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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01MH118211-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Pine Rest Christian Mental Health Services | OTHER |
| Columbia University | OTHER |
| National Institute of Mental Health (NIMH) | NIH |
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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| Measure | Description | Time Frame |
|---|---|---|
| Suicidal behavior of participants | 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. | One year. |
| Establish metabolic biomarkers that indicate risk for suicidal behavior | 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). | One year. |
| Establish inflammatory biomarkers that indicate risk for suicidal behavior | 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). | One year. |
| Determine epigenetic marks in blood cells from patients with suicidal behavior | DNA methylation will be measured by Illumina Infinum methylationEPIC BeadChip microarrays, and compacted between patients with suicidal behavior and patients without suicidal behavior. | One year. |
| Functional validation of the significant methylation changes | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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People who are above age of 18, have a Major Depressive Disorder diagnosis and no ongoing immune disorders.
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pine Rest Christian Mental Health Services | Grand Rapids | Michigan | 49501 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Center for Disease Control and Prevention. Preventing Suicide. 2018. | ||
| 26511788 | Background | Shepard DS, Gurewich D, Lwin AK, Reed GA Jr, Silverman MM. Suicide and Suicidal Attempts in the United States: Costs and Policy Implications. Suicide Life Threat Behav. 2016 Jun;46(3):352-62. doi: 10.1111/sltb.12225. Epub 2015 Oct 29. | |
| 27111185 |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| D013406 | Suicide, Attempted |
| D003863 | Depression |
| D013405 | Suicide |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D016728 | Self-Injurious Behavior |
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blood draw
| One year. |
| Background |
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| D001526 |
| Behavioral Symptoms |
| D001519 | Behavior |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |