The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder; Perinatal Depression
• Intervention / Treatment: Other: Pregnancy

Detailed Description

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)

Aims:

• Determine if depressive symptoms from late pregnancy to 6 months postpartum map onto molecular brain imaging markers of serotonin signaling early postpartum (week 3-5), and evaluate if such markers and/or symptoms are dependent on serotonin transporter genotype and/or predicted by candidate gene transcription biomarkers for estrogen sensitivity.
• Evaluate how markers of stress-regulation capacity, brain activity, brain structure (hippocampal volume) and central markers of neurotransmission are associated with the emergence of depressive symptoms in women postpartum.
• Map the association between serotonin-4 receptor binding and cerebrospinal fluid markers of serotonergic tone (serotonin and 5-hydroxyindolacetic acid levels).
• Determine if markers of mental distress in women during pregnancy and the postpartum period are associated with infant markers of stress-regulation and serotonergic signaling in placenta and umbilical cord blood.

Hypotheses:

• Women with high-expressing SERT genotypes are more sensitive to estradiol exposure in late pregnancy in terms of changes in proxies for serotonergic tone (PET imaging or csf based) and emergence of depressive symptoms in late pregnancy and/or postpartum and such an association will be stronger in the presence of candidate gene transcript PND biomarkers.
• CSF levels of 5-hydroxyindolacetic acid are associated with serotonin 4 receptor brain PET (Positron Emission Tomography) binding.

Study design:

150 pregnant women between 18-40 years of age who deliver by planned caesarean section, due to breech presentation of the fetus or previous caesarean section, will be included in a longitudinal study. Participants will be recruited at the midwife clinic of Rigshospitalet, Copenhagen, Denmark. Based on natural variation in European populations the expected distribution of high vs. low expressing SERT genotypes is 40/60, respectively, thus genotype status can be included in the analysis structure. Self-reported psychometrics and questionnaires will be collected online at inclusion, across the pre- to postpartum transition and up to 6 months postpartum (basic program: 2-5 days postpartum, 6 weeks postpartum and 6 months postpartum; imaging program: 2-5 days postpartum, 3-5 weeks postpartum, 12 weeks postpartum, 6 months postpartum). CSF will be collected as part of the anesthetic procedures for a planned caesarean section, thus avoiding any additional invasive procedures. CSF markers of serotonergic tone (serotonin and its main metabolite, 5-HIAA) will be measured by HPLC techniques. Corresponding blood samples for determining relevant biomarkers (sex-steroids, DNA, mRNA and microRNA) and saliva for hypothalamic-pituitary-adrenal axis dynamics, will be taken just before the planned caesarean section. Hair from mother and infant will be collected around delivery for further cortisol analyses. Placenta tissue and umbilical cord blood will also be collected for determining relevant markers of serotonergic and hypothalamic-pituitary-adrenal axis functioning.

A subgroup of the study cohort selected towards high (N=35) or low risk for later manifest PND (N=35), based on symptoms of mental distress 2-5 days postpartum (in-house interview, high-risk scores correspond to at least 12 on the Kennerley Maternity Blues Questionnaire and at least 8 on Stein's Maternity Blues Scale), will participate in an extended brain imaging program. This program will include 5-HT4R ([11C]SB207145) PET, structural MRI, functional MRI (including emotional processing, reward processing and resting state fMRI), neuropsychological testing and face to face rating of mental state with a semi-structured interview (HAM-D17).

The study includes long-term follow-up at six months. Collected data will enter the Center for Integrated Molecular Brain Imaging database, thus providing a basis for longitudinal follow-up, data sharing and crossvalidation.

Statistics:

Power calculations based on inter-subject variability of the 5-HT4R show that an imaging group size of 35 is required to detect a 15% difference with a power of 0.8 for the brain regions of interest. With the full cohort number of 150 and due to oversampling of high and low risk women, about 25 women are expected to develop manifest PND episodes and more will display subclinical depressive symptoms, which will allow for correlation analyses with relevant outcome parameters including the candidate gene transcript based biomarker of estrogen sensitivity.

Highly correlated self-reported psychometric outcomes will be included in a latent variable construct of self-reported mental state (composite measure) using structural equation modelling.

