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.

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 PER3, MTPAP, SLC25A26, CD19, SOX9, 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."

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]

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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