Biological Triggers of Depression in Pregnancy

The Role of Kynurenine Pathway Metabolites in Perinatal Depression and Suicidality

The goal of the study is to define and measure biological processes that contribute to the underlying pathophysiologic process of peri-partum depression to be used for identifying those at risk for developing it. This knowledge may also generate novel drug targets for peripartum depression that may be applicable to other types of depression.

Study Overview

• Status: Completed
• Conditions: Mood Disorders; Depression and Suicide; Other Perinatal Conditions

Detailed Description

This study analyses the role of inflammation and metabolites of inflammation in perinatal depression. Psychiatric assessments of depression and suicidality will be compared to blood levels of two metabolites of inflammation, quinolinic acid (QUIN) and picolinic acid (PIC), that might regulate nerve cell communication. The levels of these metabolites are regulated by kynurenine pathway enzymes.

Psychiatric symptoms, inflammatory cytokines and levels of the metabolites will be measured throughout pregnancy. Additionally, the investigators are gathering placentas at delivery and determining the degree of inflammation in the tissue in the investigators' laboratory. Inflammatory biomarkers, antibody titers, and key kynurenine pathway enzymes and metabolites from pre- and post partum women, placenta, and cord blood will be measured.

• Study Type: Observational
• Enrollment (Actual): 209

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Grand Rapids, Michigan, United States, 49548
      • Pine Rest Christian Mental Health Services
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health System
    • Grand Rapids, Michigan, United States, 49503
      • Van Andel Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Pregnant females age 18 and older, psychiatrically healthy or depressed; post-partum females experiencing perinatal depression with and without suicide ideation.

Description

Inclusion Criteria

Pre-partum cohort:

• All races and national origins of pregnant females.
• Age 18 and older.
• English speaking.
• Able to give informed consent.
• Able to comply with study procedures.

Exclusion Criteria

Pre-partum cohort:

• Non-pregnant females
• Patients with psychotic symptoms and/or severe cognitive impairment that interfere with their ability to give informed consent or to complete study assessments.
• Patients that cannot read and write in English as research measures used have only been validated in English speaking populations.
• Patients that have blood-borne chronic infections including hepatitis B, C, or HIV as established at routine pregnancy blood screens; they will be excluded as the laboratory facilities do not approve processing of their tissue for safety reasons.
• Patients who have any schizophrenia spectrum disorder or bipolar disorder type 1 (based on self report and SCID interview); these patients will be excluded as the neurobiology of these disorders are different from peripartum depression.
• Patients who report ongoing substance abuse or dependence (in the past 3 months).

Inclusion criteria

Post-partum cohort:

• All races and national origins of females who delivered a child vaginally or by caesarian section up to 6 months prior to enrollment.
• Age 18 and older.
• Edinburgh Perinatal Depression Rating Scale score of 10 and above and/or endorsed suicide ideation on the CSSRS.
• Depressive symptoms which began or worsened (if already present) during pregnancy or up to 4 weeks post-partum.
• Able to give informed consent.
• Able to comply with and complete study procedures.
• English speaking.

Exclusion criteria

Post-partum cohort:

