Abstract
Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
Highlights
Suicide is defined as the intentional termination of one’s own life, and constitutes the 10th leading cause of death globally.[1]According to a recent report by the World Health Organization, 4800 000 deaths by suicide occur around the world each year.[2]
cerebrospinal fluid (CSF) cohort We found that the levels of picolinic acid (PIC) were significantly decreased in the CSF of suicide attempters (n = 64) compared with healthy controls (n = 36; t-test, P o 0.001, n = 100; Figure 2a)
There were no differences in the degree of IDO/TDO activation in the peripheral blood between the suicide attempters and the DISCUSSION To our knowledge, our study provides the first evidence of healthy controls as indicated by an unaltered kynurenine/ reduced levels of PIC in CSF and blood in conjunction to a suicide attempt in two independent cohorts, as well as over a longitudinal follow-up period in patients initially enrolled in the CSF cohort
Summary
Suicide is defined as the intentional termination of one’s own life, and constitutes the 10th leading cause of death globally.[1]According to a recent report by the World Health Organization, 4800 000 deaths by suicide occur around the world each year.[2]. Suicide is defined as the intentional termination of one’s own life, and constitutes the 10th leading cause of death globally.[1]. Recent meta-analyses on inflammation in suicidal patients conclude that there are aberrant cytokine levels in blood, cerebrospinal fluid (CSF), and post-mortem brain samples from suicidal patients.[3,4] Increased blood levels of tumor necrosis factor-α, interleukin-1β (IL-1β) and IL-6 are associated with suicidal ideation and behavior, and these cytokines have been proposed to constitute biomarkers to help distinguish suicidal from nonsuicidal patients.[5,6] We have found that the CSF levels of IL-6 were increased threefold in patients who recently attempted suicide compared with healthy controls.[7]
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