Ethics:

The PET scans convey no known risk for adults. Infants will not be exposed to radiation and will be nursed by special staff or a close relative while the mother is scanned. Participants who develop levels of mental distress or depressive symptoms that approach clinical thresholds will be referred to relevant and timely psychiatric care. The study has been approved by the local ethics committee.

• Study Type: Observational
• Enrollment (Actual): 100

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Participants will be recruited from the midwife clinic at Rigshospitalet, Copenhagen, i.e., included women will be residents of the central Copenhagen area.

Description

Inclusion Criteria:

• Age 18-40 years
• Healthy pregnant women planned to deliver by caesarean section due to breech position of the fetus or previous caesarean section.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Basic, non-imaging group; Pregnant women who will deliver by planned caesarian. Participants enrolled in the study that are not eligible for the imaging subgroup. All participants start in the basic program. Includes collection of blood, cerebrospinal fluid, saliva, hair, placenta tissues, umbilical cord blood and psychometrics.	Other: Pregnancy; Peripartum transition from pregnant to postpartum state
Extended, imaging group; A subgroup of 70 pregnant women who will deliver by planned caesarian selected towards either high (N=35) or low (N=35) risk for perinatal depression will undergo brain imaging in addition to the elements of the basic program. The extended imaging program includes functional and structural magnetic resonance imaging, positron emission tomography (PET) and a semistructured interview for depression symptoms (HAM-D17).	Other: Pregnancy; Peripartum transition from pregnant to postpartum state

