Relationships between inflammatory markers and suicide risk status in major depression
Introduction
According to the World Health Organization, 800,000 people die by suicide annually, with a rate of 10.7 per 100,000 individuals (WHO, 2020). Among psychiatric illnesses, depression is most commonly associated with suicide, accounting for 30% of cases (Bachmann, 2018). Despite efforts to develop new interventions, the suicide rate has consistently risen over the past two decades (Hedegaard et al., 2018). We also know little about the fundamental neurobiological causes of suicidal behaviors (van Heeringen and Mann, 2014). Many previously identified risk factors are not modifiable, such as prior attempt history, sex and age (Hawton et al., 2013) although depression severity is modifiable and effects a reduction in suicide risk (Gibbons et al., 2012). Thus, a paramount goal of suicide research is the identification of etiologic processes amenable to clinical intervention.
Inflammation is one promising candidate for modification that may affect suicide risk, because pro-inflammatory states are associated with major depression and with suicidal behavior (reviewed in (Ganança et al., 2016)). Higher levels of pro-inflammatory (Lindqvist et al., 2009) cytokines are associated with suicidal ideation (Karlović et al., 2012; Martinez et al., 2012; Monfrim et al., 2014; O'Donovan et al., 2013), with suicide attempt in both blood (Janelidze et al., 2011) and CSF (Lindqvist et al., 2009, 2011; Martinez et al., 2012), and with completed suicide in postmortem brain tissue (Hoyo-Becerra et al., 2013; Pandey et al., 2012; Tonelli et al., 2008) and in CSF of patients with previous violent suicide attempts and those who subsequently died by suicide (Lindqvist et al., 2011). Therefore, cytokine activation may exert some influence over suicidal behaviors in predisposed individuals (reviewed in (Ganança et al., 2016)). Increased cytokine levels are associated not only with lower serotonin concentrations, depression, and increased risk of suicidal behavior, but also with activation of the kynurenine pathway (Achtyes et al., 2019; Raison et al., 2010). In major depressive disorder (MDD), kynurenine is elevated in suicide attempters compared with non-attempters (Sublette et al., 2011a).
Essential polyunsaturated fatty acids (PUFAs) play a key role in inflammation regulation, mainly by affecting the expression of pro-inflammatory mediators, and resolution through the actions of their active metabolites, generally known as specialized pro-resolving mediators (SPMs) (Calder, 2017; Layé et al., 2018); omega-3 PUFAs correlate negatively with pro-inflammatory cytokines (Ferrucci et al., 2006; McNamara et al., 2010; Micallef et al., 2009) and positively with anti-inflammatory cytokines (Ferrucci et al., 2006). Moreover, omega-3 PUFA supplementation reduces pro-inflammatory cytokine levels and enhances anti-inflammatory cytokine secretion (Oliver et al., 2012). Low omega-3 PUFA levels are also observed in major depression (Lin et al., 2010), in suicide attempters (Huan et al., 2004) and in suicide decedents (Lewis et al., 2011), and predicted future suicide attempts in one small study (Sublette et al., 2006).
Low intake of omega-3 PUFAs may enhance suicide risk by affecting lipid raft composition, which in turn can impact: a) monoaminergic receptors and neurotransmission (Alfaidi et al., 2018; Liu et al., 2018), and b) toll-like receptors (TLR) (Wong et al., 2009), both of which are implicated in suicidal behaviors (Pandey et al., 2014). Possible mechanistic intermediates in relationships between PUFAs and suicide risk have been reviewed in detail in (Daray et al., 2018).
In this study we aimed to clarify relationships between suicide risk and specific pro-inflammatory cytokines or essential polyunsaturated fatty acids (PUFAs). From prior studies comparing these biomarkers in depressed patients with or without suicide risk (reviewed by us in (Ganança et al., 2016)), we selected three pro-inflammatory cytokines with strong evidence for an association between elevated levels and suicidal behaviors or ideation: IL-6 (Hoyo-Becerra et al., 2013; Janelidze et al., 2011; Karlović et al., 2012; Lindqvist et al., 2011; Lindqvist et al., 2009; Martinez et al., 2012; O'Donovan et al., 2013; Pandey et al., 2012), IL-1β (Martinez et al., 2012; Monfrim et al., 2014; Pandey et al., 2012, 2018), and TNF-α (Janelidze et al., 2011; Martinez et al., 2012; Pandey et al., 2012).
