Major depressive disorder affects over 300 million people worldwide, but so far there have been no established biomarkers that clinicians can rely on to detect early-stage depression symptoms. Now, in a new study published in Scientific Reports, scientists at Fujita Health University led by Professor Yasuko Yamamoto have shown that the levels of anthranilic acid in blood may provide a basis for identifying patients at risk of major depressive disorder. [ Fujita Health University]

The results of research headed by scientists at Japan’s Fujita Health University suggest that a metabolite in the kynurenine (KYN) pathway could represent a clinical biomarker for identifying individuals with depression-like symptoms who are at risk of developing major depressive disorder. The KYN pathway is the main pathway involved in tryptophan (TRP) metabolism.

Studies by Kuniaki Saito, PhD, Yasuko Yamamoto, PhD, and colleagues found individuals who were at high risk of major depressive disorder (HRMDD) exhibited elevated blood levels of the KYN pathway metabolite anthranilic acid (AA), and decreased levels of tryptophan when compared with control individuals, but no changes to other metabolites. “Various lines of scientific evidence suggest that tryptophan metabolism is involved in the symptoms of major depressive disorder,” Yamamoto noted. “Monitoring the levels of tryptophan metabolites may be useful for the realization of preemptive medicine for depressive symptoms,” Saito added. The researchers reported their studies in Scientific Reports, in a paper titled, “Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder.”

More than 300 million people suffered from major depressive disorder (MDD) in 2017, and the incidence is on the rise year on year, the authors wrote. There are multiple theories of MDD onset. “The monoamine hypothesis, the chronic inflammation hypothesis, and the abnormalities in the hypothalamus-pituitary-adrenal (HPA) system hypothesis are the predominant hypotheses regarding the pathogenesis of MDD.” Of these, the chronic inflammation hypothesis is linked with the KYN pathway. “Increasing evidence has been gathered regarding the relationship between the activation of the KYN pathway and the onset of depression,” the investigators suggested.

Scientists have long studied different metabolic pathways related to inflammation, and past research has indicated that patients with depression and other conditions involving depression-like symptoms exhibit increased blood levels of various tryptophan metabolites produced by the kynurenine pathway. “Interestingly, the KYN pathway is more highly activated in patients with various psychiatric disorders than healthy subjects,” they further noted. The combined findings from previous studies prompted Saito’s team to speculate that metabolites of the kynurenine pathway may serve as biomarkers that could allow early detection of patients at risk of developing depression.

To test this idea, Saito’s team analyzed serum samples from 61 patients who had clinical test scores that indicated a high risk of developing major depressive disorder, and from another 51 healthy control individuals. Compared to control individuals, the patients—both men and women—at risk of depression had increased serum levels of anthranilic acid. “In both males and females, the concentration of AA was significantly higher in the HRMDD group than the healthy control group,” the authors wrote. Women in the HRMDD group also had reduced levels of TRP. “The concentration of TRP in females of HRMDD group was significantly lower than that of the healthy control group.” Given that the kynurenine pathway uses tryptophan and produces anthranilic acid, the findings are in agreement with previous study results reporting increased kynurenine pathway activity in patients at risk of developing major depressive disorder. “These data suggest that TRP metabolites could be useful markers for depressive symptoms,” the authors stated.

The scientists also wanted to find out whether tryptophan metabolite profiles could predict the progression of depression-related symptoms. They carried out additional analyses on samples and data from 33 patients at risk of depression, whose scores on a clinical depression scale at different time points indicated regression from a healthy state to a depressed state. The results showed that increasing anthranilic acid levels over time correlated with worsening clinical test scores. “These results suggest that AA is a good biomarker for HRMDD, the team noted. Saito further stated, “This finding confirms that there is indeed a strong, direct correlation between anthranilic acid levels in blood and the severity of depression on the clinical depression scale.”

Chronic pain can also cause depression and related symptoms, so the scientists then assessed tryptophan metabolite profiles in patients with chronic pain disorders affecting the mouth, jaw, and face. A comparative analysis of serum samples from 48 patients with chronic pain disorders and another 42 healthy individuals indicated that chronic pain was associated with elevated serum levels of anthranilic acid and lower serum levels of tryptophan. The results were similar to those recorded for patients who were at risk of major depressive disorder.

Interestingly, the researchers also identified elevated blood serum AA levels in a mouse model of stress known as the chronic unpredictable mild stress (CUMS) mouse model, which develop depression-like behaviors.

The collective results indicate that monitoring serum anthranilic acid levels could represent a workable approach to identifying patients who might be at risk of developing major depressive disorder. “We speculate from these data that TRP metabolites are useful biomarkers for the realization of preemptive medicine in depressive symptoms,” they commented. Preemptive medicine refers to the goal of predicting disease before its onset, and preventing or delaying that onset, a concept that would hinge on the availability of predictive biomarkers. “To facilitate pre-emptive medical care, it is important to develop effective biomarkers for the early diagnosis of disease,” they wrote. However, in the case of MDD, “… there are currently no effective established biomarkers that can be used to diagnose depressive symptoms in the early stages.” The reported work is thus particularly encouraging, as it points to potential biomarkers for MDD in high risk patients.

While the researchers acknowledged that more research will be needed to validate the clinical relevance of serum anthranilic acid levels and to understand how tryptophan metabolism influences outwardly aspects like mood, they suggest AA may have clinical utility as an early stage biomarker, and also help to identify more individualized care. “Although further study is needed to elucidate the relationship between the onset of depression and the change in the concentration of AA, our data show that AA may be a useful biomarker to detect the early stages of depression … Monitoring TRP metabolites may be useful for determining disease progression in depression. Furthermore, it may provide a benefit in terms of the establishment of personalized treatment options.”

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