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depressive symptoms	Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group	Week 3-6 postpartum
Depressive symptoms	Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group	Week 3-6 postpartum
Gene transcript and DNA methylation markers of estrogen sensitivity	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.	Prior to caesarean section
Cerebral serotonin 4 receptor binding 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.	Week 3-6 postpartum
CSF levels of GABA	Assessed in total group	On day of caesarean section
CSF levels of serotonin metabolite (5-HIAA)	Assessed in total group	On day of caesarean section
Cortisol awakening response	Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.	Week 3-6 postpartum
Hair cortisol level mothers	Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group	On day of caesarean section.
Hair cortisol level newborns	Provides an estimate of fetal cortisol exposure, infants from total group	Day 0-5 postpartum.
Hippocampal volumes	Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.	Week 3-6 postpartum.
functional MRI response to reward	fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli. Assessed in imaging cohort	Week 3-6 postpartum.
Resting state functional connectivity MRI	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.	Week 3-6 postpartum
Change in epigenetic SERT status	Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.	From just before delivery to 3-6 weeks postpartum
Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood	Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group	At week 3-6
functional MRI response to emotional faces	fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.	Week 3-6 postpartum.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depressive symptoms	Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group	Day 3-5 postpartum
Depressive symptoms	Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group	Week 12 postpartum
Depressive symptoms	Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in total group	Day 3-5 postpartum
Depressive symptoms	Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in all	6 months postpartum
CSF levels of serotonin	Assessed in total group	On day of caesarean section
CSF levels of dopamine metabolites	Assessed in total group	On day of caesarean section
CSF levels of noradrenaline metabolites	Assessed in total group	On day of caesarean section
CSF levels of inflammatory markers	Composite measure of IFN-c, IFN-alfa TNF-alfa og IL-6, in total group	On day of caesarean section
Estradiol level	Estradiol level in peripheral blood, total group	Prior to caesarean section.
Estradiol level	Estradiol level peripheral blood, total group	At week 3-6 postpartum.
Change in estradiol level	Estradiol change pre- to postpartum, peripheral blood total group	From baseline (caesarean section to week 3-6 postpartum)
Progesterone level	Progesterone level in peripheral blood	Prior to caesarean section.
Progesterone level	Progesterone level in peripheral blood	At week 3-6 postpartum.
Change in progesterone level	Progesterone change pre- to postpartum, peripheral blood total group	From baseline (caesarean section to week 3-6 postpartum)
Allopregnanolone level	Allopregnanolone level in peripheral blood	Prior to caesarean section.
Allopregnanolone level	Allopregnanolone level in peripheral blood	At week 3-6 postpartum.
Change in allopregnanolone level	Change in allopregnanolone level in peripheral blood	From baseline (caesarean section to week 3-6 postpartum)
Change in cortisol level	Cortisol change pre- to postpartum, peripheral blood total group	From baseline (caesarean section to week 3-6 postpartum)
Cortisol awakening response	Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.	Week 12 postpartum
Cortisol awakening response	Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.	Prior to caesarean section
Change in cortisol awakening response	Change in cortisol awakening response, from caesarean section to 3-6 weeks postpartum.	´From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the SERT gene	Methylation status for the SERT gene, total group	Prior to caesarean section
DNA methylation of the SERT gene	DNA Methylation status for the SERT gene, total group	Week 3-6 postpartum
DNA methylation of the FK506-binding protein 51 (FKBP5) gene	Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group	Prior to caesarean section.
DNA methylation of the FK506-binding protein 51 (FKBP5) gene	Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group	Week 3-6 postpartum
Change in DNA methylation of the FK506-binding protein 51 (FKBP5) gene	Change in methylation status for the FK506-binding protein 51 (FKBP5) gene from late pregnancy to postpartum week 3-6.	From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the glucocorticoid receptor gene	Methylation status for the glucocorticoid receptor gene, total group	Prior to caesarean section.
DNA methylation of the glucocorticoid receptor gene	Methylation status for the glucocorticoid receptor gene, total group	Week 3-6 postpartum
Change in DNA methylation of the glucocorticoid receptor gene	Change in methylation status for the glucocorticoid receptor gene from late pregnancy to postpartum week 3-6.	From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the COMT gene	Methylation status for the COMT gene, total group	Prior to caesarean section.
DNA methylation of the COMT gene	Methylation status for the COMT gene, total group	Week 3-6 postpartum
Change in DNA methylation of the COMT gene	Change in methylation status for the COMT gene from just before delivery to 3-6 weeks postpartum	From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the MAO-A gene	Methylation status for the MAO-A gene, total group	Prior to caesarean section.
Change in DNA methylation of the MAO-A gene	Change in methylation status for the MAO-A gene, total group	From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the MAO-A gene	Methylation status for the MAO-A gene, total group	Week 3-6 postpartum
DNA methylation of the oxytocin receptor gene	Methylation status for the oxytocin receptor gene, total group	Prior to caesarean section.
DNA methylation of the oxytocin receptor gene	Methylation status for the oxytocin receptor gene, total group	Week 3-6 postpartum
Change in DNA methylation of the oxytocin receptor gene	Change in methylation status for the oxytocin receptor gene, total group	From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the oxytocin gene	Methylation status for the oxytocin gene, total group	Prior to caesarean section.
DNA methylation of the oxytocin gene	Methylation status for the oxytocin gene, total group	Week 3-6 postpartum
Change in DNA methylation of the oxytocin gene	Change methylation status for the oxytocin gene, total group	From baseline (caesarean section to week 3-6 postpartum)
Systemic inflammation peripheral blood hsCRP and immunoactive cytokines	Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group	Prior to caesarean section.
Change in systemic inflammation peripheral blood hsCRP and immunoactive cytokines	Change in composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group	From baseline (caesarean section to week 3-6 postpartum
