Medline ® Abstracts for References 28,29

BACKGROUND: Major psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls.

METHODS: We identified articles by searching MEDLINE, PsycINFO, and Thomson Reuters Web of Knowledge databases and the reference lists of identified studies.

RESULTS: Study inclusion criteria were met by 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. Levels of interleukin (IL)-1βand IL-6 were significantly increased in blood and postmortem brain samples of patients with suicidality compared with both patients without suicidality and healthy control subjects (p<.05 for each). In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p<.01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p<.05).

CONCLUSIONS: We found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1βand IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients. Rigorously designed longitudinal studies are needed to evaluate these associations further.

BACKGROUND: Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-d-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF).

METHODS: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n=143, individuals n=30) and healthy controls (n=36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale.

RESULTS: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms.

CONCLUSIONS: We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression.