<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03795688</url>
  </required_header>
  <id_info>
    <org_study_id>PND1</org_study_id>
    <secondary_id>H-18029563</secondary_id>
    <nct_id>NCT03795688</nct_id>
  </id_info>
  <brief_title>The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health</brief_title>
  <official_title>The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vibe G Frøkjær, MD, PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mental Health Centre Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hormonal transitions such as across pregnancy and postpartum may trigger depressive episodes&#xD;
      in some women. It is not known why, but estrogen sensitivity may play a critical role. A&#xD;
      preclinical human risk model showed that depressive symptoms induced by pharmacological&#xD;
      sex-hormone manipulation is linked to increases in serotonin transporter (SERT) brain&#xD;
      binding, which lowers serotonergic brain tone. It is currently unknown if these findings&#xD;
      translates to women across pre- to postpartum transitions.&#xD;
&#xD;
      This longitudinal project studies a group of women who will deliver by planned caesarian,&#xD;
      thus permitting the collection of cerebrospinal fluid (csf) containing central markers of&#xD;
      serotonergic signaling, at the latest point in pregnancy. The women are followed across late&#xD;
      pregnancy, delivery and 6 months postpartum to illuminate relations between sex-hormones,&#xD;
      stress-regulation, estradiol sensitivity, csf markers of neurotransmission, serotonin&#xD;
      transporter genotype variance, and potential development of subclinical or manifest&#xD;
      depressive symptoms. Further, markers of relevance for the infant brain development and&#xD;
      stress-regulation will be obtained from placenta tissue and umbilical cord blood. A subgroup&#xD;
      of 70 women will participate in a brain imaging program early postpartum (week 3-5), which&#xD;
      includes an evaluation of brain activity and structure and in vivo molecular brain imaging&#xD;
      serotonergic markers. Thus, serotonergic markers in csf can be combined with postpartum&#xD;
      molecular brain imaging of key features of serotonin signaling. Women in the imaging program&#xD;
      are selected based on variation in their level of mental distress immediately postpartum (day&#xD;
      2-5).&#xD;
&#xD;
      The study's main hypothesis is that women with high-expressing SERT genotypes are more&#xD;
      sensitive to peripartum hormonal transition in terms of changes in serotonergic tone and&#xD;
      emergence of depressive symptoms and that such an association will be stronger in the&#xD;
      presence of candidate gene transcript biomarkers of oestrogen sensitivity. A further&#xD;
      hypothesis is that in vivo molecular brain imaging and csf based serotonergic markers will be&#xD;
      associated with depressive symptoms both early and later postpartum.&#xD;
&#xD;
      Ideally, this project will provide a rationale for future targeted prevention and/or&#xD;
      treatment of perinatal depression in women at high risk, which holds grand potential to&#xD;
      protect not only mother but also infant brain health long-term.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Motivation:&#xD;
&#xD;
      Major depressive disorder (MDD) affects twice as many women as men and women are at an&#xD;
      increased risk during hormonal transition phases such as pregnancy and birth. A highly&#xD;
      relevant subpopulation within the mixed MDD diagnostic category comprises women who develop&#xD;
      perinatal depression (PND). PND is defined as a depressive episode with onset during&#xD;
      pregnancy or up to 4 weeks postpartum, however epidemiological studies show that the risk of&#xD;
      developing depression is heightened for 6 months postpartum. PND affects 10-15% of mothers&#xD;
      postpartum. Why certain women are at high risk of developing perinatal depression (PND)&#xD;
      remains unclear but recent studies suggest that these women might be particularly sensitive&#xD;
      to the transition from high levels of placenta-produced sex-steroids in pregnancy to the&#xD;
      hormone withdrawal phase postpartum. Further, pharmacologically induced changes in ovarian&#xD;
      sex-hormones can produce depressive symptoms in a subgroup of otherwise healthy women and&#xD;
      that the emergence of depressive symptoms is linked to both estrogen fluctuations and&#xD;
      increases in serotonin transporter (SERT) brain binding (which putatively lowers serotonergic&#xD;
      brain tone). Intriguingly, common gene variants that index SERT expression levels show &quot;gene&#xD;
      BY environment&quot; associations with risk for depression, such that high-expressing SERT&#xD;
      genotypes render women more vulnerable to depressive symptoms early - but not late -&#xD;
      postpartum in a &quot;gene-dose&quot; dependent manner. Further, DNA methylation and gene expression&#xD;
      markers of estradiol sensitivity predispose to PND and are linked to the estradiol&#xD;
      stimulation phase in the pharmacological manipulation of sex-steroids risk model, thus&#xD;
      constituting a candidate biomarker for PND.&#xD;
&#xD;
      It is currently unknown if estradiol sensitivity during pregnancy confers to PND risk through&#xD;
      mechanism that (transiently) affect serotonergic tone in susceptible women. Changes in brain&#xD;
      function late in pregnancy may extend to the early postpartum and shape how the brain&#xD;
      integrates additional neurobiological changes that are associated with the postpartum&#xD;
      hormonal withdrawal phase. This study will examine these mechanisms in a group of pregnant&#xD;
      women that are followed from late pregnancy across early to late postpartum up to 6 month.&#xD;
&#xD;
      Natural variation in SERT-genotypes provides a unique opportunity to specifically address the&#xD;
      interaction between SERT-gene expression-capacity and estradiol exposure through pregnancy in&#xD;
      processes driving changes in serotonergic tone, brain structure and activity, and mental&#xD;
      health from late pregnancy to 6 months postpartum. The time-points comprise: basic program:&#xD;
      2-5 days postpartum, 6 weeks postpartum and 6 months postpartum for all participants and for&#xD;
      the imaging program participants: 2-5 days postpartum, 3-5 weeks postpartum, 12 weeks&#xD;
      postpartum, 6 months postpartum.&#xD;
&#xD;
      By including women who undergo planned caesarean section, cerebrospinal fluid (CSF) can be&#xD;
      obtained and thus, for the first time combine CSF markers of serotonergic tone and other&#xD;
      transmitter systems (serotonin, 5-hydroxyindolacetic acid, other monoamines, γ-aminobutyric&#xD;
      acid) with molecular brain imaging methods that index serotonergic tone (i.e. serotonin 4&#xD;
      receptor binding)&#xD;
&#xD;
      Aims:&#xD;
