The role of cytokines in the pathophysiology of suicidal behavior

Abstract

Objective: Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk.

Methods: We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors.

Results: The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-4, and soluble Il-2 receptors.

Conclusions: Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk.

Keywords: Cytokines; Depression; Inflammation; Stress; Suicide.

Conflict of interest statement

Conflicts of interest: Drs. Mann and Oquendo receive royalties from the commercial use of the Columbia Suicide Severity Rating Scale (C-SSRS) from the Research Foundation for Mental Hygiene. Dr. Oquendo's family owns stock in Bristol Myers Squibb. Drs. Gananca, Sublette, Cisneros-Trujillo and Tyrka have no conflicts to report.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Algorithm employed to perform literature search and article selection process

This flowchart describes the databases used for article search, the number of retrieved articles and the process and criteria used to achieve the final article selection.

Figure 2. Hypothetical pathways through which pro-inflammatory cytokines may influence suicide risk

Stressors and constitutional factors associated with suicidal behaviors reciprocally interact with the immune system resulting in increased levels of pro-inflammatory cytokine in vulnerable individuals. Pro-inflammatory cytokines strongly induce IDO enzyme favoring the kynurenine pathway, which results in decreased serotonin and increased quinolinic acid, both associated with depression and suicidal behaviors. Abbreviations: 5-HT - 5-hydroxytryptamine (serotonin); IDO - Indoleamine 2,3-dioxygenase; NMDA - N-Methyl-D-aspartate.