Self reported family history of mood disorders	Family History Assessment Module (OS-FHAM). Number of first degree relatives with a history of depressive episodes or bipolar disorder. Total group.	Day 3-5 postpartum or before
Self reported impulsiveness score	Barratt Impulsiveness Scale (BIS-11), self-reported. Range: 30-120. Total group.	Day 3-5 postpartum or before
Self reported Neuroticism score from NEO personality questionnaire	NEO-PI-R - Revised NEO Personality Inventory, self-reported. Participants may score 20-80 for each of the personality traits: openness, conscientiousness, extraversion, agreeableness, and neuroticism. The higher the score, the more prominent is the personality trait. Total group.	Day 3-5 postpartum or before
Self reported parental bonding quality	Parental bonding instrument (PBI), both parents, self-reported. Total group.	Day 3-5 postpartum or before
Self-reported perceived stress	Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.	Day 3-5 postpartum
Self-reported perceived stress	Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.	Week 3-6 postpartum
Change in self-reported perceived stress	Change in Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported anhedonia	Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.	Day 3-5 postpartum
Self-reported anhedonia	Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.	Week 3-6 postpartum
Change in self-reported anhedonia	Change in Snaith-Hamilton Pleasure Scale (SHAPS) score, range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported rumination	Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.	Day 3-5 postpartum
Self-reported rumination	Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.	Week 3-6 postpartum
Change in elf-reported rumination	Change in Rumination Response Scale (RRS) score, range 22-88, a score of 22 indicates no ruminative symptoms. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported mood	Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.	Day 3-5 postpartum
Self-reported mood	Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.	Week 3-6 postpartum
Change in self-reported mood	Change in Profile of Mood States (POMS) score, range 0-260, a score of 0 indicates no mood disturbance. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported sleep quality	Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.	Day 3-5 postpartum
Self-reported sleep quality	Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.	Week 3-6 postpartum
Change in self-reported sleep quality	Change in Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported psychiatric symptoms	Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.	Day 3-5 postpartum
Self-reported psychiatric symptoms	Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.	Week 3-6 postpartum
Change in self-reported psychiatric symptoms	Change in Brief symptom Inventory-53 item (BSI-53) score, range 0-212, increasing score means worsening of symptoms.Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported well-being	WHO-5 well-being index, range 0-100, low score means less well-being. Total group.	Day 3-5 postpartum
Self-reported well-being	WHO-5 well-being index, range 0-100, low score means less well-being. Total group.	Week 3-6 postpartum
Change in self-reported well-being	Change in WHO-5 well-being index, range 0-100, low score means less well-being. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported anxiety	State Trait Anxiety Inventory (STAI-AD-D), state and trait subscales each have a range of 20-80, 20 means no anxiety. Total group.	Day 3-5 postpartum
Self-reported anxiety	State Trait Anxiety Inventory (STAI-AD-D), state subscale range 20-80, 20 means no anxiety. Total group.	Week 3-6 postpartum
Change in self-reported anxiety	Change in State Trait Anxiety Inventory (STAI-AD-D) score, state subscale range 20-80, 20 means no anxiety. Total group.	Change from day 3-5 to week 3-6 postpartum
Self-reported obsessive and compulsive symptoms	Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.	Day 3-5
Self-reported obsessive and compulsive symptoms	Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.	Week 3-6 postpartum
Change in self-reported obsessive and compulsive symptoms	Change in Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.	Change from day 3-5 to week 3-6 postpartum
Performance on Simple Reaction Time	Performance on Simple Reaction Time, in imaging cohort.	Week 3-6 postpartum
Gray matter brain volume prefrontal cortex and anterior cingulate cortex	Gray matter brain volume prefrontal cortex and anterior cingulate cortex	At week 3-6 postpartum
Serotonergic turnover in placenta	Composite measure of serotonin, tryptophan og tryptofan hydroxylase levels relative to 5-HIAA, in placenta sample. Infants from total group	At delivery.
11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta	11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta. Infants from total group	At delivery
Methylation status of genes relevant for stress-hormone regulation in placenta	Composite measure of methylation status for the FKBP5, glucocorticoid receptor, 11-beta hydroxysteroid dehydrogenase type 2 genes. Infants from total group	At delivery
Methylation status of genes related to serotonergic signaling in placenta	Composite measure of the methylation status for monoamine oxidase, serotonin receptor and serotonin transporter genes. Infants from total group	At delivery
Methylation status and gene transcript profiles of relevance for early brain development and stress regulation in newborn infants	Composite measure of methylation status and gene transcript profiles of Glucocorticoid receptor, FKBP5, oxytocin and oxytocin receptors, Brain-derived neurotrophic factor (BDNF) genes. Assessed in blood from umbilical cord blood sample from infants, total group.	At delivery.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
COMT-genotype (rs4680) variant, i.e met/met vs other polymorphisms	val158met (rs4680) status, binary variable, i.e. "val/val, val/met" vs "met/met" variants	Prior to caesarean section.
BDNF genotype (rs6265) status, i.e. val/val versus met-carrier variants	BDNF val66met (rs6265) status, binary variable, i.e. "val/val" versus "met-carrier" status	Prior to caesarean section.
5-HTT genotype status, i.e LALA vs low-expressing (S or LG) variants	5-HTTLPR genotype status (binary), i.e. high-expressing LALA vs low-expressing (S or LG) variants, based on SLC6A4, i.e. L or S variants, and further subtyping on rs25531 haplotype L(A)L(A) vs LGLA, LGLG or variants containing as S as specified above.	Prior to caesarean section.
Postpartum blues symptoms	In house interview based on Kennerley Maternity Blues Questionnaire, range: 0-28, higher score indicates more severe postpartum blues symptoms. High blues score is associated with greater risk for perinatal depression at week 3-6.	Day 3-5 postpartum.
Postpartum blues symptoms	In house interview based on Stein's Maternity Blues Scale, range 0-26. High blues score is associated with greater risk for perinatal depression at week 3-6.	Day 3-5 postpartum.