&#xD;
        -  Determine if depressive symptoms from late pregnancy to 6 months postpartum map onto&#xD;
           molecular brain imaging markers of serotonin signaling early postpartum (week 3-5), and&#xD;
           evaluate if such markers and/or symptoms are dependent on serotonin transporter genotype&#xD;
           and/or predicted by candidate gene transcription biomarkers for estrogen sensitivity.&#xD;
&#xD;
        -  Evaluate how markers of stress-regulation capacity, brain activity, brain structure&#xD;
           (hippocampal volume) and central markers of neurotransmission are associated with the&#xD;
           emergence of depressive symptoms in women postpartum.&#xD;
&#xD;
        -  Map the association between serotonin-4 receptor binding and cerebrospinal fluid markers&#xD;
           of serotonergic tone (serotonin and 5-hydroxyindolacetic acid levels).&#xD;
&#xD;
        -  Determine if markers of mental distress in women during pregnancy and the postpartum&#xD;
           period are associated with infant markers of stress-regulation and serotonergic&#xD;
           signaling in placenta and umbilical cord blood.&#xD;
&#xD;
      Hypotheses:&#xD;
&#xD;
        -  Women with high-expressing SERT genotypes are more sensitive to estradiol exposure in&#xD;
           late pregnancy in terms of changes in proxies for serotonergic tone (PET imaging or csf&#xD;
           based) and emergence of depressive symptoms in late pregnancy and/or postpartum and such&#xD;
           an association will be stronger in the presence of candidate gene transcript PND&#xD;
           biomarkers.&#xD;
&#xD;
        -  CSF levels of 5-hydroxyindolacetic acid are associated with serotonin 4 receptor brain&#xD;
           PET (Positron Emission Tomography) binding.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      150 pregnant women between 18-40 years of age who deliver by planned caesarean section, due&#xD;
      to breech presentation of the fetus or previous caesarean section, will be included in a&#xD;
      longitudinal study. Participants will be recruited at the midwife clinic of Rigshospitalet,&#xD;
      Copenhagen, Denmark. Based on natural variation in European populations the expected&#xD;
      distribution of high vs. low expressing SERT genotypes is 40/60, respectively, thus genotype&#xD;
      status can be included in the analysis structure. Self-reported psychometrics and&#xD;
      questionnaires will be collected online at inclusion, across the pre- to postpartum&#xD;
      transition and up to 6 months postpartum (basic program: 2-5 days postpartum, 6 weeks&#xD;
      postpartum and 6 months postpartum; imaging program: 2-5 days postpartum, 3-5 weeks&#xD;
      postpartum, 12 weeks postpartum, 6 months postpartum). CSF will be collected as part of the&#xD;
      anesthetic procedures for a planned caesarean section, thus avoiding any additional invasive&#xD;
      procedures. CSF markers of serotonergic tone (serotonin and its main metabolite, 5-HIAA) will&#xD;
      be measured by HPLC techniques. Corresponding blood samples for determining relevant&#xD;
      biomarkers (sex-steroids, DNA, mRNA and microRNA) and saliva for&#xD;
      hypothalamic-pituitary-adrenal axis dynamics, will be taken just before the planned caesarean&#xD;
      section. Hair from mother and infant will be collected around delivery for further cortisol&#xD;
      analyses. Placenta tissue and umbilical cord blood will also be collected for determining&#xD;
      relevant markers of serotonergic and hypothalamic-pituitary-adrenal axis functioning.&#xD;
&#xD;
      A subgroup of the study cohort selected towards high (N=35) or low risk for later manifest&#xD;
      PND (N=35), based on symptoms of mental distress 2-5 days postpartum (in-house interview,&#xD;
      high-risk scores correspond to at least 12 on the Kennerley Maternity Blues Questionnaire and&#xD;
      at least 8 on Stein's Maternity Blues Scale), will participate in an extended brain imaging&#xD;
      program. This program will include 5-HT4R ([11C]SB207145) PET, structural MRI, functional MRI&#xD;
      (including emotional processing, reward processing and resting state fMRI),&#xD;
      neuropsychological testing and face to face rating of mental state with a semi-structured&#xD;
      interview (HAM-D17).&#xD;
&#xD;
      The study includes long-term follow-up at six months. Collected data will enter the Center&#xD;
      for Integrated Molecular Brain Imaging database, thus providing a basis for longitudinal&#xD;
      follow-up, data sharing and crossvalidation.&#xD;
&#xD;
      Statistics:&#xD;
&#xD;
      Power calculations based on inter-subject variability of the 5-HT4R show that an imaging&#xD;
      group size of 35 is required to detect a 15% difference with a power of 0.8 for the brain&#xD;
      regions of interest. With the full cohort number of 150 and due to oversampling of high and&#xD;
      low risk women, about 25 women are expected to develop manifest PND episodes and more will&#xD;
      display subclinical depressive symptoms, which will allow for correlation analyses with&#xD;
      relevant outcome parameters including the candidate gene transcript based biomarker of&#xD;
      estrogen sensitivity.&#xD;
&#xD;
      Highly correlated self-reported psychometric outcomes will be included in a latent variable&#xD;
      construct of self-reported mental state (composite measure) using structural equation&#xD;
      modelling.&#xD;
&#xD;
      Ethics:&#xD;
&#xD;
      The PET scans convey no known risk for adults. Infants will not be exposed to radiation and&#xD;
      will be nursed by special staff or a close relative while the mother is scanned. Participants&#xD;
      who develop levels of mental distress or depressive symptoms that approach clinical&#xD;
      thresholds will be referred to relevant and timely psychiatric care. The study has been&#xD;
      approved by the local ethics committee.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 24, 2019</start_date>
  <completion_date type="Actual">December 1, 2020</completion_date>
  <primary_completion_date type="Actual">December 1, 2020</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>6 Months</target_duration>
  <primary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Gene transcript and DNA methylation markers of estrogen sensitivity</measure>
    <time_frame>Prior to caesarean section</time_frame>
    <description>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.&#xD;
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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cerebral serotonin 4 receptor binding postpartum</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>CSF levels of GABA</measure>
    <time_frame>On day of caesarean section</time_frame>
    <description>Assessed in total group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>CSF levels of serotonin metabolite (5-HIAA)</measure>
    <time_frame>On day of caesarean section</time_frame>
