Major Depressive DisorderNCT03795688
The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health
An observational study of Major Depressive Disorder and Perinatal Depression, run by Vibe G Frøkjær, MD, PhD at 1 site in Denmark.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Major Depressive Disorder, Perinatal Depression
- What is being tested?
- Pregnancy
- How many people
- 100 participants
- Where
- 1 siteDenmark
- Study dates
- 24 Jan 2019to 1 Dec 2020
- How long will I take part?
- 6 Months
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- Healthy volunteers accepted
- Adult
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.
Who may be able to join
- Age 18-40 years
- Healthy pregnant women planned to deliver by caesarean section due to breech position of the fetus or previous caesarean section.
Who cannot join
- 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
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- MRI contraindications (claustrophobia, metal implants)
- Previous exposure to radioactivity > 10 millisievert (mSv) within the last year
- Alcohol or drug abuse
Trial locations and contacts
1 site in 1 country.
About this study
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).
Read more
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.
Read the 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.
- Conditions
- Major Depressive Disorder, Perinatal Depression
- Being tested
- Pregnancy
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PregnancyOther
Peripartum transition from pregnant to postpartum state
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Other: Pregnancy | |
| 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). Receives: Other: Pregnancy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Depressive symptoms
Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group
Measured: 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
Measured: 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.
Measured: 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.
Measured: Week 3-6 postpartum
CSF levels of GABA
Assessed in total group
Measured: On day of caesarean section
CSF levels of serotonin metabolite (5-HIAA)
Assessed in total group
Measured: 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.
Measured: Week 3-6 postpartum
Hair cortisol level mothers
Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group
Measured: On day of caesarean section.
Hair cortisol level newborns
Provides an estimate of fetal cortisol exposure, infants from total group
Measured: Day 0-5 postpartum.
Hippocampal volumes
Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.
Measured: 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
Measured: 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.
Measured: Week 3-6 postpartum
Change in epigenetic SERT status
Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.
Measured: 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
Measured: 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.
Measured: Week 3-6 postpartum.
Secondary outcomes (81)
Depressive symptoms
Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group
Measured: 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
Measured: 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
Measured: 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
Measured: 6 months postpartum
CSF levels of serotonin
Assessed in total group
Measured: On day of caesarean section
CSF levels of dopamine metabolites
Assessed in total group
Measured: On day of caesarean section
CSF levels of noradrenaline metabolites
Assessed in total group
Measured: 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
Measured: On day of caesarean section
Estradiol level
Estradiol level in peripheral blood, total group
Measured: Prior to caesarean section.
Estradiol level
Estradiol level peripheral blood, total group
Measured: At week 3-6 postpartum.
Change in estradiol level
Estradiol change pre- to postpartum, peripheral blood total group
Measured: From baseline (caesarean section to week 3-6 postpartum)
Progesterone level
Progesterone level in peripheral blood
Measured: Prior to caesarean section.
Progesterone level
Progesterone level in peripheral blood
Measured: At week 3-6 postpartum.
Change in progesterone level
Progesterone change pre- to postpartum, peripheral blood total group
Measured: From baseline (caesarean section to week 3-6 postpartum)
Allopregnanolone level
Allopregnanolone level in peripheral blood
Measured: Prior to caesarean section.
Allopregnanolone level
Allopregnanolone level in peripheral blood
Measured: At week 3-6 postpartum.
Change in allopregnanolone level
Change in allopregnanolone level in peripheral blood
Measured: From baseline (caesarean section to week 3-6 postpartum)
Change in cortisol level
Cortisol change pre- to postpartum, peripheral blood total group
Measured: 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.
Measured: Week 12 postpartum
Cortisol awakening response
Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.
Measured: Prior to caesarean section
Change in cortisol awakening response
Change in cortisol awakening response, from caesarean section to 3-6 weeks postpartum.
Measured: ´From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the SERT gene
Methylation status for the SERT gene, total group
Measured: Prior to caesarean section
DNA methylation of the SERT gene
DNA Methylation status for the SERT gene, total group
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: Prior to caesarean section.
DNA methylation of the glucocorticoid receptor gene
Methylation status for the glucocorticoid receptor gene, total group
Measured: 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.
Measured: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the COMT gene
Methylation status for the COMT gene, total group
Measured: Prior to caesarean section.
DNA methylation of the COMT gene
Methylation status for the COMT gene, total group
Measured: 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
Measured: 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
Measured: Prior to caesarean section.
Change in DNA methylation of the MAO-A gene
Change in methylation status for the MAO-A gene, total group
Measured: 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
Measured: Week 3-6 postpartum
DNA methylation of the oxytocin receptor gene
Methylation status for the oxytocin receptor gene, total group
Measured: Prior to caesarean section.
DNA methylation of the oxytocin receptor gene
Methylation status for the oxytocin receptor gene, total group
Measured: Week 3-6 postpartum
Change in DNA methylation of the oxytocin receptor gene
Change in methylation status for the oxytocin receptor gene, total group
Measured: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the oxytocin gene
Methylation status for the oxytocin gene, total group
Measured: Prior to caesarean section.
