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A Longitudinal Study of Inflammatory Pathways in Depression

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ClinicalTrials.gov Identifier: NCT04159207
Recruitment Status : Recruiting
First Posted : November 12, 2019
Last Update Posted : March 30, 2021
Sponsor:
Collaborators:
Pine Rest Christian Mental Health Services
Columbia University
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Lena Brundin, Van Andel Research Institute

Tracking Information
First Submitted Date September 30, 2019
First Posted Date November 12, 2019
Last Update Posted Date March 30, 2021
Actual Study Start Date October 1, 2019
Estimated Primary Completion Date June 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: November 7, 2019)
  • Suicidal behavior of participants [ Time Frame: One year. ]
    The presence of suicidal behavior over one year will be classified as yes/no as the primary outcome measure. The Identification of participants with suicidal behavior at each study time point will be achieved by assessment using the Columbia Suicide Severity Rating Scale (C-SSRS) regarding attempt, interrupted or aborted attempt, or preparatory acts over the past 7 days.
  • Establish metabolic biomarkers that indicate risk for suicidal behavior [ Time Frame: One year. ]
    Evaluate if metabolic biomarkers are predictive of suicidal behavior (planning, attempting) among patients with depression. Metabolites will be measured by high-pressure liquid chromatography, ultra-high performace liquid-chromatography and gas-chromatography mass-spectrometry). The main metabolite biomarker outcomes are quinolinic, kynurenic and picolinic acids as well as 3-HK and kynurenine (nM).
  • Establish inflammatory biomarkers that indicate risk for suicidal behavior [ Time Frame: One year. ]
    Evaluate if inflammatory biomarkers are predictive of suicidal behavior (planning, attempting) among patients with depression. Inflammatory markers will be measured using high-sensitivity ELISAs, Mesoscale platform or Luminex platforms. The main cytokine outcomes are TNF-alpha and IL-6 (pg/ml).
  • Determine epigenetic marks in blood cells from patients with suicidal behavior [ Time Frame: One year. ]
    DNA methylation will be measured by Illumina Infinum methylationEPIC BeadChip microarrays, and compacted between patients with suicidal behavior and patients without suicidal behavior.
  • Functional validation of the significant methylation changes [ Time Frame: One year. ]
    mRNA will be quantified by qPCR in the same peripheral blood samples as used for the EPIC array for functional validation of the significant methylation changes.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title A Longitudinal Study of Inflammatory Pathways in Depression
Official Title A Longitudinal Study of Inflammatory Pathways in Depression
Brief Summary

Suicide accounts for at least 1 million deaths globally each year. This is likely a significant underestimate, because suicide is under-reported in many countries. In the US, over 42,000 people die from suicide annually. Despite increased focus on identification and treatment, the rate of suicide has increased steadily over the past 15 years.

Our project aims both to improve our understanding of factors that increase the risk for suicide by comparing blood biomarkers associated with inflammation in patients with depression without suicidal behavior and patients with depression and suicidal behavior. The 160 individuals in this study will be followed with psychiatric assessments and blood samples at repeated time points over one year.

Detailed Description

Suicide is a leading cause of death in the US, and its rate continues to increase. Most individuals who die by suicide are in contact with health care, but clinical risk assessment is challenging. Inflammatory biomarkers have tentatively been linked to suicide. However, longitudinal studies establishing their accuracy in tracking suicidal behavior and critical symptoms are lacking. This study is a longitudinal study, with 1,280 total assessments planned, measuring suicidal ideation and behavior, associated clinical symptoms and blood biomarkers of inflammation.

Our overriding aim is to identify a set of biomarkers that distinguish patients with suicidal behavior from depressive patients without suicidal behavior. Further, the investigators intend to define biomarkers that are elevated during active suicidal behavior (at- risk periods) within the same patients (longitudinally).