    <description>Assessed in total group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cortisol awakening response</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hair cortisol level mothers</measure>
    <time_frame>On day of caesarean section.</time_frame>
    <description>Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hair cortisol level newborns</measure>
    <time_frame>Day 0-5 postpartum.</time_frame>
    <description>Provides an estimate of fetal cortisol exposure, infants from total group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hippocampal volumes</measure>
    <time_frame>Week 3-6 postpartum.</time_frame>
    <description>Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>functional MRI response to reward</measure>
    <time_frame>Week 3-6 postpartum.</time_frame>
    <description>fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli. Assessed in imaging cohort</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Resting state functional connectivity MRI</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in epigenetic SERT status</measure>
    <time_frame>From just before delivery to 3-6 weeks postpartum</time_frame>
    <description>Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood</measure>
    <time_frame>At week 3-6</time_frame>
    <description>Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>functional MRI response to emotional faces</measure>
    <time_frame>Week 3-6 postpartum.</time_frame>
    <description>fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>Week 12 postpartum</time_frame>
    <description>Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>6 months postpartum</time_frame>
    <description>Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in all</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF levels of serotonin</measure>
    <time_frame>On day of caesarean section</time_frame>
    <description>Assessed in total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF levels of dopamine metabolites</measure>
    <time_frame>On day of caesarean section</time_frame>
    <description>Assessed in total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF levels of noradrenaline metabolites</measure>
    <time_frame>On day of caesarean section</time_frame>
    <description>Assessed in total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF levels of inflammatory markers</measure>
    <time_frame>On day of caesarean section</time_frame>
    <description>Composite measure of IFN-c, IFN-alfa TNF-alfa og IL-6, in total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Estradiol level</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Estradiol level in peripheral blood, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Estradiol level</measure>
    <time_frame>At week 3-6 postpartum.</time_frame>
    <description>Estradiol level peripheral blood, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in estradiol level</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Estradiol change pre- to postpartum, peripheral blood total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progesterone level</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Progesterone level in peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progesterone level</measure>
    <time_frame>At week 3-6 postpartum.</time_frame>
    <description>Progesterone level in peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in progesterone level</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Progesterone change pre- to postpartum, peripheral blood total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Allopregnanolone level</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Allopregnanolone level in peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Allopregnanolone level</measure>
    <time_frame>At week 3-6 postpartum.</time_frame>
    <description>Allopregnanolone level in peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in allopregnanolone level</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in allopregnanolone level in peripheral blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cortisol level</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Cortisol change pre- to postpartum, peripheral blood total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortisol awakening response</measure>
    <time_frame>Week 12 postpartum</time_frame>
    <description>Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortisol awakening response</measure>
    <time_frame>Prior to caesarean section</time_frame>
    <description>Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cortisol awakening response</measure>
    <time_frame>´From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in cortisol awakening response, from caesarean section to 3-6 weeks postpartum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the SERT gene</measure>
    <time_frame>Prior to caesarean section</time_frame>
    <description>Methylation status for the SERT gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the SERT gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>DNA Methylation status for the SERT gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the FK506-binding protein 51 (FKBP5) gene</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the FK506-binding protein 51 (FKBP5) gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DNA methylation of the FK506-binding protein 51 (FKBP5) gene</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in methylation status for the FK506-binding protein 51 (FKBP5) gene from late pregnancy to postpartum week 3-6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the glucocorticoid receptor gene</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Methylation status for the glucocorticoid receptor gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the glucocorticoid receptor gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Methylation status for the glucocorticoid receptor gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DNA methylation of the glucocorticoid receptor gene</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in methylation status for the glucocorticoid receptor gene from late pregnancy to postpartum week 3-6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the COMT gene</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Methylation status for the COMT gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the COMT gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Methylation status for the COMT gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DNA methylation of the COMT gene</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in methylation status for the COMT gene from just before delivery to 3-6 weeks postpartum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the MAO-A gene</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Methylation status for the MAO-A gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DNA methylation of the MAO-A gene</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in