• Patients with psychotic symptoms and/or severe cognitive impairment that interfere with their ability to give informed consent or to complete study assessments.
• Patients who cannot read and write in English as research measures used have only been validated in English speaking populations.
• Patients that have blood-borne chronic infections including hepatitis B, C, or HIV; as established at their routine pregnancy blood screens.
• Patients who have any schizophrenia spectrum disorder or bipolar type 1 (based on the self report and SCID interview).
• Patients who report ongoing substance abuse or dependence (past 3 months).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Pre-partum; 130 pregnant women will be enrolled in first trimester. Healthy women or those with any degree of depressive symptoms are eligible. Blood samples and psychiatric assessments will take place once every trimester and once in the post-partum. At delivery placenta will be collected. Enrollment takes place at Spectrum Health Ob/gyn out-patient clinics in Grand Rapids, Michigan.
Post-partum; 50-100 women experiencing perinatal depression with and without suicidality will be enrolled from a partial hospitalization program, the Mother and Baby unit as well as outpatient clinics at Pine Rest Christian Mental Health Services, Grand Rapids, Michigan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in activity of the enzyme aminocarboxymuconate semialdehyde decarboxylase ACMSD in blood during pregnancy	Blood levels of quinolinic acid and picolinic acid (product of ACMSD) at three timepoints during pregnancy and one time-point after pregnancy	Up to pregnancy week 13 (1st sample), up to week 25 (second sample) and up to delivery (3rd sample) and post-partum (4th sample, within 6 months after delivery)
Activity of the enzyme aminocarboxymuconate semialdehyde decarboxylase ACMSD in placenta	Placenta levels of quinolinic acid and picolinic acid	At delivery
Increase in depressive symptoms	Assessment of depressive symptoms by means of the Edinburgh Postnatal Depression Scale	Up to pregnancy week 13 (1st assessment), up to week 25 (second assessment) and up to delivery (3rd assessment) and post-partum (4th assessment, within 6 months after delivery)
Suicidal symptoms	Assessment of suicidal symptoms by means of the Columbia Suicide Severity Rating Scale	Post-partum (within 6 months after delivery).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood inflammation	Analysis of the inflammatory cytokine IL-6 in blood	Up to pregnancy week 13 (1st sample), up to week 25 (second sample) and up to delivery (3rd sample) and post-partum (4th sample, within 6 months after delivery)
Placenta inflammation	Analysis of the expression of the inflammatory cytokine IL-6 in placental tissue	At delivery

Collaborators and Investigators

• Sponsor: Michigan State University
• Collaborators: National Institute of Mental Health (NIMH); Spectrum Health Hospitals; Van Andel Research Institute; Pine Rest Christian Mental Health Services
• Investigators: Principal Investigator: Lena Brundin, MD, PhD, Michigan State University, Van Andel Research Institute