Collaborators and Investigators

• Sponsor: Vibe G Frøkjær, MD, PhD
• Collaborators: University of Copenhagen; Mental Health Centre Copenhagen; Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak
• Investigators: Principal Investigator: Vibe Frokjaer, MD, PhD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Carpenter LL, Anderson GM, Siniscalchi JM, Chappell PB, Price LH. Acute changes in cerebrospinal fluid 5-HIAA following oral paroxetine challenge in healthy humans. Neuropsychopharmacology. 2003 Feb;28(2):339-47. doi: 10.1038/sj.npp.1300025.
• Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry. 2010 May;167(5):509-27. doi: 10.1176/appi.ajp.2010.09101452. Epub 2010 Mar 15.
• Guintivano J, Arad M, Gould TD, Payne JL, Kaminsky ZA. Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. Mol Psychiatry. 2014 May;19(5):560-7. doi: 10.1038/mp.2013.62. Epub 2013 May 21. Erratum In: Mol Psychiatry. 2014 May; 19(5):633.
• Haahr ME, Fisher PM, Jensen CG, Frokjaer VG, Mahon BM, Madsen K, Baare WF, Lehel S, Norremolle A, Rabiner EA, Knudsen GM. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study. Mol Psychiatry. 2014 Apr;19(4):427-32. doi: 10.1038/mp.2013.147. Epub 2013 Nov 5.
• Klengel T, Binder EB. Gene-environment interactions in major depressive disorder. Can J Psychiatry. 2013 Feb;58(2):76-83. doi: 10.1177/070674371305800203.
• Knudsen GM, Jensen PS, Erritzoe D, Baare WFC, Ettrup A, Fisher PM, Gillings N, Hansen HD, Hansen LK, Hasselbalch SG, Henningsson S, Herth MM, Holst KK, Iversen P, Kessing LV, Macoveanu J, Madsen KS, Mortensen EL, Nielsen FA, Paulson OB, Siebner HR, Stenbaek DS, Svarer C, Jernigan TL, Strother SC, Frokjaer VG. The Center for Integrated Molecular Brain Imaging (Cimbi) database. Neuroimage. 2016 Jan 1;124(Pt B):1213-1219. doi: 10.1016/j.neuroimage.2015.04.025. Epub 2015 Apr 17.
• Marner L, Gillings N, Madsen K, Erritzoe D, Baare WF, Svarer C, Hasselbalch SG, Knudsen GM. Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET. Neuroimage. 2010 Apr 15;50(3):855-61. doi: 10.1016/j.neuroimage.2010.01.054. Epub 2010 Jan 22.
• Mehta D, Newport DJ, Frishman G, Kraus L, Rex-Haffner M, Ritchie JC, Lori A, Knight BT, Stagnaro E, Ruepp A, Stowe ZN, Binder EB. Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling. Psychol Med. 2014 Aug;44(11):2309-22. doi: 10.1017/S0033291713003231. Epub 2014 Feb 5.
• Mehta D, Rex-Haffner M, Sondergaard HB, Pinborg A, Binder EB, Frokjaer VG. Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study. Br J Psychiatry. 2019 Sep;215(3):519-527. doi: 10.1192/bjp.2018.234.
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Study record dates

Study Major Dates

• Study Start (ACTUAL): January 24, 2019
• Primary Completion (ACTUAL): December 1, 2020
• Study Completion (ACTUAL): December 1, 2020

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: January 3, 2019
• First Posted (ACTUAL): January 8, 2019

Study Record Updates

• Last Update Posted (ACTUAL): December 17, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: PND1; H-18029563 (OTHER: Regional ethics committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage) data will be available for neuroscience research community contingent on approval by scientific board.
• IPD Sharing Time Frame: 2020-2035
• IPD Sharing Access Criteria: Approval by scientific board
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No