methylation status for the MAO-A gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the MAO-A gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Methylation status for the MAO-A gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the oxytocin receptor gene</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Methylation status for the oxytocin receptor gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the oxytocin receptor gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Methylation status for the oxytocin receptor gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DNA methylation of the oxytocin receptor gene</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change in methylation status for the oxytocin receptor gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the oxytocin gene</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Methylation status for the oxytocin gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation of the oxytocin gene</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Methylation status for the oxytocin gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DNA methylation of the oxytocin gene</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum)</time_frame>
    <description>Change methylation status for the oxytocin gene, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic inflammation peripheral blood hsCRP and immunoactive cytokines</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in systemic inflammation peripheral blood hsCRP and immunoactive cytokines</measure>
    <time_frame>From baseline (caesarean section to week 3-6 postpartum</time_frame>
    <description>Change in composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self reported family history of mood disorders</measure>
    <time_frame>Day 3-5 postpartum or before</time_frame>
    <description>Family History Assessment Module (OS-FHAM). Number of first degree relatives with a history of depressive episodes or bipolar disorder. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self reported impulsiveness score</measure>
    <time_frame>Day 3-5 postpartum or before</time_frame>
    <description>Barratt Impulsiveness Scale (BIS-11), self-reported. Range: 30-120. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self reported Neuroticism score from NEO personality questionnaire</measure>
    <time_frame>Day 3-5 postpartum or before</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self reported parental bonding quality</measure>
    <time_frame>Day 3-5 postpartum or before</time_frame>
    <description>Parental bonding instrument (PBI), both parents, self-reported. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported perceived stress</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported perceived stress</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported perceived stress</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported anhedonia</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported anhedonia</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported anhedonia</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Snaith-Hamilton Pleasure Scale (SHAPS) score, range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported rumination</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported rumination</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in elf-reported rumination</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Rumination Response Scale (RRS) score, range 22-88, a score of 22 indicates no ruminative symptoms. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported mood</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported mood</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported mood</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Profile of Mood States (POMS) score, range 0-260, a score of 0 indicates no mood disturbance. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported sleep quality</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported sleep quality</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported sleep quality</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported psychiatric symptoms</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported psychiatric symptoms</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported psychiatric symptoms</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Brief symptom Inventory-53 item (BSI-53) score, range 0-212, increasing score means worsening of symptoms.Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported well-being</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>WHO-5 well-being index, range 0-100, low score means less well-being. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported well-being</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>WHO-5 well-being index, range 0-100, low score means less well-being. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported well-being</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in WHO-5 well-being index, range 0-100, low score means less well-being. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported anxiety</measure>
    <time_frame>Day 3-5 postpartum</time_frame>
    <description>State Trait Anxiety Inventory (STAI-AD-D), state and trait subscales each have a range of 20-80, 20 means no anxiety. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported anxiety</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>State Trait Anxiety Inventory (STAI-AD-D), state subscale range 20-80, 20 means no anxiety. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported anxiety</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in State Trait Anxiety Inventory (STAI-AD-D) score, state subscale range 20-80, 20 means no anxiety. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported obsessive and compulsive symptoms</measure>
    <time_frame>Day 3-5</time_frame>
    <description>Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported obsessive and compulsive symptoms</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-reported obsessive and compulsive symptoms</measure>
    <time_frame>Change from day 3-5 to week 3-6 postpartum</time_frame>
    <description>Change in Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Performance on Simple Reaction Time</measure>
    <time_frame>Week 3-6 postpartum</time_frame>
    <description>Performance on Simple Reaction Time, in imaging cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gray matter brain volume prefrontal cortex and anterior cingulate cortex</measure>
    <time_frame>At week 3-6 postpartum</time_frame>
    <description>Gray matter brain volume prefrontal cortex and anterior cingulate cortex</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serotonergic turnover in placenta</measure>
    <time_frame>At delivery.</time_frame>
    <description>Composite measure of serotonin, tryptophan og tryptofan hydroxylase levels relative to 5-HIAA, in placenta sample. Infants from total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta</measure>
