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

NCT03795688 | Completed DMC

• 2 other identifiers: PND1H-18029563
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Major Depressive Disorder; Perinatal Depression

Outcome Measures

Primary Outcomes (15)

• Depressive symptoms

  Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group

  Week 3-6 postpartum

• Depressive symptoms

  Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group

  Week 3-6 postpartum

• Gene transcript and DNA methylation markers of estrogen sensitivity

  116 a priori defined gene transcripts, which where differentially expressed in third trimester of women who later developed perinatal depression with postpartum onset relative to pregnant women who did not and to other depressed (reference Mehta et al, 2014, Psychological Medicine) and confirmed to be coupled to estrogen fluctuations (Mehtaet al. 2018 British Journal of Psychiatry) will be evaluated in the total group. Also DNA methylation of the genes of these transcripts will be determined and analysed in terms of their predictive value (above chance) for perinatal depression.

  Prior to caesarean section

• Cerebral serotonin 4 receptor binding postpartum

  Latent variable construct of brain 5-HT4R level based on quantification of 5-HT4R binding from 11C-SB207145 positron emission tomography in primary volumes of interest; neocortex, nucleus caudatus, putamen and hippocampus. Assessed in imaging group.

  Week 3-6 postpartum

• CSF levels of GABA

  Assessed in total group

  On day of caesarean section

• CSF levels of serotonin metabolite (5-HIAA)

  Assessed in total group

  On day of caesarean section

• Cortisol awakening response

  Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.

  Week 3-6 postpartum

• Hair cortisol level mothers

  Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group

  On day of caesarean section.

• Hair cortisol level newborns

  Provides an estimate of fetal cortisol exposure, infants from total group

  Day 0-5 postpartum.

• Hippocampal volumes

  Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.

  Week 3-6 postpartum.

• functional MRI response to reward

  fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli. Assessed in imaging cohort

  Week 3-6 postpartum.

• Resting state functional connectivity MRI

  rsfMRI based spontaneous co-fluctuations in low frequency BOLD signal, (functional connectivity). Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake. Assessed in imaging group.

  Week 3-6 postpartum

• Change in epigenetic SERT status

  Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.

  From just before delivery to 3-6 weeks postpartum

• Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood

  Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group

  At week 3-6

• functional MRI response to emotional faces

  fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.

  Week 3-6 postpartum.

Secondary Outcomes (81)

• Depressive symptoms

  Day 3-5 postpartum

• Depressive symptoms

  Week 12 postpartum

• Depressive symptoms

  Day 3-5 postpartum

• Depressive symptoms

  6 months postpartum

• CSF levels of serotonin

  On day of caesarean section

Other Outcomes (5)

• COMT-genotype (rs4680) variant, i.e met/met vs other polymorphisms

  Prior to caesarean section.

• BDNF genotype (rs6265) status, i.e. val/val versus met-carrier variants

  Prior to caesarean section.

• 5-HTT genotype status, i.e LALA vs low-expressing (S or LG) variants

  Prior to caesarean section.

Study Arms (2)

Basic, non-imaging group

Pregnant women who will deliver by planned caesarian. Participants enrolled in the study that are not eligible for the imaging subgroup. All participants start in the basic program. Includes collection of blood, cerebrospinal fluid, saliva, hair, placenta tissues, umbilical cord blood and psychometrics.

Other: Pregnancy

Extended, imaging group

A subgroup of 70 pregnant women who will deliver by planned caesarian selected towards either high (N=35) or low (N=35) risk for perinatal depression will undergo brain imaging in addition to the elements of the basic program. The extended imaging program includes functional and structural magnetic resonance imaging, positron emission tomography (PET) and a semistructured interview for depression symptoms (HAM-D17).

Other: Pregnancy

Interventions

Pregnancy OTHER

Peripartum transition from pregnant to postpartum state

Basic, non-imaging group; Extended, imaging group

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• 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.

You may qualify if:

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

You may not qualify if:

• Current or previous severe psychiatric disorder such as psychotic disorders, eating disorder and bipolar disorder or current or previous psychiatric disorder requiring hospitalization.
• Current or previous neurological diseases, severe somatic disease, severe postpartum hemorrhage or use of medication that can interfere with study outcomes
• Severe disease or malformations in infants
• Obesity or underweight (pre-gestational BMI below 18 or above 35)
• Not fluent in Danish or severe visual or hearing impairments
• Earlier or present learning disabilities
• MRI contraindications (claustrophobia, metal implants)
• Previous exposure to radioactivity \> 10 millisievert (mSv) within the last year
• Alcohol or drug abuse

Sponsors & Collaborators

• Vibe G Frøkjær, MD, PhD: lead
• Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak: collaborator
• Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital: collaborator
• University of Copenhagen: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (11)

• 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.

  PMID: 12589387 BACKGROUND

• 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.

  PMID: 20231323 BACKGROUND

• 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.

  PMID: 23689534 BACKGROUND

• 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.

  PMID: 24189342 BACKGROUND

• Klengel T, Binder EB. Gene-environment interactions in major depressive disorder. Can J Psychiatry. 2013 Feb;58(2):76-83. doi: 10.1177/070674371305800203.

  PMID: 23442893 BACKGROUND

• 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.

  PMID: 25891375 BACKGROUND

• 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.

  PMID: 20096787 BACKGROUND

• 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.

  PMID: 24495551 BACKGROUND

• 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.

  PMID: 30457060 BACKGROUND

• 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.

  PMID: 17148723 BACKGROUND

• 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.

  PMID: 18978318 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Pregnancy

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Reproduction; Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena

Study Officials

• Vibe Frokjaer, MD, PhD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 6 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Senior researcher, Principal investigator

Study Record Dates

• First Submitted: December 18, 2018
• First Posted: January 8, 2019
• Study Start: January 24, 2019
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: December 17, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: 2020-2035
• Access Criteria: Approval by scientific board

Locations

DK (1)