Our working model is that inflammation (via pro-inflammatory cytokines) induces the kynurenine pathway, leading to an increased production of neurotoxic kynurenine metabolites (i.e., the NMDA-receptor agonist quinolinic acid, or others), which trigger suicidal behavior. The Investigators predict that immunomodulatory cells and molecules, including cytokines and kynurenine metabolites in plasma, may constitute biomarkers of suicidal behavior. The Investigators also predict that elevated inflammatory markers in suicidal individuals will be associated with epigenetic changes, regulating the expression of kynurenine enzymes in blood cells.

Aims:

  1. Establish biomarkers that indicate risk for active suicidal behavior;
  2. Determine epigenetic markers in the blood of patients with suicidal behavior.

In Aim 1, the investigators will enroll patients with Major Depressive Disorder (MDD) and active suicidal behavior (planning or attempts), and MDD patients without current or past suicidal behavior. Each subject will be assessed at eight time-points over one year. The Investigators will measure interleukins and acute phase reactants as well as tryptophan, serotonin and metabolites of the kynurenine pathway in peripheral blood.

For aim 2, the investigators will perform whole-genome methylation analysis using Illumina EPIC arrays, followed by gene pathway analyses, in blood of the enrolled patients.

Our project will aid the implementation of biomarkers in clinical care for patients with suicide risk, in order to enable intensified intervention during critical time-points. The biological insight obtained here can guide therapeutic development specifically targeting suicidality, with the ultimate goal of reducing suicide numbers.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
blood draw
Sampling Method Non-Probability Sample
Study Population People who are above age of 18, have a Major Depressive Disorder diagnosis and no ongoing immune disorders.
Condition
  • Major Depressive Disorder
  • Suicide, Attempted
Intervention Not Provided
Study Groups/Cohorts A Longitudinal Study of Inflammatory Pathways in Depression
We target to recruit 80 patients with Major Depression Disorder diagnosis and 80 patients with Major Depression Disorder with suicidal behavior.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: November 7, 2019)
160
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 30, 2024
Estimated Primary Completion Date June 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Men and women ages 18 years and older will be included in the study.
  • 80 who are diagnosed with MDD by SCID but do not endorse current or past suicidal behaviors.
  • 80 who are diagnosed with MDD by SCID and endorse current suicidal behavior as defined by C-SSRS (preparatory acts, aborted or interrupted attempts, as well as completed attempts).
  • English speaking.
  • Willing and able to take part of the different steps in the study, including follow-up interviews and blood draws.

Exclusion Criteria:

  • Vulnerable populations (e.g. incarcerated individuals).
  • Subjects with dementia or otherwise cognitively impaired subjects with difficulty understanding the study procedures.
  • Patients with a primary psychiatric diagnosis other than MDD.
  • Patients with an active somatic disorder primarily involving the immune system (autoimmune diseases such as Crohns disease, multiple sclerosis, or rheumatoid arthritis; or hematological diseases such as lymphoma or leukemia).
  • Patients on chronic and systemic immunomodulatory treatment. Examples are patients with a liver- or kidney transplant or medications used for disorders involving the immune system, as mentioned above. Examples of immunomodulatory treatments are cyclosporin, azathioprine, infliximab, corticosteroid treatment.
  • Patients undergoing active treatment for any form of cancer (chemotherapy or immunomodulatory treatments).
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: William Boshoven 616.259.7626 william.boshoven@pinerest.org
Contact: LeAnn Smart 616.222.4592 leann.smart@pinerest.org
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT04159207
Other Study ID Numbers 19010
1R01MH118211-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Lena Brundin, Van Andel Research Institute
Study Sponsor Van Andel Research Institute
Collaborators
  • Pine Rest Christian Mental Health Services
  • Columbia University
  • National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Lena C Brundin, M.D.; Ph.D. Van Andel Research Institute
Principal Investigator: Eric Achtyes, M.D. Pine Rest Christian Mental Health Services
Principal Investigator: Joseph Mann, M.D. Columbia University Health Sciences
PRS Account Van Andel Research Institute
Verification Date March 2021