Likewise, we studied three PUFA species commonly associated with suicide risk: docosahexaenoic acid (DHA, 22:6n-3), eicosapentaenoic acid (EPA, 20:5n-3), and arachidonic acid (AA, 20:4n-6) (Huan et al., 2004; Lewis et al., 2011; Sublette et al., 2006). As aggression also has been associated with suicide risk (Hartley et al., 2018), with PUFA status (Gajos and Beaver, 2016; Virkkunen et al., 1987; Zaalberg et al., 2016), and with inflammation (Suarez, 2003; Suarez et al., 2002, 2004), we additionally explored whether aggression could affect the relationships between PUFAs or cytokines and risk of suicidal behavior.
Section snippets
Sample
This research study was approved by the Institutional Review Board of the New York State Psychiatric Institute. We recruited adult participants with a diagnosis of DSM-IV Major Depressive Episode in the context of Major Depressive Disorder (MDD; n = 80) who scored at least 16 on the 17-item Hamilton Depression Rating Scale (17-HDRS) (Hamilton, 1967), and HC (n = 24). All participants gave informed consent to participate in the study. Depressed patients were recruited according to the following
Sample characteristics
Eighty patients with DSM-IV MDD, ages 18–63 yrs, and twenty-four healthy controls (HC), ages 18–51 yrs, were recruited. Demographic and clinical characteristics are presented in Table 1. No significant differences were found between groups with regard to sex, age, smoker status, BMI, race or ethnicity. The depressed group presented with moderate depression severity and, as expected, patients with current suicidal ideation had higher HDRS severity scores than past attempters and low suicide risk
Discussion
To our knowledge, this is the first published study to simultaneously assess the relationships of PUFA and pro-inflammatory cytokine levels to suicide risk stratification. Our finding of low DHA% in depressed patients with a history of suicide attempt is in accordance with previous studies linking low omega-3 status and suicide risk (Huan et al., 2004; Lewis et al., 2011; Sublette et al., 2006). Contrary to expectations, however, we did not find elevated pro-inflammatory cytokine levels in
Conclusions
Our results are consistent with prior observations of low DHA associated with suicidal behavior but do not support a role for a persisting pro-inflammatory state within five years of suicide attempt. For a nuanced understanding of inflammation and suicide risk, future studies focusing prospectively on the timing of cytokine responses related to suicidal behaviors may be of fundamental importance. Understanding the complex network of immune mediators and timing of the immune response related to
Funding
This work was supported by the American Foundation for Suicide Prevention (AFSP) [(PI: Sublette) 10/1/13 – 9/30/15], the Association for Research and Development of the School of Medicine, University of Lisbon (Ganança), and by the National Institutes of Health [5 R01 MH48514-20 (PI: Oquendo) 12/01/08-11/30/14] and [1 P50 MH090964-01A1 (PI: Mann) 7/19/13 – 6/30/18].
Author statement
Licínia Ganança: Data curation; Formal analysis; Investigation; Methodology; Project administration; Visualization; Roles/Writing – original draft, Hanga C. Galfalvy: Formal analysis; Writing – review & editing, Sebastian Cisneros-Trujillo: Data curation; Investigation; Writing – review & editing. Zahra Basseda: Data curation; Investigation; Writing – review & editing. Thomas B. Cooper: Methodology; Investigation; Writing – review & editing. Xinguo Ren: Methodology; Investigation; Writing –
Declaration of competing interest
Dr. Oquendo owns equity in Mantra, Inc. Her family owns stock in Bristol Myers Squibb. Drs. Oquendo and Mann receive royalties from the Research Foundation for Mental Hygiene for the commercial use of the C-SSRS. All other authors have no conflicts to report.
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