The Role of Sex Steroids and Serotonin Brain Dynamics in Perinatal Mental Health
Condition: Major Depressive Disorder; Perinatal Depression
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Observational [Patient Registry]

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. 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.
    

Intervention name(s): Pregnancy
Intervention type(s): Other
Intervention description(s): Peripartum transition from pregnant to postpartum state
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Participants will be recruited from the midwife clinic at Rigshospitalet, Copenhagen, i.e.,
        included women will be residents of the central Copenhagen area.