DNA methylation of the oxytocin gene
Methylation status for the oxytocin gene, total group
Measured: Week 3-6 postpartum
Change in DNA methylation of the oxytocin gene
Change methylation status for the oxytocin gene, total group
Measured: 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
Measured: 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
Measured: 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.
Measured: Day 3-5 postpartum or before
Self reported impulsiveness score
Barratt Impulsiveness Scale (BIS-11), self-reported. Range: 30-120. Total group.
Measured: 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.
Measured: Day 3-5 postpartum or before
Self reported parental bonding quality
Parental bonding instrument (PBI), both parents, self-reported. Total group.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 3-5 postpartum
Self-reported rumination
Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 3-5 postpartum
Self-reported well-being
WHO-5 well-being index, range 0-100, low score means less well-being. Total group.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Change from day 3-5 to week 3-6 postpartum
Performance on Simple Reaction Time
Performance on Simple Reaction Time, in imaging cohort.
Measured: Week 3-6 postpartum
Gray matter brain volume prefrontal cortex and anterior cingulate cortex
Gray matter brain volume prefrontal cortex and anterior cingulate cortex
Measured: 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
Measured: At delivery.
11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta
11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta. Infants from total group
Measured: 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
Measured: 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
Measured: 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.
Measured: At delivery.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jan 2019
- Study start24 Jan 2019
- Primary completion1 Dec 2020
- Study completion1 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 100 participants (actual)
- Target duration
- 6 Months
Sponsor and investigators
- Lead sponsor
- Vibe G Frøkjær, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak, Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital, University of Copenhagen
- Responsible party
- Sponsor-investigator, Vibe G Frøkjær, MD, PhD, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Vibe Frokjaer, MD, PhD, Principal investigator, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03795688
- Sponsor's protocol ID
- PND1
- Other IDs
- H-18029563
- Status last verified
- Dec 2020
- First submitted
- 18 Dec 2018
- Last updated
- 17 Dec 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
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.
PubMed 12589387Caspi 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.
PubMed 20231323Guintivano 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.
PubMed 23689534Haahr 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.
PubMed 24189342Klengel T, Binder EB. Gene-environment interactions in major depressive disorder. Can J Psychiatry. 2013 Feb;58(2):76-83. doi: 10.1177/070674371305800203.
PubMed 23442893Knudsen 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.
PubMed 25891375Marner 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.
PubMed 20096787Mehta 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.
PubMed 24495551Mehta 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.
PubMed 30457060Munk-Olsen T, Laursen TM, Pedersen CB, Mors O, Mortensen PB. New parents and mental disorders: a population-based register study. JAMA. 2006 Dec 6;296(21):2582-9. doi: 10.1001/jama.296.21.2582.
PubMed 17148723Sanjuan J, Martin-Santos R, Garcia-Esteve L, Carot JM, Guillamat R, Gutierrez-Zotes A, Gornemann I, Canellas F, Baca-Garcia E, Jover M, Navines R, Valles V, Vilella E, de Diego Y, Castro JA, Ivorra JL, Gelabert E, Guitart M, Labad A, Mayoral F, Roca M, Gratacos M, Costas J, van Os J, de Frutos R. Mood changes after delivery: role of the serotonin transporter gene. Br J Psychiatry. 2008 Nov;193(5):383-8. doi: 10.1192/bjp.bp.107.045427.
PubMed 18978318
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health
- ClinicalTrials.gov ID
- NCT03795688
- Acronym / sponsor ID
- PND1
- Conditions
- Major Depressive Disorder, Perinatal Depression
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 100 participants (actual)
- Lead sponsor
- Vibe G Frøkjær, MD, PhDUniversity, hospital or other
- Collaborators
- Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak, Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital, University of Copenhagen
- Study start
- 24 Jan 2019 (actual)
- Primary completion
- 1 Dec 2020 (actual)
- Study completion
- 1 Dec 2020 (actual)
- First posted
- 8 Jan 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 6 Months
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Basic, non-imaging group | – | Other: PregnancyPregnant 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. |
| Extended, imaging group | – | Other: PregnancyA 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). |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
- 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.
Key inclusion criteria (2 listed)
- Age 18-40 years
- Healthy pregnant women planned to deliver by caesarean section due to breech position of the fetus or previous caesarean section.
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PregnancyPeripartum transition from pregnant to postpartum state | Other | Basic, non-imaging group, Extended, imaging group |
Primary outcome
Depressive symptoms
Time frame: Week 3-6 postpartum
Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group
Depressive symptoms
Time frame: 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
Time frame: 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
Time frame: 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.
CSF levels of GABA
Time frame: On day of caesarean section
Assessed in total group
CSF levels of serotonin metabolite (5-HIAA)
Time frame: On day of caesarean section
Assessed in total group
Cortisol awakening response
Time frame: 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 mothers
Time frame: On day of caesarean section.
Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group
Hair cortisol level newborns
Time frame: Day 0-5 postpartum.
Provides an estimate of fetal cortisol exposure, infants from total group
Hippocampal volumes
Time frame: Week 3-6 postpartum.
Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.
functional MRI response to reward
Time frame: 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
Time frame: 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.
