERT-gene expression-capacity and estradiol exposure through pregnancy in processes driving changes in serotonergic tone, brain structure and activity, and mental health from late pregnancy to 6 months postpartum. The time-points comprise: basic program: 2-5 days postpartum, 6 weeks postpartum and 6 months postpartum for all participants and for the imaging program participants: 2-5 days postpartum, 3-5 weeks postpartum, 12 weeks postpartum, 6 months postpartum.
By including women who undergo planned caesarean section, cerebrospinal fluid (CSF) can be obtained and thus, for the first time combine CSF markers of serotonergic tone and other transmitter systems (serotonin, 5-hydroxyindolacetic acid, other monoamines, γ-aminobutyric acid) with molecular brain imaging methods that index serotonergic tone (i.e. serotonin 4 receptor binding)
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Age 18-40 years
- •Healthy pregnant women planned to deliver by caesarean section due to breech position of the fetus or previous caesarean section.
排除标准
- •Current or previous severe psychiatric disorder such as psychotic disorders, eating disorder and bipolar disorder or current or previous psychiatric disorder requiring hospitalization.
- •Current or previous neurological diseases, severe somatic disease, severe postpartum hemorrhage or use of medication that can interfere with study outcomes
- •Severe disease or malformations in infants
- •Obesity or underweight (pre-gestational BMI below 18 or above 35)
- •Not fluent in Danish or severe visual or hearing impairments
- •Earlier or present learning disabilities
- •MRI contraindications (claustrophobia, metal implants)
- •Previous exposure to radioactivity > 10 millisievert (mSv) within the last year
- •Alcohol or drug abuse
结局指标
主要结局
Cortisol awakening response
时间窗: Week 3-6 postpartum
Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.
Hair cortisol level newborns
时间窗: Day 0-5 postpartum.
Provides an estimate of fetal cortisol exposure, infants from total group
Depressive symptoms
时间窗: Week 3-6 postpartum
Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group
Gene transcript and DNA methylation markers of estrogen sensitivity
时间窗: Prior to caesarean section
116 a priori defined gene transcripts, which where differentially expressed in third trimester of women who later developed perinatal depression with postpartum onset relative to pregnant women who did not and to other depressed (reference Mehta et al, 2014, Psychological Medicine) and confirmed to be coupled to estrogen fluctuations (Mehtaet al. 2018 British Journal of Psychiatry) will be evaluated in the total group. Also DNA methylation of the genes of these transcripts will be determined and analysed in terms of their predictive value (above chance) for perinatal depression.
Cerebral serotonin 4 receptor binding postpartum
时间窗: Week 3-6 postpartum
Latent variable construct of brain 5-HT4R level based on quantification of 5-HT4R binding from 11C-SB207145 positron emission tomography in primary volumes of interest; neocortex, nucleus caudatus, putamen and hippocampus. Assessed in imaging group.
Hair cortisol level mothers
时间窗: On day of caesarean section.
Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group
Hippocampal volumes
时间窗: Week 3-6 postpartum.
Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.
functional MRI response to reward
时间窗: Week 3-6 postpartum.
fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli. Assessed in imaging cohort
Resting state functional connectivity MRI
时间窗: Week 3-6 postpartum
rsfMRI based spontaneous co-fluctuations in low frequency BOLD signal, (functional connectivity). Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake. Assessed in imaging group.
Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood
时间窗: At week 3-6
Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group
CSF levels of GABA
时间窗: On day of caesarean section
Assessed in total group
CSF levels of serotonin metabolite (5-HIAA)
时间窗: On day of caesarean section
Assessed in total group
Change in epigenetic SERT status
时间窗: From just before delivery to 3-6 weeks postpartum
Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.
functional MRI response to emotional faces
时间窗: Week 3-6 postpartum.
fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.
次要结局
- Cortisol awakening response(Prior to caesarean section)
- CSF levels of inflammatory markers(On day of caesarean section)
- Progesterone level(At week 3-6 postpartum.)
- Allopregnanolone level(At week 3-6 postpartum.)
- Estradiol level(At week 3-6 postpartum.)