    <time_frame>At delivery</time_frame>
    <description>11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta. Infants from total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Methylation status of genes relevant for stress-hormone regulation in placenta</measure>
    <time_frame>At delivery</time_frame>
    <description>Composite measure of methylation status for the FKBP5, glucocorticoid receptor, 11-beta hydroxysteroid dehydrogenase type 2 genes. Infants from total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Methylation status of genes related to serotonergic signaling in placenta</measure>
    <time_frame>At delivery</time_frame>
    <description>Composite measure of the methylation status for monoamine oxidase, serotonin receptor and serotonin transporter genes. Infants from total group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Methylation status and gene transcript profiles of relevance for early brain development and stress regulation in newborn infants</measure>
    <time_frame>At delivery.</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>COMT-genotype (rs4680) variant, i.e met/met vs other polymorphisms</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>val158met (rs4680) status, binary variable, i.e. &quot;val/val, val/met&quot; vs &quot;met/met&quot; variants</description>
  </other_outcome>
  <other_outcome>
    <measure>BDNF genotype (rs6265) status, i.e. val/val versus met-carrier variants</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>BDNF val66met (rs6265) status, binary variable, i.e. &quot;val/val&quot; versus &quot;met-carrier&quot; status</description>
  </other_outcome>
  <other_outcome>
    <measure>5-HTT genotype status, i.e LALA vs low-expressing (S or LG) variants</measure>
    <time_frame>Prior to caesarean section.</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Postpartum blues symptoms</measure>
    <time_frame>Day 3-5 postpartum.</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Postpartum blues symptoms</measure>
    <time_frame>Day 3-5 postpartum.</time_frame>
    <description>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.</description>
  </other_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">100</enrollment>
  <condition>Major Depressive Disorder</condition>
  <condition>Perinatal Depression</condition>
  <arm_group>
    <arm_group_label>Basic, non-imaging group</arm_group_label>
    <description>Pregnant women who will deliver by planned caesarian. Participants enrolled in the study that are not eligible for the imaging subgroup.&#xD;
All participants start in the basic program. Includes collection of blood, cerebrospinal fluid, saliva, hair, placenta tissues, umbilical cord blood and psychometrics.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Extended, imaging group</arm_group_label>
    <description>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).</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pregnancy</intervention_name>
    <description>Peripartum transition from pregnant to postpartum state</description>
    <arm_group_label>Basic, non-imaging group</arm_group_label>
    <arm_group_label>Extended, imaging group</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Participants will be recruited from the midwife clinic at Rigshospitalet, Copenhagen, i.e.,&#xD;
        included women will be residents of the central Copenhagen area.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-40 years&#xD;
&#xD;
          -  Healthy pregnant women planned to deliver by caesarean section due to breech position&#xD;
             of the fetus or previous caesarean section.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current or previous severe psychiatric disorder such as psychotic disorders, eating&#xD;
             disorder and bipolar disorder or current or previous psychiatric disorder requiring&#xD;
             hospitalization.&#xD;
&#xD;
          -  Current or previous neurological diseases, severe somatic disease, severe postpartum&#xD;
             hemorrhage or use of medication that can interfere with study outcomes&#xD;
&#xD;
          -  Severe disease or malformations in infants&#xD;
&#xD;
          -  Obesity or underweight (pre-gestational BMI below 18 or above 35)&#xD;
&#xD;
          -  Not fluent in Danish or severe visual or hearing impairments&#xD;
&#xD;
          -  Earlier or present learning disabilities&#xD;
&#xD;
          -  MRI contraindications (claustrophobia, metal implants)&#xD;
&#xD;
          -  Previous exposure to radioactivity &gt; 10 millisievert (mSv) within the last year&#xD;
&#xD;
          -  Alcohol or drug abuse&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vibe Frokjaer, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>12589387</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20231323</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23689534</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24189342</PMID>
  </reference>
  <reference>
    <citation>Klengel T, Binder EB. Gene-environment interactions in major depressive disorder. Can J Psychiatry. 2013 Feb;58(2):76-83. doi: 10.1177/070674371305800203.</citation>
    <PMID>23442893</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>25891375</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20096787</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24495551</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>30457060</PMID>
  </reference>
  <reference>
    <citation>Munk-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.</citation>
    <PMID>17148723</PMID>
  </reference>
  <reference>
    <citation>Sanjuan 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.</citation>
    <PMID>18978318</PMID>
  </reference>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>December 16, 2020</last_update_submitted>
  <last_update_submitted_qc>December 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Vibe G Frøkjær, MD, PhD</investigator_full_name>
    <investigator_title>Senior researcher, Principal investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_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_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>2020-2035</ipd_time_frame>
    <ipd_access_criteria>Approval by scientific board</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03795688
org study id: PND1
secondary id: H-18029563
nct id: NCT03795688
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
observational model: Cohort
time perspective: Prospective
measure: Depressive symptoms
time frame: Week 3-6 postpartum
description: Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group
measure: Depressive symptoms
time frame: Week 3-6 postpartum
description: Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group
measure: Gene transcript and DNA methylation markers of estrogen sensitivity
time frame: Prior to caesarean section
description: 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.