Change in epigenetic SERT status
Time frame: From just before delivery to 3-6 weeks postpartum
Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.
Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood
Time frame: At week 3-6
Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group
functional MRI response to emotional faces
Time frame: Week 3-6 postpartum.
fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.
81 secondary outcomes
Depressive symptoms
Time frame: Day 3-5 postpartum
Depressive symptoms
Time frame: Week 12 postpartum
Depressive symptoms
Time frame: Day 3-5 postpartum
Depressive symptoms
Time frame: 6 months postpartum
CSF levels of serotonin
Time frame: On day of caesarean section
CSF levels of dopamine metabolites
Time frame: On day of caesarean section
CSF levels of noradrenaline metabolites
Time frame: On day of caesarean section
CSF levels of inflammatory markers
Time frame: On day of caesarean section
Estradiol level
Time frame: Prior to caesarean section.
Estradiol level
Time frame: At week 3-6 postpartum.
Change in estradiol level
Time frame: From baseline (caesarean section to week 3-6 postpartum)
Progesterone level
Time frame: Prior to caesarean section.
Progesterone level
Time frame: At week 3-6 postpartum.
Change in progesterone level
Time frame: From baseline (caesarean section to week 3-6 postpartum)
Allopregnanolone level
Time frame: Prior to caesarean section.
Allopregnanolone level
Time frame: At week 3-6 postpartum.
Change in allopregnanolone level
Time frame: From baseline (caesarean section to week 3-6 postpartum)
Change in cortisol level
Time frame: From baseline (caesarean section to week 3-6 postpartum)
Cortisol awakening response
Time frame: Week 12 postpartum
Cortisol awakening response
Time frame: Prior to caesarean section
Change in cortisol awakening response
Time frame: ´From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the SERT gene
Time frame: Prior to caesarean section
DNA methylation of the SERT gene
Time frame: Week 3-6 postpartum
DNA methylation of the FK506-binding protein 51 (FKBP5) gene
Time frame: Prior to caesarean section.
DNA methylation of the FK506-binding protein 51 (FKBP5) gene
Time frame: Week 3-6 postpartum
Change in DNA methylation of the FK506-binding protein 51 (FKBP5) gene
Time frame: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the glucocorticoid receptor gene
Time frame: Prior to caesarean section.
DNA methylation of the glucocorticoid receptor gene
Time frame: Week 3-6 postpartum
Change in DNA methylation of the glucocorticoid receptor gene
Time frame: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the COMT gene
Time frame: Prior to caesarean section.
DNA methylation of the COMT gene
Time frame: Week 3-6 postpartum
Change in DNA methylation of the COMT gene
Time frame: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the MAO-A gene
Time frame: Prior to caesarean section.
Change in DNA methylation of the MAO-A gene
Time frame: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the MAO-A gene
Time frame: Week 3-6 postpartum
DNA methylation of the oxytocin receptor gene
Time frame: Prior to caesarean section.
DNA methylation of the oxytocin receptor gene
Time frame: Week 3-6 postpartum
Change in DNA methylation of the oxytocin receptor gene
Time frame: From baseline (caesarean section to week 3-6 postpartum)
DNA methylation of the oxytocin gene
Time frame: Prior to caesarean section.
DNA methylation of the oxytocin gene
Time frame: Week 3-6 postpartum
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2020.
- Background: PubMed 12589387Carpenter 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.
- Background: PubMed 20231323Caspi 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.
- Background: PubMed 23689534Guintivano 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.
- Background: PubMed 24189342Haahr 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.
- Background: PubMed 23442893Klengel T, Binder EB. Gene-environment interactions in major depressive disorder. Can J Psychiatry. 2013 Feb;58(2):76-83. doi: 10.1177/070674371305800203.
- Background: PubMed 25891375Knudsen 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.
- Background: PubMed 20096787Marner 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.
- Background: PubMed 24495551Mehta 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.
- Background: PubMed 30457060Mehta 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.
- Background: PubMed 17148723Munk-Olsen T, Laursen TM, Pedersen CB, Mors O, Mortensen PB. New parents and mental disorders: a population-based register study. JAMA. 2006 Dec 6;296(21):2582-9. doi: 10.1001/jama.296.21.2582.
- Background: PubMed 18978318Sanjuan J, Martin-Santos R, Garcia-Esteve L, Carot JM, Guillamat R, Gutierrez-Zotes A, Gornemann I, Canellas F, Baca-Garcia E, Jover M, Navines R, Valles V, Vilella E, de Diego Y, Castro JA, Ivorra JL, Gelabert E, Guitart M, Labad A, Mayoral F, Roca M, Gratacos M, Costas J, van Os J, de Frutos R. Mood changes after delivery: role of the serotonin transporter gene. Br J Psychiatry. 2008 Nov;193(5):383-8. doi: 10.1192/bjp.bp.107.045427.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vibe Frokjaer, MD, PhD principal investigator
Copenhagen University Hospital, Rigshospitalet
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Major Depressive Disorder and Perinatal Depression, run by Vibe G Frøkjær, MD, PhD at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Depressive symptoms (time frame: Week 3-6 postpartum). The study lists 15 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03795688, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2020.