- Change in DNA methylation of the MAO-A gene(From baseline (caesarean section to week 3-6 postpartum))
- Change in DNA methylation of the oxytocin receptor gene(From baseline (caesarean section to week 3-6 postpartum))
- DNA methylation of the FK506-binding protein 51 (FKBP5) gene(Week 3-6 postpartum)
- CSF levels of serotonin(On day of caesarean section)
- Change in estradiol level(From baseline (caesarean section to week 3-6 postpartum))
- Change in progesterone level(From baseline (caesarean section to week 3-6 postpartum))
- Change in allopregnanolone level(From baseline (caesarean section to week 3-6 postpartum))
- Change in cortisol awakening response(´From baseline (caesarean section to week 3-6 postpartum))
- DNA methylation of the SERT gene(Week 3-6 postpartum)
- Change in DNA methylation of the glucocorticoid receptor gene(From baseline (caesarean section to week 3-6 postpartum))
- Change in DNA methylation of the COMT gene(From baseline (caesarean section to week 3-6 postpartum))
- Change in DNA methylation of the oxytocin gene(From baseline (caesarean section to week 3-6 postpartum))
- Depressive symptoms(6 months postpartum)
- CSF levels of dopamine metabolites(On day of caesarean section)
- CSF levels of noradrenaline metabolites(On day of caesarean section)
- Change in cortisol level(From baseline (caesarean section to week 3-6 postpartum))
- Self reported impulsiveness score(Day 3-5 postpartum or before)
- Self-reported well-being(Week 3-6 postpartum)
- Change in self-reported obsessive and compulsive symptoms(Change from day 3-5 to week 3-6 postpartum)
- DNA methylation of the glucocorticoid receptor gene(Week 3-6 postpartum)
- DNA methylation of the COMT gene(Week 3-6 postpartum)
- Systemic inflammation peripheral blood hsCRP and immunoactive cytokines(Prior to caesarean section.)
- Self reported Neuroticism score from NEO personality questionnaire(Day 3-5 postpartum or before)
- Change in self-reported perceived stress(Change from day 3-5 to week 3-6 postpartum)
- Change in self-reported sleep quality(Change from day 3-5 to week 3-6 postpartum)
- Self-reported anxiety(Week 3-6 postpartum)
- Change in self-reported anxiety(Change from day 3-5 to week 3-6 postpartum)
- 11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta(At delivery)
- Methylation status of genes related to serotonergic signaling in placenta(At delivery)
- Change in DNA methylation of the FK506-binding protein 51 (FKBP5) gene(From baseline (caesarean section to week 3-6 postpartum))
- DNA methylation of the MAO-A gene(Week 3-6 postpartum)
- DNA methylation of the oxytocin receptor gene(Week 3-6 postpartum)
- Change in systemic inflammation peripheral blood hsCRP and immunoactive cytokines(From baseline (caesarean section to week 3-6 postpartum)
- Self reported parental bonding quality(Day 3-5 postpartum or before)
- Change in elf-reported rumination(Change from day 3-5 to week 3-6 postpartum)
- Self-reported psychiatric symptoms(Week 3-6 postpartum)
- Change in self-reported well-being(Change from day 3-5 to week 3-6 postpartum)
- Self-reported obsessive and compulsive symptoms(Week 3-6 postpartum)
- Performance on Simple Reaction Time(Week 3-6 postpartum)
- Serotonergic turnover in placenta(At delivery.)
- DNA methylation of the oxytocin gene(Week 3-6 postpartum)
- Change in self-reported anhedonia(Change from day 3-5 to week 3-6 postpartum)
- Self-reported rumination(Week 3-6 postpartum)
- Methylation status of genes relevant for stress-hormone regulation in placenta(At delivery)
- Methylation status and gene transcript profiles of relevance for early brain development and stress regulation in newborn infants(At delivery.)
- Self reported family history of mood disorders(Day 3-5 postpartum or before)
- Self-reported perceived stress(Week 3-6 postpartum)
- Self-reported anhedonia(Week 3-6 postpartum)
- Self-reported mood(Week 3-6 postpartum)
- Change in self-reported mood(Change from day 3-5 to week 3-6 postpartum)
- Self-reported sleep quality(Week 3-6 postpartum)
- Change in self-reported psychiatric symptoms(Change from day 3-5 to week 3-6 postpartum)
- Gray matter brain volume prefrontal cortex and anterior cingulate cortex(At week 3-6 postpartum)
研究者
Vibe G Frøkjær, MD, PhD
Senior researcher, Principal investigator
Rigshospitalet, Denmark