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CME / ABIM MOC / CE

Could Blood Biomarkers Help Identify Suicide Risk?

  • Authors: News Author: Megan Brooks; CME Author: Laurie Barclay, MD
  • CME / ABIM MOC / CE Released: 6/24/2022
  • Valid for credit through: 6/24/2023
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

    Nurses - 0.25 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)

    Physician Assistant - 0.25 AAPA hour(s) of Category I credit

    IPCE - 0.25 Interprofessional Continuing Education (IPCE) credit

    You Are Eligible For

    • Letter of Completion
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Target Audience and Goal Statement

This activity is intended for psychiatrists, family medicine and primary care clinicians, geneticists, genomic specialists, internists, nurses, physician assistants, and other members of the health care team for patients who may be at risk for suicide.

The goal of this activity is that learners of the health care team will be better able to describe gene expression changes in brain and blood associated with suicide that could facilitate development of biomarkers for suicide risk, based on a postmortem study of patients with major depressive disorder and nonpsychiatric controls.

Upon completion of this activity, participants will:

  • Assess gene expression changes in brain and blood associated with suicide, based on a postmortem study of patients with major depressive disorder who died by suicide, patients with major depressive disorder who died by other means, and nonpsychiatric controls
  • Evaluate clinical and research implications of gene expression changes in brain and blood associated with suicide, based on a postmortem study of patients with major depressive disorder who died by suicide, patients with major depressive disorder who died by other means, and nonpsychiatric controls
  • Outline implications for the healthcare team


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News Author

  • Megan Brooks

    Freelance writer, Medscape

    Disclosures

    Megan Brooks has no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Laurie Barclay, MD, has the following relevant financial relationships:
    Formerly owned stocks in: AbbVie 

Editor/Compliance Reviewer

  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Yaisanet Oyola, MD, has no relevant financial relationships.

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC / CE

Could Blood Biomarkers Help Identify Suicide Risk?

Authors: News Author: Megan Brooks; CME Author: Laurie Barclay, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 6/24/2022

Valid for credit through: 6/24/2023

processing....

Clinical Context

Worldwide, suicide is a serious public health problem, causing nearly 800,000 deaths per year. In the United States, suicide rates increased by more than 35% during the past 2 decades, and suicide was the tenth leading cause of death.

Despite frequent health care contacts many individuals do not disclose suicidal intentions and are especially at risk shortly after psychiatric hospital discharge. Clinicians and members of the health care team have a critical opportunity to assess persons at risk with a blood biomarker test for suicidal risk.

Study Synopsis and Perspective

Newly identified serum biomarkers have the potential, via blood testing, to flag patients who have major depressive disorder (MDD) at high risk for suicide.

Investigators found that patients with MDD who died by suicide had a gene expression signature in blood distinct from patients with MDD who died by other means.

The signature included genes involved in stress response changes, including polyamine metabolism, circadian rhythm, immune dysregulation, and telomere maintenance.

"These blood biomarkers are an important step toward developing blood tests to identify patients with imminent risk of ending their lives," study investigator Adolfo Sequeira, PhD, associate researcher in the Department of Psychiatry & Human Behavior, University of California Irvine School of Medicine, said in a news release.

"To our knowledge, this is the first study to analyze blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide," Dr Sequeira added.

The findings were published online April 14 in Translational Psychiatry.

A Pressing Challenge

Suicide rates in the US have jumped by more than 35% during the past 2 decades, with more than 48,000 deaths by suicide occurring just in 2021. MDD is the most common diagnosis among completed suicides and identifying individuals at the highest risk for suicide remains a "pressing challenge," the researchers note.

They looked for changes in gene expression associated with suicide in archived postmortem blood and brain samples from adults with MDD who died by suicide (MDD-S) or by other means (MDD-NS), as well as a group of controls with no psychiatric illness.

In total, there were blood and brain samples for 45 adults, including 53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) tissue samples.

In blood, investigators identified 14 genes that significantly differentiated MDD-S from MDD-NS. The top 6 genes differentially expressed in blood were PER3MTPAPSLC25A26CD19SOX9, and GAR1.

In addition, 4 genes showed significant changes in brain and blood between the MDD-S and MDD-NS groups. SOX9 was decreased and PER3 was increased in MDD-S in both blood and brain samples, whereas CD19 and TERF1 were increased in blood but decreased in DLPFC.

SOX9, an astrocytic marker in the brain and B-cell marker in blood, has been shown to be decreased in MDD-S compared with controls in the prefrontal cortex.

In the current study, researchers found that SOX9 expression was significantly reduced both in blood and brain in MDD-S compared with MDD-NS, "suggesting similar immune/astrocytic dysregulations in suicide that could be further investigated."

Potential Signatures, Potential Targets

PER3 is a circadian rhythm gene implicated in sleep disorders associated with shifts in circadian rhythms and is thought to increase susceptibility to MDD.

