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Lower inflammatory markers in women with antenatal depression brings the M1/M2 balance into focus from a new direction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.ORCID iD: 0000-0002-6246-7218
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.ORCID iD: 0000-0002-6246-7218
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2017 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 80, p. 15-25Article in journal (Refereed) Published
Abstract [en]

Background: Antenatal depression and use of serotonin reuptake inhibitors (SSRI) in pregnancy have both been associated with an increased risk of poor pregnancy outcomes, such as preterm birth and impaired fetal growth. While the underlying biological pathways for these complications are poorly understood, it has been hypothesized that inflammation may be a common physiological pathway. The aim of the present study was to assess peripheral inflammatory markers in healthy women, women with antenatal depression, and in women using SSRI during pregnancy.

Methods: 160 healthy pregnant controls, 59 women with antenatal depression and 39 women on treatment with SSRIs were included. The relative levels of 92 inflammatory proteins were analyzed by proximity extension assay technology.

Results: Overall, 23 of the inflammatory markers were significantly lower in women with antenatal depression and in women on treatment with SSRIs in comparison with the healthy controls. No difference in any of the inflammatory markers was observed between women with antenatal depression and those who were using SSRI. Top three inflammatory markers that were down-regulated in women with antenatal depression were TNF-related apoptosis-inducing ligand (TRAIL), p = 0.000001, macrophage colony-stimulating factor 1 (CSF-1), p = 0.000004, and fractalkine (CX3CL1), p =0.000005. Corresponding inflammatory markers in SSRI users were CSF-1, p = 0.000011, vascular endothelial growth factor A (VEGF-A), p =0.000016, and IL-15 receptor subunit alpha (IL-15RA), p = 0.000027. The inflammatory markers were negatively correlated with cortisone serum concentrations in controls, but not in the cases. Differential DNA methylation of was found for seven of these inflammatory markers in an independent epigenetics cohort.

Conclusion: Women with antenatal depression or on SSRI treatment have lower levels of a number of peripheral inflammatory markers than healthy pregnant controls. Hypothetically, this could be due to dysregulated switch to the pro-M2 milieu that characterizes normal third trimester pregnancy. However, longitudinal blood sampling is needed to elucidate whether the presumably dysregulated M2 shift is driving the development of antenatal depression or is a result of the depression.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD , 2017. Vol. 80, p. 15-25
Keywords [en]
Antenatal depression, Pregnancy, Inflammatory markers, Proximity extension assay, Selective serotonin reuptake inhibitors
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-326211DOI: 10.1016/j.psyneuen.2017.02.027ISI: 000402352200003PubMedID: 28292683OAI: oai:DiVA.org:uu-326211DiVA, id: diva2:1130213
Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2018-12-05
In thesis
1. Biological Aspects of Peripartum Depression
Open this publication in new window or tab >>Biological Aspects of Peripartum Depression
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peripartum depression affects around 12% of women in pregnancy and postpartum, and about 2–3% of European pregnant women use antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). An increased risk of poor pregnancy outcomes has been described in women with antenatal depression and SSRI treatment during pregnancy. The biological mechanisms behind these complications are not fully understood and here we investigated several biological correlates of peripartum depression, and discriminated between the effects of antidepressant treatment and depression itself.

In Paper I, attentional biases in pregnant and postpartum women were studied by using the Emotional Stroop Task, measuring reaction times to different stimuli. The major finding was shorter reaction times in postpartum depressed women, for emotionally valenced stimuli, which can be interpreted as emotional numbing.

In Paper II, peripheral inflammatory markers were assessed by proximity extension assay technology in depressed, SSRI-treated and healthy pregnant women. Lower levels of 23 markers were found in women with antenatal depression, independent of treatment, compared with healthy controls. These findings suggest a dysregulated switch to the anti-inflammatory M2 milieu characterizing a normal third trimester.

In Paper III, normal changes in inflammatory markers across pregnancy and postpartum were assessed in healthy pregnant and postpartum women. The majority (41) of the 50 markers that differed between groups were lower postpartum. These results clearly reflect the change in the immune system in pregnancy to postpartum transition.

In Paper IV, placental gene and protein expression were investigated and nominally significant findings were noted for serotonin receptor 1A (HTR1A) and neuropeptide Y2 receptor (NPY2R), where women with untreated depression displayed higher gene expression than healthy controls. Protein expression analyses revealed higher levels of HTR1A in placentas from SSRI-treated women, compared with healthy controls and women with untreated depression. This suggests possible involvement of HTR1A in the effect of antenatal depression on the placenta.

Overall, peripartum depression is associated with altered cognitive-emotional processing, lower levels of several mostly anti-inflammatory markers, and altered placental gene and protein expression. However, we found no major differences between untreated and treated depression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 114
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1520
Keywords
Peripartum depression, antenatal depression, postpartum depression, antidepressant treatment, selective serotonin reuptake inhibitor, SSRI, pregnancy, postpartum, attentional bias, Emotional Stroop Task, inflammatory markers, proximity extension assay, placenta, gene expression, TaqMan low-density array, protein expression, immunohistochemistry, HTR1A, NPY2R
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-367385 (URN)978-91-513-0522-6 (ISBN)
Public defence
2019-02-01, Sal IX, Universitetshuset, Biskopsgatan 3, Uppsala, 09:15 (Swedish)
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Supervisors
Available from: 2019-01-09 Created: 2018-12-05 Last updated: 2019-01-21

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Edvinsson, ÅsaBränn, EmmaHellgren, CharlotteFreyhult, EvaKamali-Moghaddam, MasoodBergquist, JonasBoström, Adrian E.Schiöth, Helgi B.Skalkidou, AlkistisCunningham, JanetSundström Poromaa, Inger

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Edvinsson, ÅsaBränn, EmmaHellgren, CharlotteFreyhult, EvaKamali-Moghaddam, MasoodBergquist, JonasBoström, Adrian E.Schiöth, Helgi B.Skalkidou, AlkistisCunningham, JanetSundström Poromaa, Inger
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Reproductive HealthObstetrics and Reproductive Health ResearchDepartment of Women's and Children's HealthScience for Life Laboratory, SciLifeLabDepartment of Medical SciencesDepartment of Immunology, Genetics and PathologyAnalytical ChemistryFunctional PharmacologyPsychiatry, University Hospital
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