Association of inflammatory markers with depressive symptoms across the perinatal period

E.Braybrook1,3, O. Sorinola2, S. Forbes-Robertson4 and D.Grammatopoulos1,3

1 Institute of Precision Diagnostics and Translational Medicine, Dept of Pathology, University Hospital Coventry and Warwickshire NHS Trust, Coventry, UK, 2 Dept of Obstetrics, Warwick Hospital, Warwick, UK , 3 Translational Medicine, Warwick Medical School, Coventry, UK , 4 Coventry University, Coventry, UK

Introduction

Methods

References (1) The Royal Society of Midwives (2014) Postnatal care funding: The case for better resourced maternity care [online] Available from:

http://eprints.lse.ac.uk/59885/1/__lse.ac.uk_storage_LIBRARY_Secondary_libfile_shared_repository_Content_Bauer%2C%20M_Bauer_Costs_perinatal_%20mental_2014_Bauer_Costs_perinatal_mental_2014_author.pdf (Accessed 2nd September). (2) Pariante, C. M. & Lightman, S. L. (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci, 31 (9): 464-468. (3) Raison, C. L., Capuron, L. & Miller, A. H. (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol, 27 (1): 24-31. (4) Leigh, B. & Milgrom, J. (2008) Risk factors for antenatal depression, postnatal depression and parenting stress. BMC Psychiatry, 8: 24 (5) Grote, N. K., Bridge, J. A., Gavin, A. R., Melville, J. L., Iyengar, S. & Katon, W. J. (2010) A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry, 67 (10): 1012-1024. (6) National Institute for Health and Care Excellence (2014) Antenatal and postnatal mental health: clinical management and service guidance. [online] Available from: https://www.nice.org.uk/guidance/cg192/chapter/1-Recommendations#recognising-mental-health-problems-in-

pregnancy-and-the-postnatal-period-and-referral-2 (Accessed 5th December) (7) Osbourne, L. M. & Monk, C. (2013) Perinatal depression--the fourth inflammatory morbidity of pregnancy?: Theory and literature review. Psychoneuroendocrinology, 38 (10): 1929-1952. (8) Maier, S. F. & Watkins, L. R. (1998) Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev, 105 (1): 83-107 (9) Miller, A. H. (2013) Conceptual Confluence: The Kynurenine Pathway as a Common Target for Ketamine and the Convergence of the Inflammation and Glutamate Hypotheses of Depression. Neuropsychopharmacology, 38: 1607-1608.

• Perinatal depression (PND) is experienced by 10-15% of women and symptoms are heterogeneous in nature.1

• Aetiology remains elusive. Proposed mechanisms include dysregulation of the HPA axis, hormonal imbalance, genetic vulnerability and psychosocial stress. 2,3,4

• PND remains undetected in 50% of cases and can result in profound consequences for the offspring, including developmental delays and enhanced susceptibility for diseases. 5

• Although several questionnaires have been validated to screen for PND, women are often reluctant to report symptoms and clinicians often attribute changes in sleep, appetite and libido to normal pregnancy or postpartum changes.6

• Urgent need for development of biomarker-based strategies to screen for women at risk and to allow for targeted therapy.7

• Part of a larger cohort research study searching for genetic and biochemical markers of PND (CWPND study) (REC reference: 09/H1203/69).

• 2000 pregnant women aged between 16 and 45 attending SWFT and UHCW NHS Trusts have currently been recruited during antenatal clinic visits.

• Screened for depressive symptoms at 24-28 wks gestation and 4-10 wks post delivery using Edinburgh Postnatal Depression Scale (EPDS) questionnaire.

• Cut-off scores of >10 classified women with increased risk for depression and women grouped into 1 of 4 groups (figure 1).

• The relative expression of 96 inflammatory markers was calculated for 193 samples using multiplex proximity extension arrays. (Olink Proteomics, Sweden)

• A Welch’s ANOVA with Games-Howell post-hoc test was used to compare marker expression between the 4 groups.

• 11.5% of women displayed depressive symptoms antenatally and 14.8% postpartum.

• 53.3% educated to degree level or above.

• 96.9% felt supported.

• 83.8% had not suffered from anxiety before.

• 81.9% did not know of any PPD family history.

• 14 analytes were below the LOD for more than 50% of the samples.

• 8 inflammatory markers identified as being significantly increased in those with raised EPDS scores during pregnancy (figure 2).

• 2 inflammatory markers significantly decreased in those with raised EPDS scores post partum (figure 2).

• Inflammatory markers highlighted as having a significant association to depression risk.

• The biological processes for markers within groups were similar, with processes differing between antenatal and postnatal risk, suggesting different aetiologies (figure 3).

• May support interaction between the central nervous system and the immune system, also known as the ‘psychoneuroimmunology model’, as a possible factor in depression.3,8

• Immune system signalling molecules cross the brain barrier to influence serotonin metabolism, neuroplasticity and HPA hyperactivity (figure 4).3,9

• The use of relative expression means there are significant limitations in the statistics that can be applied to this data. Further work to quantify markers of interest and measure in a second cohort.

Significantly altered inflammatory marker levels identified in women with increased risk of depressive symptoms.

Relationship between biological processes and markers of significance.

Supports the idea that antenatal and postpartum depression may be caused by differing aetiologies.

These early results suggest it may be possible to predict risk of depression early in pregnancy through screening, and differentiate between antenatal and postpartum depression. This would allow for closer monitoring and the potential for targeted therapy.

Key Points

Figure 1. Research Protocol. Subjects asked to complete the EPDS

questionnaire at 2 time points; once during pregnancy and once following delivery (referred to as the PNEPDS). Samples were taken at 24-26 weeks gestation, with plasma utilised for inflammatory marker analysis.

Figure 2. Olink Results. Summary of Olink markers that following Welch’s ANOVA indicated

significance between groups. G0 – EPDS and PNEDPS score <10, G1 – High post-natal risk, PNEPDS score >10, G2 – High antenatal risk, EPDS score >10

Marker G0 G1 G2

Significance Level

Mean Mean Mean

STAM-binding protein 3.53 3.56 4.48 0.001

Antenatal concentrations higher than all other groups

Tumour necrosis factor ligand superfamily

member 14

3.10 3.05 3.49 0.009

Antenatal concentrations

higher than control and postnatal groups

SIR2-like protein 2 2.64 2.65 3.72 0.001

Caspase 8 2.10 2.15 2.71 0.009

CD40L receptor 9.94 9.87 10.32 0.003

Adenosine Deaminase 2.83 2.86 3.15 0.016

Natural killer cell receptor 2B4

6.21 6.21 6.49 0.011

Monocyte chemotactic protein 4

11.76 11.63 12.19 0.011

Monocyte chemotactic protein 1

9.37 9.20 9.44 0.007 Postnatal concentrations lower than all other groups

Matrix metalloproteinase-1

12.24 11.77 12.63 <0.001

Discussion

(a)

(b)

Figure 4. Stress–Immune Interactions and Depression. Immune system signalling molecules cross the brain barrier resulting in:(i) activation of the kynurenine pathway, depleting tryptophan, (ii) enhanced glutamate receptor N-methyl-d-aspartate activation, stimulating the CRH neurones and (iii) reduction of brain-derived neurotrophic factor (BDNF) expression, important in neuroplasticity and neurogenesis. Increased cytokines have also been linked to impaired GR function, not illustrated in this diagram.4

Figure 3. Biological Processes. Processes

identified in the UniProt database linked to (a) antenatal risk and (b) postnatal risk significant markers

Results

For further information or discussion, please contact: emma.braybrook@uhcw.nhs.uk