A first-of-its-kind study has identified overactive inflammation and loss of critical protective mechanisms in the brain as potential contributors to suicide risk. The findings could lead to the use of anti-inflammatory medications as a way of reducing this risk, especially where suicidal ideation can be ascertained early.
Global suicide rates continue to be a concern. Although there was an overall decline in suicide rates in the US between 2019 and 2021, the number has risen again according to the Centers for Disease Control and Prevention (CDC). The UK has seen a similar pattern, whereas in Australia, deaths by suicide have been on the rise since 2013.
Suicidal behavior is driven by a combination of psychological, social and biological factors. Previous studies have suggested that inflammation may contribute to altered brain chemistry and elevate suicide risk. Researchers from Van Andel Institute in the US have, in a first-of-its-kind study, examined the biological mechanisms occurring in the brain at the time of death by suicide to understand how they contribute to suicidal behavior.
“Our goal is to prevent suicide by better understanding the brain function associated with it,” said J John Mann, one of the study’s co-authors. “We focused on the brain because that’s where the biological processes that affect mood, suicidal ideation and intent, and decision-making reside. This study enabled us to see the brain at the moment of greatest risk and pinpoint biological markers of that risk.”
The researchers compared postmortem brain tissue samples from 29 people who died by suicide to samples from 32 people who died suddenly from other causes such as accident, homicide, or heart attack (the control group). The samples were taken from people aged from 17 to 77. Toxicology screening established that those who’d died by suicide were largely free of antidepressant and antipsychotic medications, which enabled the researchers to see more clearly suicide-related molecular changes that might otherwise have been masked.
After performing RNA sequencing and differential gene expression analysis on the samples, the researchers found that, in suicide decedents, the NPAS4 gene, a key regulator of inflammation and brain cell health, was significantly downregulated. When the researchers looked at gene methylation, the process by which genes are switched ‘on’ or ‘off’, they found 40 differentially methylated regions mapping to seven genes related to inflammation and immune response in people who died by suicide. There was a significant association between NPAS4 methylation and NPAS4 expression in the control group that was absent in the suicide decedent group, confirming its dysregulation.
Overall, the suicide decedent group showed an activation of gene sets related to inflammation and excitotoxic mechanisms. In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise safe and necessary neurotransmitters become pathologically high. The balance of inhibitor and excitatory neurotransmitter levels plays a significant role in several psychiatric disorders, including major depressive disorder.
In addition to overactive inflammatory mechanisms, there was a suppression of gene sets related to the maturation of oligodendrocytes, specialized cells that ensheath axons in myelin and protect neurons against oxidative injury. Fewer numbers of oligodendrocytes were observed.
The researchers say their study provides support for further exploration of anti-inflammatory medications to reduce the risk of suicidal behavior, especially where suicidal ideation has been ascertained.
“As suicide rates continue to rise, we must develop additional evidence-based strategies to address all the factors that contribute to suicide risk,” said Lena Brundin, corresponding author of the study. “Our study pinpoints several key changes in the brain that one day could be targeted for treatment with the goal of reducing risk and saving lives.”
The current study’s findings are also useful for researchers who are searching for blood biomarkers that correspond to suicide risk. Future studies will focus on further understanding the role of inflammation in suicide risk, identifying biomarkers and devising strategies to evaluate potential treatment options.
The study was published in the journal Molecular Psychiatry.
Source: Van Andel Institute