measure: Cerebral serotonin 4 receptor binding postpartum
time frame: Week 3-6 postpartum
description: 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.
measure: CSF levels of GABA
time frame: On day of caesarean section
description: Assessed in total group
measure: CSF levels of serotonin metabolite (5-HIAA)
time frame: On day of caesarean section
description: Assessed in total group
measure: Cortisol awakening response
time frame: Week 3-6 postpartum
description: Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.
measure: Hair cortisol level mothers
time frame: On day of caesarean section.
description: Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group
measure: Hair cortisol level newborns
time frame: Day 0-5 postpartum.
description: Provides an estimate of fetal cortisol exposure, infants from total group
measure: Hippocampal volumes
time frame: Week 3-6 postpartum.
description: Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.
measure: functional MRI response to reward
time frame: Week 3-6 postpartum.
description: fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli. Assessed in imaging cohort
measure: Resting state functional connectivity MRI
time frame: Week 3-6 postpartum
description: 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.
measure: Change in epigenetic SERT status
time frame: From just before delivery to 3-6 weeks postpartum
description: Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.
measure: Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood
time frame: At week 3-6
description: Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group
measure: functional MRI response to emotional faces
time frame: Week 3-6 postpartum.
description: fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.
measure: Depressive symptoms
time frame: Day 3-5 postpartum
description: Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group
measure: Depressive symptoms
time frame: Week 12 postpartum
description: Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group
measure: Depressive symptoms
time frame: Day 3-5 postpartum
description: Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in total group
measure: Depressive symptoms
time frame: 6 months postpartum
description: Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in all
measure: CSF levels of serotonin
time frame: On day of caesarean section
description: Assessed in total group
measure: CSF levels of dopamine metabolites
time frame: On day of caesarean section
description: Assessed in total group
measure: CSF levels of noradrenaline metabolites
time frame: On day of caesarean section
description: Assessed in total group
measure: CSF levels of inflammatory markers
time frame: On day of caesarean section
description: Composite measure of IFN-c, IFN-alfa TNF-alfa og IL-6, in total group
measure: Estradiol level
time frame: Prior to caesarean section.
description: Estradiol level in peripheral blood, total group
measure: Estradiol level
time frame: At week 3-6 postpartum.
description: Estradiol level peripheral blood, total group
measure: Change in estradiol level
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Estradiol change pre- to postpartum, peripheral blood total group
measure: Progesterone level
time frame: Prior to caesarean section.
description: Progesterone level in peripheral blood
measure: Progesterone level
time frame: At week 3-6 postpartum.
description: Progesterone level in peripheral blood
measure: Change in progesterone level
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Progesterone change pre- to postpartum, peripheral blood total group
measure: Allopregnanolone level
time frame: Prior to caesarean section.
description: Allopregnanolone level in peripheral blood
measure: Allopregnanolone level
time frame: At week 3-6 postpartum.
description: Allopregnanolone level in peripheral blood
measure: Change in allopregnanolone level
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change in allopregnanolone level in peripheral blood
measure: Change in cortisol level
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Cortisol change pre- to postpartum, peripheral blood total group
measure: Cortisol awakening response
time frame: Week 12 postpartum
description: Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.
measure: Cortisol awakening response
time frame: Prior to caesarean section
description: Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.
measure: Change in cortisol awakening response
time frame: ´From baseline (caesarean section to week 3-6 postpartum)
description: Change in cortisol awakening response, from caesarean section to 3-6 weeks postpartum.
