Gender-Based Suicide Tests on the Horizon

Megan Brooks

April 25, 2016

Building on their work in men, researchers from Indiana report that blood-based biomarkers and questionnaire-based apps may help predict suicidal thoughts and actions in women being treated for psychiatric disorders.

Together, the biomarkers and apps predicted in women future instances of suicidal thoughts with 82% accuracy and future suicide-associated hospital admissions with 78% accuracy, they report.

Lead investigator Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, believes gender-based tests for suicidality are on the horizon.

"We uncovered gender differences in terms of the biomarkers and in terms of some of the items of our suicide risk questionnaire/app. The diagnostic and preventive treatment aspects can and should be tailored by gender," he told Medscape Medical News.

Last year in Molecular Psychiatry, Dr Niculescu and colleagues reported that they had identified blood-based biomarkers and clinical predictors of suicidality in men with psychiatric disorders.

The investigators' latest research was published online April 5 in Molecular Psychiatry. The new article describes pilot studies in women using similar discovery and validation methods.

A Work in Progress

Using a "powerful" within-participant discovery approach, the researchers identified genes that change in expression in states characterized by no suicidal ideation (no SI) and in states with high suicidal ideation (high SI) in 12 of 51 women with bipolar disorder, depression, schizoaffective disorder, or schizophrenia.

They then used a Convergent Functional Genomics approach to prioritize the candidate biomarkers identified in the discovery step using prior evidence in the field.

With help from the coroner's office in Marion County, Indianapolis, they then validated the prioritized biomarkers using blood samples from six women who had committed suicide by assessing which markers changed stepwise from no SI to high SI to suicide completion.

They ended up with 50 biomarkers (49 genes; one gene had two different probesets that were validated) that survived Bonferroni correction. The researchers then evaluated the 50 biomarkers in an independent cohort of women with the same psychiatric disorders for the ability of those biomarkers to predict suicidal ideation (33 women) and psychiatric hospitalization due to suicidality (24 women).

Simultaneously, the researchers examined how two clinical app-based questionnaires, previously tested in men, perform in women. The Convergent Functional Information for Suicidality (CFI-S) is a 22-item scale and Android app for suicide risk that integrates in a simple yes-no format information about life issues such as physical and mental health, social isolation, stress, addiction, and cultural factors that can influence suicide risk. The other app, the Simplified Affective State Scale (SASS), is an 11-item scale for measuring mood and anxiety. Neither directly asks whether the individual is having suicidal thoughts.

The top CFI-S item distinguishing high SI from no SI states was the chronic stress of social isolation, the team notes. They also showed that the clinical information apps, when combined with the 50 validated biomarkers, constitutes a broad universal predictor of suicide (UP-Suicide) that successfully predicts suicidality in women.

UP-Suicide had a receiver-operating characteristic (ROC) area under the curve (AUC) of 82% for predicting SI and an AUC of 78% for predicting future hospitalizations for suicidality, they report.

"Some of the individual components of the UP-Suicide showed even better results," they note. "SASS had an AUC of 81% for predicting SI, CFI-S had an AUC of 84% and the combination of the two apps had an AUC of 87%."

One woman committed suicide while the study was ongoing. In retrospect, when the analyses were completed, her UP-Suicide risk prediction score was at the 100 percentile of all participants tested, the researchers say.

Plausible Pathways

The panel of 50 validated biomarkers (BioM-50) predicted future hospitalizations due to suicidality with an AUC of 94%. Key individual predictive biomarkers include B-cell lymphoma 2 (BCL2), which predicted future hospitalizations due to suicidality with an AUC of 89%, and PIK3C3, which had an AUC of 65% for SI and an AUC of 90% for future hospitalizations.

The researchers note that BCL2 and PIK3C3, as well as another top performer, glycogen synthase kinase 3 beta, have antiapoptotic and neurotrophic effects, are decreased in expression in suicidality, and are known targets of the antisuicidal mood stabilizing drug lithium, which increases their expression and/or activity.

Circadian clock genes were also "overrepresented" among the top biomarkers. Circadian clock abnormalities are related to mood disorder, and sleep abnormalities have been implicated in suicide, they point out.

"Docosahexaenoic acid signaling was one of the top biological pathways overrepresented in validated biomarkers, which is of interest given the potential therapeutic and prophylactic benefits of omega-3 fatty acids," they report. "Some of the top biomarkers from the current work in women showed co-directionality of change in expression with our previous work in men, whereas others had changes in opposite directions, underlying the issue of biological context and differences in suicidality between the two genders," they note.

Although the biomarkers and clinical tools were effective in predicting suicidality, Dr Niculescu cautioned that because the women had been diagnosed with psychiatric illnesses, it remains unclear how well the biomarkers would work in a nonpsychiatric population.

Further studies are planned or underway in several different populations.

"We have started studies in [emergency department] settings to translate the apps and biomarkers into practice in men and women, psychiatric and nonpsychiatric. We also started a study in military personnel and are planning a study in women in the postpartum period with colleagues in Australia," he told Medscape Medical News.

Scientifically Rigorous

"I like this paper, and the methodology they used is scientifically rigorous," Zachary A. Kaminsky, PhD, assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

"I have a good opinion of their discovery approach, which involves empirical evidence but also combined with biological understanding and putting multiple pieces of evidence together with a rigorous validation design," said Dr Kaminsky, who was not involved in the research.

He cautioned that the effects they uncovered might be specific to women, but they might not be. "This paper does not necessarily address to a large extent how this set of markers works in men. Whether or not this is female specific is unclear; it definitely could be. The key message is, while these biomarkers may work in a female-specific way, there may very well be biomarkers that work across the sexes.

"Suicide is, of course, a major problem, and what is lacking are objective measures to assess for suicidality. I think it's important to come up with objective predictors of suicidality beyond just asking someone if they are thinking of killing themselves or having thoughts of death or self-harm. These biomarkers may very well work in the general population," Dr Kaminsky said.

He added that he is "very optimistic" that a blood-based test for suicidality will eventually reach the clinic. "I think Alexander Niculescu's work, as well as other people's in the field, are really showing some promise in terms of replicability that gene regulation might give us a metric of what is going on. Things that these papers are finding, like dysregulation in stress response, suicide researchers have known for a long time are part of the etiology of suicide. For anything that happens on a behavioral level, there are going to be molecular changes. The question is, are we going to see them in the blood? Well, these studies suggest, 'maybe,' " Dr Kaminsky said.

This research was supported by a National Institutes of Health Directors' New Innovator Award and a Veterans Affairs Merit Award to Dr Niculescu. Dr Niculescu is listed as an inventor on a patent application being filed by Indiana University.

Mol Psychiatry. Published online April 5, 2016. Abstract

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