Publications and helpful links

General Publications

• Meltzer-Brody S, Boschloo L, Jones I, Sullivan PF, Penninx BW. The EPDS-Lifetime: assessment of lifetime prevalence and risk factors for perinatal depression in a large cohort of depressed women. Arch Womens Ment Health. 2013 Dec;16(6):465-73. doi: 10.1007/s00737-013-0372-9. Epub 2013 Aug 1.
• Centers for Disease Control and Prevention (CDC). Prevalence of self-reported postpartum depressive symptoms--17 states, 2004-2005. MMWR Morb Mortal Wkly Rep. 2008 Apr 11;57(14):361-6.
• Davalos DB, Yadon CA, Tregellas HC. Untreated prenatal maternal depression and the potential risks to offspring: a review. Arch Womens Ment Health. 2012 Feb;15(1):1-14. doi: 10.1007/s00737-011-0251-1. Epub 2012 Jan 4.
• National Institute of Mental Health (NIMH), Statistics Use of Mental Health Services and Treatment among Adults. Availabe on-line at http://www.nimh.nih.gov/statistics/3USE_MT_ADULT.shtml.
• World Health Organization (WHO). What Is Depression. Available on-line at http://www.who.int/mental_health/management/depression/definition/en/
• First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders - Patient Edition (SCID-I/P, Version 2.0), Biometrics Research Department, New York State Psychiatric Institute, 1995.
• Dietz PM, Williams SB, Callaghan WM, Bachman DJ, Whitlock EP, Hornbrook MC. Clinically identified maternal depression before, during, and after pregnancies ending in live births. Am J Psychiatry. 2007 Oct;164(10):1515-20. doi: 10.1176/appi.ajp.2007.06111893.
• Marcus SM, Heringhausen JE. Depression in childbearing women: when depression complicates pregnancy. Prim Care. 2009 Mar;36(1):151-65, ix. doi: 10.1016/j.pop.2008.10.011.
• Mian AI. Depression in pregnancy and the postpartum period: balancing adverse effects of untreated illness with treatment risks. J Psychiatr Pract. 2005 Nov;11(6):389-96. doi: 10.1097/00131746-200511000-00005.
• Anderson G, Maes M. Postpartum depression: psychoneuroimmunological underpinnings and treatment. Neuropsychiatr Dis Treat. 2013;9:277-87. doi: 10.2147/NDT.S25320. Epub 2013 Feb 21.
• Groer MW, Morgan K. Immune, health and endocrine characteristics of depressed postpartum mothers. Psychoneuroendocrinology. 2007 Feb;32(2):133-9. doi: 10.1016/j.psyneuen.2006.11.007. Epub 2007 Jan 3.
• Jolley SN, Elmore S, Barnard KE, Carr DB. Dysregulation of the hypothalamic-pituitary-adrenal axis in postpartum depression. Biol Res Nurs. 2007 Jan;8(3):210-22. doi: 10.1177/1099800406294598.
• Koleva H, Stuart S, O'Hara MW, Bowman-Reif J. Risk factors for depressive symptoms during pregnancy. Arch Womens Ment Health. 2011 Apr;14(2):99-105. doi: 10.1007/s00737-010-0184-0. Epub 2010 Sep 25.
• Meltzer-Brody S. Mental illness is prevalent among U.K. women in the perinatal period and is associated with socioeconomic deprivation. Evid Based Ment Health. 2013 May;16(2):57. doi: 10.1136/eb-2013-101226. Epub 2013 Mar 16. No abstract available.
• Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. Nat Med. 2013 May;19(5):548-56. doi: 10.1038/nm.3160. Epub 2013 May 7.
• Rowe JH, Ertelt JM, Xin L, Way SS. Regulatory T cells and the immune pathogenesis of prenatal infection. Reproduction. 2013 Oct 21;146(6):R191-203. doi: 10.1530/REP-13-0262. Print 2013 Dec.
• Honig A, Rieger L, Kapp M, Sutterlin M, Dietl J, Kammerer U. Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol. 2004 Apr;61(2):79-86. doi: 10.1016/j.jri.2003.11.002.
• Zhu BT. Development of selective immune tolerance towards the allogeneic fetus during pregnancy: Role of tryptophan catabolites (Review). Int J Mol Med. 2010 Jun;25(6):831-5. doi: 10.3892/ijmm_00000411.
• Manuelpillai U, Ligam P, Smythe G, Wallace EM, Hirst J, Walker DW. Identification of kynurenine pathway enzyme mRNAs and metabolites in human placenta: up-regulation by inflammatory stimuli and with clinical infection. Am J Obstet Gynecol. 2005 Jan;192(1):280-8. doi: 10.1016/j.ajog.2004.06.090.
• Lindqvist D, Janelidze S, Hagell P, Erhardt S, Samuelsson M, Minthon L, Hansson O, Bjorkqvist M, Traskman-Bendz L, Brundin L. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry. 2009 Aug 1;66(3):287-92. doi: 10.1016/j.biopsych.2009.01.030. Epub 2009 Mar 6.
• Janelidze S, Mattei D, Westrin A, Traskman-Bendz L, Brundin L. Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav Immun. 2011 Feb;25(2):335-9. doi: 10.1016/j.bbi.2010.10.010. Epub 2010 Oct 15.
• Erhardt S, Lim CK, Linderholm KR, Janelidze S, Lindqvist D, Samuelsson M, Lundberg K, Postolache TT, Traskman-Bendz L, Guillemin GJ, Brundin L. Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology. 2013 Apr;38(5):743-52. doi: 10.1038/npp.2012.248. Epub 2012 Dec 3.
• Sha Q, Madaj Z, Keaton S, Escobar Galvis ML, Smart L, Krzyzanowski S, Fazleabas AT, Leach R, Postolache TT, Achtyes ED, Brundin L. Cytokines and tryptophan metabolites can predict depressive symptoms in pregnancy. Transl Psychiatry. 2022 Jan 26;12(1):35. doi: 10.1038/s41398-022-01801-8.

Helpful Links

• Van Andel Institutes
• Pine Rest Christian Mental Health Services
• Spectrum Health

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2014
• Primary Completion (Actual): February 28, 2017
• Study Completion (Actual): February 28, 2017

Study Registration Dates

• First Submitted: September 25, 2015
• First Submitted That Met QC Criteria: October 1, 2015
• First Posted (Estimate): October 2, 2015

Study Record Updates

• Last Update Posted (Actual): June 28, 2018
• Last Update Submitted That Met QC Criteria: June 27, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: depression; inflammation; mood disorder; suicidality; perinatal depression; glutamate; post-partum depression; post-partum suicidality; perinatal mood disorder; kynurenine pathway
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Self-Injurious Behavior; Depression; Depressive Disorder; Suicide; Mood Disorders
• Other Study ID Numbers: 14-458M; 1R01MH104622-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No