measure: DNA methylation of the SERT gene
time frame: Prior to caesarean section
description: Methylation status for the SERT gene, total group
measure: DNA methylation of the SERT gene
time frame: Week 3-6 postpartum
description: DNA Methylation status for the SERT gene, total group
measure: DNA methylation of the FK506-binding protein 51 (FKBP5) gene
time frame: Prior to caesarean section.
description: Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group
measure: DNA methylation of the FK506-binding protein 51 (FKBP5) gene
time frame: Week 3-6 postpartum
description: Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group
measure: Change in DNA methylation of the FK506-binding protein 51 (FKBP5) gene
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change in methylation status for the FK506-binding protein 51 (FKBP5) gene from late pregnancy to postpartum week 3-6.
measure: DNA methylation of the glucocorticoid receptor gene
time frame: Prior to caesarean section.
description: Methylation status for the glucocorticoid receptor gene, total group
measure: DNA methylation of the glucocorticoid receptor gene
time frame: Week 3-6 postpartum
description: Methylation status for the glucocorticoid receptor gene, total group
measure: Change in DNA methylation of the glucocorticoid receptor gene
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change in methylation status for the glucocorticoid receptor gene from late pregnancy to postpartum week 3-6.
measure: DNA methylation of the COMT gene
time frame: Prior to caesarean section.
description: Methylation status for the COMT gene, total group
measure: DNA methylation of the COMT gene
time frame: Week 3-6 postpartum
description: Methylation status for the COMT gene, total group
measure: Change in DNA methylation of the COMT gene
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change in methylation status for the COMT gene from just before delivery to 3-6 weeks postpartum
measure: DNA methylation of the MAO-A gene
time frame: Prior to caesarean section.
description: Methylation status for the MAO-A gene, total group
measure: Change in DNA methylation of the MAO-A gene
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change in methylation status for the MAO-A gene, total group
measure: DNA methylation of the MAO-A gene
time frame: Week 3-6 postpartum
description: Methylation status for the MAO-A gene, total group
measure: DNA methylation of the oxytocin receptor gene
time frame: Prior to caesarean section.
description: Methylation status for the oxytocin receptor gene, total group
measure: DNA methylation of the oxytocin receptor gene
time frame: Week 3-6 postpartum
description: Methylation status for the oxytocin receptor gene, total group
measure: Change in DNA methylation of the oxytocin receptor gene
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change in methylation status for the oxytocin receptor gene, total group
measure: DNA methylation of the oxytocin gene
time frame: Prior to caesarean section.
description: Methylation status for the oxytocin gene, total group
measure: DNA methylation of the oxytocin gene
time frame: Week 3-6 postpartum
description: Methylation status for the oxytocin gene, total group
measure: Change in DNA methylation of the oxytocin gene
time frame: From baseline (caesarean section to week 3-6 postpartum)
description: Change methylation status for the oxytocin gene, total group
measure: Systemic inflammation peripheral blood hsCRP and immunoactive cytokines
time frame: Prior to caesarean section.
description: Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group
measure: Change in systemic inflammation peripheral blood hsCRP and immunoactive cytokines
time frame: From baseline (caesarean section to week 3-6 postpartum
description: Change in composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group
measure: Self reported family history of mood disorders
time frame: Day 3-5 postpartum or before
description: Family History Assessment Module (OS-FHAM). Number of first degree relatives with a history of depressive episodes or bipolar disorder. Total group.
measure: Self reported impulsiveness score
time frame: Day 3-5 postpartum or before
description: Barratt Impulsiveness Scale (BIS-11), self-reported. Range: 30-120. Total group.
measure: Self reported Neuroticism score from NEO personality questionnaire
time frame: Day 3-5 postpartum or before
description: 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.
measure: Self reported parental bonding quality
time frame: Day 3-5 postpartum or before
description: Parental bonding instrument (PBI), both parents, self-reported. Total group.
measure: Self-reported perceived stress
time frame: Day 3-5 postpartum
description: Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.
measure: Self-reported perceived stress
time frame: Week 3-6 postpartum
description: Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.
measure: Change in self-reported perceived stress
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.
measure: Self-reported anhedonia
time frame: Day 3-5 postpartum
description: Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.
measure: Self-reported anhedonia
time frame: Week 3-6 postpartum
description: Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.
measure: Change in self-reported anhedonia
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Snaith-Hamilton Pleasure Scale (SHAPS) score, range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.
measure: Self-reported rumination
time frame: Day 3-5 postpartum
description: Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.
measure: Self-reported rumination
time frame: Week 3-6 postpartum
description: Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.
measure: Change in elf-reported rumination
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Rumination Response Scale (RRS) score, range 22-88, a score of 22 indicates no ruminative symptoms. Total group.
measure: Self-reported mood
time frame: Day 3-5 postpartum
description: Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.
measure: Self-reported mood
time frame: Week 3-6 postpartum
description: Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.
measure: Change in self-reported mood
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Profile of Mood States (POMS) score, range 0-260, a score of 0 indicates no mood disturbance. Total group.