Mutations in PER3 have been shown previously to alter multiple systems, including response to antidepressants, and increased blood expression of PER1 has been linked to suicidality in women, the researchers note. 

There were also significantly higher levels of 2 inflammatory markers (CD19 and CD6 genes) in the blood of patients with MDD-S compared with patients with MDD-NS.

Another "significant" finding was the involvement of several mitochondrial genes in suicide, the researchers note. 

Two nuclear genes coding for mitochondria-located proteins MTPAP (a mitochondrial poly(A) polymerase) and the mitochondrial polyamine transporter SLC25A26 were increased in blood in patients with MDD-S compared with patients with MDD-NS and controls, suggesting that "mitochondrial alterations could be used as potential signatures to differentiate MDD-S from MDD-NS patients and also from controls," the authors write.

They add that the genes found to be dysregulated in suicide represent potential targets for future drug therapies to prevent suicide and could also be used to develop a molecular test to identify individuals at high risk for suicide.

The study was funded by the National Institute of Mental Health, the American Society for Suicide Prevention, and the Pritzker Family Philanthropic Fund. The investigators have reported no relevant financial relationships.

Transl Psychiatry. Published online April 14, 2022.[1]

Study Highlights

  • Blood (n=53) and DLPFC (n=69) samples were available for 45 subjects: patients with MDD-S, patients with MDD-NS, and age- and sex-matched controls.
  • Gene expression was analyzed using RNA and the NanoString platform.
  • In blood, 14 genes significantly differentiated MDD-S from MDD-NS.
  • The top 6 genes differentially expressed in blood were PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1.
  • Four genes showed significant changes in brain and blood between MDD-S and MDD-NS: in MDD-S, SOX9 was decreased and PER3 was increased in both tissues, whereas CD19 and TERF1 were increased in blood but decreased in DLPFC.
  • Patients with MDD-S vs MDD-NS had significantly higher blood levels of CD19 and CD6, both of which are inflammatory markers.
  • Compared with patients with MDD-NS and controls, patients with MDD-S had increased blood levels of 2 nuclear genes coding for mitochondria-located proteins MTPAP and the mitochondrial polyamine transporter SLC25A26.
  • The investigators concluded that their findings strongly suggest that blood gene expression is highly informative for clarifying molecular changes in suicide.
  • In this study, significantly decreased SOX9 expression both in blood and brain in MDD-S vs MDD-NS suggests immune and/or astrocytic dysregulations in suicide meriting further investigation.
  • PER3 mutations have been implicated in antidepressant response, and increased PER1 blood expression in suicidality among women.
  • The variability in direction of CD19 and TERF1 between blood and brain is understandable, as blood and brain may not be exposed to the same metabolic environment or stress-related factors, which could affect expression levels for some genes.
  • Differential gene expression in blood between MDD-S and MDD-NS reflects involvement of genes affecting stress response and polyamine metabolism, circadian rhythm, immune dysregulation, and telomere maintenance in patients at risk for suicide.
  • In this study, upregulated expression of CD19 and CD6 genes, markers for B and T cells, respectively, and increased expression of the glucocorticoid receptor in MDD-S vs MDD-NS highlight stress/inflammation upregulation in suicides.
  • This suggests a significant relationship between suicide and an overactive immune system in patients with MDD, leading to the hypothesis that inflammation plays a role in the suicidal tendencies of depressed individuals.
  • Increased blood expression of several mitochondrial genes in suicide suggests that mitochondrial alterations could be used as potential signatures to differentiate patients with MDD-S from patients with MDD-NS and also from controls.
  • Future studies in large clinical populations investigating these systems might help clinicians identify acutely suicidal patients with MDD by testing for a suicide biomarker signature in blood.
  • Genes shown to be dysregulated in suicide also represent potential targets for future drug therapies to help prevent suicide.
  • Study limitations include a higher proportion of males than females, small sample, and analysis of only 1 brain region.
  • Future, larger studies of SNP (trait) markers could be combined with investigations of gene expression suicide phenotype signatures (state) to examine more comprehensively how these factors affect suicide risk.

Clinical Implications

  • Blood gene expression is highly informative for clarifying molecular changes in suicide, a postmortem study suggests.
  • Future studies in large clinical populations investigating these systems might help clinicians and members of the health care team to identify acutely suicidal patients with MDD by testing for a suicide biomarker signature in blood.
  • Implications for the Health Care Team: Genes shown to be dysregulated in suicide also represent potential targets for future drug therapies to help prevent suicide. In this study, upregulated expression of CD19 and CD6 genes, markers for B and T cells, respectively, and increased expression of the glucocorticoid receptor in MDD-S vs MDD-NS highlight stress/inflammation upregulation in suicides. This suggests a significant relationship between suicide and an overactive immune system in patients with MDD, leading to the hypothesis that inflammation plays a role in the suicidal tendencies of depressed individuals.

 

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