MIAMI — Elevated activation of the kynurenine pathway (KP) may be an objective signal of suicidality in adolescents with major depressive disorder (MDD), new research indicates.

In a study of 50 depressed teens with MDD, KP activation was elevated in those with a history of suicide attempt and those who were acutely suicidal, but not in those who were not suicidal.

"We're trying to find biological markers that can help us identify adolescents who are at risk for suicide, because right now, all we have when trying to assess suicide risk is the kids' words that they are suicidal or that they are not. We don't have any good, clear way in the medical world to measure that quantitatively," Kailyn Bradley, PhD, from the Icahn School of Medicine at Mount Sinai, in New York City, told Medscape Medical News.

The study was presented here at the American Society of Clinical Psychopharmacology (ASCP) 2015 Annual Meeting.

The neuroimmunologic KP has been implicated in MDD in adults and adolescents and, more recently, in suicidality in adults, Dr Bradley said.

The pathway is initiated by proinflammatory cytokines, she explained. "Inflammation in the body activates indoleamine 2,3-dioxygenase (IDO), which breaks tryptophan into kynurenine, which is further broken down into neurotoxins. We thought this was a good set of metabolites to examine with regard to creating toxicity in this reward circuitry that might lead people to have suicidal behavior and depression."

The researchers hypothesized that depressed adolescents at high risk for suicide would exhibit elevations in levels of IDO, kynurenine, and 3-hydroxyanthranilic acid (3-HAA) and decreased levels of tryptophan.

The study population consisted of 20 teens with MDD who were at high risk for suicide, determined on the basis of past attempts or because they expressed active suicidal intent, 30 nonsuicidal depressed teens, and 22 healthy control individuals.

The researchers measured plasma levels of tryptophan, kynurenine, 3-HAA, and IDO, as indexed by the kynurenine-to-tryptophan ratio (KYN/TRP), in the three groups of adolescents.

Dr Kailyn Bradley

They found that the teens with MDD who were at high risk for suicide showed decreased levels of tryptophan compared with the teens who were depressed but who were not suicidal and with the healthy control participants (P = .012).

Similarly, the teens who were suicidal showed elevations in KYN/TRP compared with both the nonsuicidal depressed teens and the healthy control individuals (P = .045).

When medicated patients were excluded, the findings became more significantly pronounced and continued to show a positive correlation between the KYN/TRP ratio and suicidality (P = .038).

The investigators also found that depressed adolescents who had a history of suicide attempt differed from adolescents who were acutely suicidal with respect to disease severity (P = .003), anhedonia (P = .012), and suicidality (P = .001), but not with respect to KP activation.

"Our acutely suicidal adolescents were very severely ill, they had higher depression scores on our depression inventory, they were highly anhedonic, obviously they were suicidal, more suicidal than our past attempters, but when we looked at activation of the KP, there's no difference between these two groups. The suicidal group is much more severely ill, but physiologically with respect to the KP, they are similar," Dr Bradley said.

"We think this helps explain that clinical phenomenon that adolescents who have previously attempted suicide are at a heightened risk for completion of suicide later. We think this is a biological way to explain why we see that phenomenon," she said.

The findings need to be replicated in larger samples, added senior author Vilma Gabbay, MD, from the Icahn School of Medicine at Mount Sinai, in New York City, and the Nathan S. Kline Institute for Psychiatric Research, in Orangeburg, New York.

"The test can now be done in multiple labs, but the translation into research needs larger samples. Similar findings are reported in adults with depression, and we hope that if the findings are replicated in larger studies, KP could become a biomarker for suicide, just like we have biomarkers for heart attack risk," Dr Gabbay told Medscape Medical News.

Dr Vilma Gabbay

"Suicide is the worst. This is what really kills our psychiatric patients. And we have no tools to identify them. At least here, if we can do a blood test in the emergency room and the KP is elevated, we can keep the patient overnight. It is some biomarker that we can identify. The common clinical risk factor is past suicide attempt, so linking it to biology and taking the clinical information along with biological phenomena can increase our chances to prevent the suicide. That is the goal," she said.

"The assessment of suicidality of a patient is one of the most common tasks that psychiatrists are asked to do. Even when we are frequently confronted with this, the accurate prediction of who will attempt or succeed in committing suicide has been problematic and elusive. It is even more problematic in children and adolescents, as it is frequently an impulsive act," said José T. Zaglul, MD, medical director, Florida Clinical Research Center, in Bradenton, told Medscape Medical News.

"The development of a biological test that could possibly add to the different factors and information that we use in the assessment of suicidal patients would be welcomed news. Again, suicidal behavior is influenced by multiple factors, and for that reason, a biological test would only point to an increased risk for the behavior and needs to be interpreted in the context of each individual patient," Dr. Zaglul, who was not involved in the research, said.

The study was funded by the National Institutes of Health. Dr Bradley, Dr Gabbay, and Dr Zaglul report no relevant financial relationships.

American Society of Clinical Psychopharmacology (ASCP) 2015 Annual Meeting. Abstract 3000407. Presented June 23, 2015.


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