Just Wait A Little Longer: Suicide Biomarkers Getting Closer to the Clinic

“We still don’t know why some people take their own lives when confronted with difficult life situations while others who experience the same problems don’t even think about suicide,” Kees van Heeringen, PhD, Ghent University, Belgium, told Medscape Medical News. “So this is why we are using the stress vulnerability model to try and understand suicidal behavior, because there are 2 aspects on the pathway to suicide — stressors such as financial or professional problems or a psychiatric illness, and then a vulnerability or predisposition to suicidal behavior. [Because] the technical possibility to disentangle the complicated contributions of both is increasing quite rapidly, we needed to put all of this information into a neurobiological model of suicidal behavior to provide a platform for further research.”

The review was published in the inaugural May 2 issue of Lancet Psychiatry.

Traitlike Diathesis

Together with coauthor J. John Mann, MD, Columbia University, New York City, Dr. van Heeringen first explains that suicide is the result of an interaction between environmental stressors and a susceptibility to suicidal behavior ― what they call a “traitlike diathesis.”

“Findings from post-mortem studies of the brain and from genomic and in-vivo neuroimaging studies indicate a biological basis for this diathesis,” they state. They also point out that suicide runs in families — indeed, about half the risk for suicide is heritable, they note. Studies done in twins have shown that certain genetic factors are crucial to suicidal behavior. “So we want to know what those genes are and how they exert their effect.”

It has also long been known that the occurrence of suicidal behavior correlates with a disturbance in the serotonin system in the brain — the first finding of the neurobiological underpinnings of suicide and a key driver to understand more of the neurobiology behind suicidal behavior, Dr. van Heeringen said. Neuroimaging studies have also linked brain circuitry and localized changes in neurochemistry to the regulation of mood, reactive aggression, and decision making in particular, they add. Impairments in structural connectivity pathways have been linked to suicidal behavior as well, and reactivity to several stimuli appears to be altered in those who are susceptible to suicide. Thus, “structural abnormalities might constitute a biological-trait susceptibility that explains maladaptive responses to stressors including an acute psychiatric illness,” the authors suggest.

A recent meta-analysis of neuropsychological studies (Psychol Med. 2013;Sep 9:1-11) found that there was an association between susceptibility to suicidal behavior and impairments in cognitive control and decision making. The review authors postulate that deficiencies in decision-making processes might so narrow a susceptible individual’s view that suicide becomes the only solution to stopping intense emotional pain.

Stressful Life Events

Stressful life events and psychiatric disorders are both risk factors for suicide, but other elements need to contribute to suicide risk, because most patients with psychiatric disorders never display suicidal behavior, as the authors observe. Longitudinal studies have shown that adversity in childhood — particularly physical and sexual abuse — is one of the strongest risk factors for suicide. Epigenetic modifications in biochemical characteristics implicated in mood regulation and decision making could explain the association between childhood adversity and reactivity to stressors in later life, they suggest.

For example, one of the effects of epigenetic mechanisms following childhood sexual abuse is a rescheduling of stress responses in the brain, as Dr. van Heeringen indicated. “In fact, we have seen that stress hormones can kill serotonergic brain cells,” he added. “And early-life adversity and genetic factors might increase suicide risk through a moulding effect on brain circuitry and chemistry involved in reactivity to particular stress.” Dr. van Heeringen suggests that a possible approach to identifying biomarkers predictive of suicidal behavior might be to combine genetic markers of heightened risk and neuroimaging studies that identify predisposition or vulnerability to suicide through alternatives in brain circuitry and chemistry. “Suicide is never the consequence of a single cause,” Dr. van Heeringen said.

But because about one third of people who die from suicide die from their first attempt, “the aim for prevention is to detect these patients before any attempt is made…. Genomic markers and neuroimaging might identify patients at high risk of suicide and help to identify personalised interventions for the prevention of suicidal behaviour.”

Stress-Vulnerability Model

Asked by Medscape Medical News to comment on the study, Fabrice Jollant, MD, PhD, McGill University and Douglas Mental Health University Institute, Montreal, Canada, noted that 40 years of research on the neurobiology of suicidal behavior have enabled a new conceptualization of these acts — notably with the stress-vulnerability model.

“This has been an important step forward, and this review paper nicely summarizes the most recent findings,” Dr. Jollant observed. However, he cautioned that many challenges are left to resolve before what is known can be clinically applied. Among these challenges is replication of results that in heterogeneous populations is difficult. “Many pathways may also lead to suicide,” he added.

For example, some suicides may be strongly related to early negative environment and its biological consequences; others to pathologic aging with different consequences; still others mainly to the expression of genes; or for some, just a mix of different factors, including major stressful events during midlife. “We will also need to test if all these biomarkers, whether genetics or neural (and maybe a combination of both), really improve prediction,” Dr. Jollant said. “The question will be, how much does a given biomarker bring to the clinical assessment in terms of prediction or organization of care? Long prospective studies of at-risk populations and therapeutic intervention trials based on biomarkers will be necessary.”

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