measure: Self-reported sleep quality
time frame: Day 3-5 postpartum
description: Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.
measure: Self-reported sleep quality
time frame: Week 3-6 postpartum
description: Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.
measure: Change in self-reported sleep quality
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.
measure: Self-reported psychiatric symptoms
time frame: Day 3-5 postpartum
description: Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.
measure: Self-reported psychiatric symptoms
time frame: Week 3-6 postpartum
description: Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.
measure: Change in self-reported psychiatric symptoms
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Brief symptom Inventory-53 item (BSI-53) score, range 0-212, increasing score means worsening of symptoms.Total group.
measure: Self-reported well-being
time frame: Day 3-5 postpartum
description: WHO-5 well-being index, range 0-100, low score means less well-being. Total group.
measure: Self-reported well-being
time frame: Week 3-6 postpartum
description: WHO-5 well-being index, range 0-100, low score means less well-being. Total group.
measure: Change in self-reported well-being
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in WHO-5 well-being index, range 0-100, low score means less well-being. Total group.
measure: Self-reported anxiety
time frame: Day 3-5 postpartum
description: State Trait Anxiety Inventory (STAI-AD-D), state and trait subscales each have a range of 20-80, 20 means no anxiety. Total group.
measure: Self-reported anxiety
time frame: Week 3-6 postpartum
description: State Trait Anxiety Inventory (STAI-AD-D), state subscale range 20-80, 20 means no anxiety. Total group.
measure: Change in self-reported anxiety
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in State Trait Anxiety Inventory (STAI-AD-D) score, state subscale range 20-80, 20 means no anxiety. Total group.
measure: Self-reported obsessive and compulsive symptoms
time frame: Day 3-5
description: Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.
measure: Self-reported obsessive and compulsive symptoms
time frame: Week 3-6 postpartum
description: Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.
measure: Change in self-reported obsessive and compulsive symptoms
time frame: Change from day 3-5 to week 3-6 postpartum
description: Change in Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.
measure: Performance on Simple Reaction Time
time frame: Week 3-6 postpartum
description: Performance on Simple Reaction Time, in imaging cohort.
measure: Gray matter brain volume prefrontal cortex and anterior cingulate cortex
time frame: At week 3-6 postpartum
description: Gray matter brain volume prefrontal cortex and anterior cingulate cortex
measure: Serotonergic turnover in placenta
time frame: At delivery.
description: Composite measure of serotonin, tryptophan og tryptofan hydroxylase levels relative to 5-HIAA, in placenta sample. Infants from total group
measure: 11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta
time frame: At delivery
description: 11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta. Infants from total group
measure: Methylation status of genes relevant for stress-hormone regulation in placenta
time frame: At delivery
description: Composite measure of methylation status for the FKBP5, glucocorticoid receptor, 11-beta hydroxysteroid dehydrogenase type 2 genes. Infants from total group
measure: Methylation status of genes related to serotonergic signaling in placenta
time frame: At delivery
description: Composite measure of the methylation status for monoamine oxidase, serotonin receptor and serotonin transporter genes. Infants from total group
measure: Methylation status and gene transcript profiles of relevance for early brain development and stress regulation in newborn infants
time frame: At delivery.
description: 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.
measure: COMT-genotype (rs4680) variant, i.e met/met vs other polymorphisms
time frame: Prior to caesarean section.
description: val158met (rs4680) status, binary variable, i.e. "val/val, val/met" vs "met/met" variants
measure: BDNF genotype (rs6265) status, i.e. val/val versus met-carrier variants
time frame: Prior to caesarean section.
description: BDNF val66met (rs6265) status, binary variable, i.e. "val/val" versus "met-carrier" status
measure: 5-HTT genotype status, i.e LALA vs low-expressing (S or LG) variants
time frame: Prior to caesarean section.
description: 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.
measure: Postpartum blues symptoms
time frame: Day 3-5 postpartum.
description: 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.
measure: Postpartum blues symptoms
time frame: Day 3-5 postpartum.
description: 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.
arm group label: Basic, non-imaging group
description: 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.
arm group label: Extended, imaging group
description: 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).
intervention type: Other
intervention name: Pregnancy
description: Peripartum transition from pregnant to postpartum state
arm group label: Basic, non-imaging group
arm group label: Extended, imaging group
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Vibe Frokjaer, MD, PhD
role: Principal Investigator
affiliation: Rigshospitalet, Denmark
facility: 
country: Denmark
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PMID: 23689534
citation: 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.
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PMID: 23442893
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PMID: 25891375
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PMID: 24495551
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PMID: 30457060
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PMID: 18978318
responsible party type: Sponsor-Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Vibe G Frøkjær, MD, PhD
investigator title: Senior researcher, Principal investigator
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
sharing ipd: Yes
ipd 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 info type: Study Protocol
ipd time frame: 2020-2035
ipd access criteria: Approval by scientific board