Summary: A new study reveals critical brain changes linked to suicide risk. The research identified overactive inflammation and the loss of protective brain mechanisms as key factors.
This breakthrough supports the potential use of anti-inflammatory medications to mitigate suicide risk, particularly in early stages of suicidal ideation.
The study, showcasing the most comprehensive analysis of gene methylation and transcriptomic data from suicide victims’ brains, offers new avenues for treatment and early risk detection.
- The study found increased brain inflammation and reduced activity in protective mechanisms in individuals who died by suicide.
- Key molecular changes identified include reduced activity in the NPAS4 gene, more excitotoxicity, and fewer protective oligodendrocytes.
- The research could pave the way for a blood test to evaluate suicide risk and treatments targeting inflammation.
Source: Van Andel Research Institute
A first-of-its-kind study has identified overactive inflammation and loss of critical protection mechanisms in the brain as potential contributors to suicide risk.
The findings support further exploration of anti-inflammatory medications to reduce risk, especially in situations where suicidal ideation can be ascertained early.
The study was published in the journal Molecular Psychiatry and led by Van Andel Institute’s Lena Brundin, M.D., Ph.D., Columbia University Department of Psychiatry’s J. John Mann, M.D., and Western Michigan University Homer Stryker M.D. School of Medicine’s Eric Achtyes, M.D., M.S.
“As suicide rates continue to rise, we must develop additional evidence-based strategies to address all the factors that contribute to suicide risk,” Brundin said. “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.”
Suicidal behavior is driven by a mix of psychological, social and biological factors. Earlier research — including previous findings by Brundin, Mann and Achtyes — suggests sustained inflammation may cause a toxic imbalance that alters brain chemistry and elevates suicide risk.
The new findings build on this earlier work by identifying key molecular differences that drive inflammation and may contribute to suicidal behavior.
The research team compared the brains of 29 people who died by suicide to brains of 32 people who died from other causes. The people who died by suicide in the study were largely free of antidepressive and antipsychotic medications, which enabled the team to more clearly see suicide-associated molecular changes that otherwise may be masked.
“Our goal is to prevent suicide by better understanding the brain function associated with it,” Mann said.
“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.”
Overall, the team found increased inflammation paired with reduced activity in mechanisms that protect the brain. Specific changes in the brains of people who died by suicide include:
- Less activity in the gene NPAS4, which regulates inflammation and helps maintain brain cell health. This reduced activity enables inflammation.
- More excitotoxicity, an inflammatory process that contributes to cell death.
- Fewer oligodendrocytes — specialized cells that protect nerve fibers. Evidence suggests these vital cells may succumb to damage caused by inflammation, leaving nerve fibers vulnerable.
The study also represents the most thorough analysis to date of integrated gene methylation and transcriptomic data derived from the brains of people who died by suicide.
Gene methylation is a process that switches genes “on” or “off” by annotating them with special chemical tags. In people who died by suicide, the study found methylation patterns that promoted aberrant inflammation.
In tandem with the current study, Brundin, Mann and Achtyes are searching for biomarkers — measurable substances — in the blood that correspond to suicide risk. They envision a future in which clinicians have a validated blood test to evaluate suicide risk and approved treatment strategies to reduce that risk, potentially by targeting inflammation.
Toward this goal, future studies will focus on further understanding inflammation’s role in suicide risk, searching for biomarkers and devising strategies to evaluate potential treatment options.
“Clinicians desperately need enhanced ways to identify patients at increased risk of suicide,” Achtyes said. “Detecting patterns in molecular markers to flag those at heightened risk could be a valuable tool for helping individuals who are struggling.”
Note:The confidential 988 Suicide & Crisis Lifeline is free and available 24/7 by dialing or texting 988.
Authors include Qiong Sha, Ph.D., Zhen Fu, Ph.D., Martha L. Escobar Galvis, Ph.D., Zach Madaj, M.S., and Jennifer A. Steiner, Ph.D., of VAI; and Mark D. Underwood, Ph.D., Andrew Dwork, M.D., Norman Simpson, Hanga Galfalvy, Ph.D., and Gorazd Rozoklija, M.D., Ph.D., of Columbia University. VAI’s Genomics Core and Bioinformatics and Biostatistics Core contributed to this work. The authors thank the families of the deceased participants for their donation of brain tissue and sharing of clinical information.
Funding: Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award no. R01MH118211 (Brundin, Mann and Achtyes). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About this neuroinflammation and mental health research news
Author: Beth Hinshaw
Source: Van Andel Research Institute
Contact: Beth Hinshaw – Van Andel Research Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Integrative transcriptome- and DNA methylation analysis of brain tissue from the temporal pole in suicide decedents and their controls” by Lena Brundin et al. Molecular Psychiatry
Integrative transcriptome- and DNA methylation analysis of brain tissue from the temporal pole in suicide decedents and their controls
Suicide rates have increased steadily world-wide over the past two decades, constituting a serious public health crisis that creates a significant burden to affected families and the society as a whole. Suicidal behavior involves a multi-factorial etiology, including psychological, social and biological factors.
Since the molecular neural mechanisms of suicide remain vastly uncharacterized, we examined transcriptional- and methylation profiles of postmortem brain tissue from subjects who died from suicide as well as their neurotypical healthy controls.
We analyzed temporal pole tissue from 61 subjects, largely free from antidepressant and antipsychotic medication, using RNA-sequencing and DNA-methylation profiling using an array that targets over 850,000 CpG sites.
Expression of NPAS4, a key regulator of inflammation and neuroprotection, was significantly downregulated in the suicide decedent group. Moreover, we identified a total of 40 differentially methylated regions in the suicide decedent group, mapping to seven genes with inflammatory function.
There was a significant association between NPAS4 DNA methylation and NPAS4 expression in the control group that was absent in the suicide decedent group, confirming its dysregulation. NPAS4 expression was significantly associated with the expression of multiple inflammatory factors in the brain tissue.
Overall, gene sets and pathways closely linked to inflammation were significantly upregulated, while specific pathways linked to neuronal development were suppressed in the suicide decedent group.
Excitotoxicity as well as suppressed oligodendrocyte function were also implicated in the suicide decedents. In summary, we have identified central nervous system inflammatory mechanisms that may be active during suicidal behavior, along with oligodendrocyte dysfunction and altered glutamate neurotransmission.
In these processes, NPAS4 might be a master regulator, warranting further studies to validate its role as a potential biomarker or therapeutic target in suicidality.