Table 1.

Most relevant cross-sectional studies showing the association between inflammatory cytokines and suicidal behavior.

Author (s), Year	Sample Characteristics	Study Design	Inflammation Measurement	Main Findings	Limitations	Conclusions
Conejerob et al. (2019) [25]	42 SA, 40 affective controls, 19 healthy controls	Cross-sectional case-control study	IL-1β IL-6 TNF-α IL-2	IL-1β was negatively associated with right orbitofrontal cortex activation in ESE vs. INC, whereas IL-2 was positively associated with activation of the right anterior cingulate cortex, insula, and orbitofrontal cortex in ESE vs. INC.	1. Medicated patients reflecting real-life conditions were recruited; 2. only females were included; 3. results for smoking status and BMI were not controlled; 4. the healthy controls group was smaller than the affective controls and SA groups.	Baseline IL-1β and IL-2 blood levels are differentially associated with cerebral activation involved in the perception of social exclusion, independently of suicidal behavior.
Wang et al. (2019) [27]	16 non-psychiatric controls and 43 suicide subjects (21 MDD-suicides and 22 suicides with other psychiatric disorders)	Cross-sectional case-control study	TNF-α	TNF-α expression was significantly higher in dlPFC of suicide subjects regardless of psychiatric diagnosis. Its expression level was also increased in MDD subjects who died by causes other than suicide. Conversely, the expression of miR-19a-3p was upregulated in suicide subjects.	1. The power of the study is quite low; 2. the study lacks depressed patients without suicidal ideation.	This study provides mechanistic insights into the dysregulation of TNF-α gene in suicide brain, which could potentially be involved in suicidal behavior.
Keaton et al. (2019) [34]	66 females with mood and anxiety disorders	Cross-sectional study	IL-6 IL-8	Increased IL-6, lymphocytes, monocytes, white blood cell count, and polymorphonuclear leukocyte count levels significantly impacted suicide risk (the latter two inferring the strongest influence). IL-8 was independently and negatively associated with enhanced suicide risk, even after adjusting for confounders.	1. The cross-sectional study design; 2. the findings may only identify associations and are not able to prove causality.	The biological profile of patients assessed to be at increased suicide risk differed from that associated with depression.
Knowles et al. (2019) [33]	1882 subjects of which 159 with SA and 135 with SI	Cross-sectional study	IL-6 IL-8	IL-8 and IL-6 shared significant genetic overlap with risk for SA (for IL-6 this was attenuated when BMI was included as a covariate). The genetic overlap between IL-8 and SA risk was significant only in females but not males.	1. Personality traits could confound or mediate the main results; 2. the results may be population (Mexican American) specific; 3. increased circulating cytokine levels were observed in response to stress; 4. environmental influences might have increased inflammation.	Cytokine abnormalities are not a secondary manifestation of suicidal behavior, but play a fundamental role in the pathophysiology of suicide attempts.
Coryell et al. (2018) [39]	Patients in major depressive episodes who had a history of two or more SA (n = 79), or no history of SA (n = 123)	Cross-sectional study	CRP IL-6 IL-1β IL-1ra TNF-α.	One of five of the inflammatory markers (IL-1β), distinguished the two groups with lower values in the SA group. IL-1β levels correlated inversely with measures of aggression but neither impulsivity or aggressive behavior appear to explain the association between IL-1β levels and SA status.	1. Small sample sizes; 2. patients described here were not treatment naïve; 3. antidepressant treatment may or may not have influenced cytokine levels.	Results identify recent aggressive behavior, higher levels of impulsivity, and lower levels of IL-1β as risk factors for a history of multiple SA in a group with major depressive episodes. These measures appear to be additive in their effects.
Melhem et al. (2018) [35]	38 with SA, 40 with SI, 37 healthy controls	Cross-sectional case-control study	HCC	Lower HCC [β = −0.55, 95% CI (−0.96, −0.13), p = 0.01, ES = −0.54] were found in those with SA for the first time compared to those with SI and controls.	1. It is not clear whether HPA axis dysregulation exists prior to suicidal behavior or as a consequence of an attempt because existing studies examine cortisol levels in subjects with history of suicidal behaviour; 2. small sample size; 3. cross-sectional study design.	This is the first study to differentiate youths who attempt suicide from those with SI on HCC. The present study also showed that low HCC precedes SA.
Pandey et al. (2018) [4]	24 depressed individuals who died by suicide and 24 non-psychiatric controls	Cross-sectional case-control study	IL-1β, IL-6, TNF-α, Lymphotoxin A, Lymphotoxin B, IL-8, IL-10, IL-13	Protein levels of IL-1β, IL-6, TNF-α, and lymphotoxin a were significantly increased, and levels of anti-inflammatory cytokine IL-10 and of IL-1ra were significantly reduced in the prefrontal cortex of depressed individuals who died by suicide compared with controls.	1. Some of the suicide group had been taking antidepressant medications at the time of death.	Alterations of cytokines may be associated with the pathophysiology of depressed suicide and there may be an imbalance between pro- and anti-inflammatory cytokines in subjects who died by suicide.
Torres-Platas et al. (2015) [47]	24 depressed suicides and 17 controls (without psychiatric, neurological or inflammatory illnesses)	Cross-sectional study	Gene expression of IBA1 and MCP-1	Gene expression of IBA1 and MCP-1 was upregulated in depressed suicides. In addition, mRNA for CD45 was also increased in depressed suicides. An increase compared to controls was found in the proportion of blood vessels surrounded by a high density of CD45-IR cells (non-significant difference).	1. Brains from depressed suicides may be more highly exposed to peripheral cytokines crossing the blood-brain barrier; 2. other types of macrophages (including microglia), together with perivascular macrophages, may account for the observed increase in IBA1-IR cells associated with blood vessels in case samples.	Depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be linked to low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.
Pandey et al. (2013) [26]	24 teenage suicide victims and 24 matched normal controls	Cross-sectional case-control study	IL-1β, IL-6, TNF-α	The mRNA and protein expression levels of IL-1β, IL-6, and TNF-α were significantly increased in Brodmann area 10 of suicide victims compared with normal controls.	1. Stress effects (with associated changes in GR-α) on the hippocampus cannot be observed in children or adolescents, but only in adults; 2. changes in the GR-α may be not related to suicidal behavior but may change as a result of early life trauma.	Increases of pro-inflammatory cytokines in the post-mortem brain of teenage suicide victims suggest that TNF-α, IL-1β, or IL-6 are associated with the neurobiology of suicide and that targeting these cytokines may help in developing new therapies for the treatment of suicidal behavior.
Kim et al., (2013) [50]	204 patients with SA and 97 control patients without SA	Cross-sectional case-control study	TNF-α, IL-10, IFN-γ	The GG genotype of the TNF-α −308G>A polymorphism significantly increased SA risk. IFN-γ +874A>T and IL-10 −1082A>G were not associated with risk for suicide. Lethality of the SA was not associated with any of the three cytokine genotypes or allele types.	1. The relatively small sample size; 2. cross-sectional study design	TNF-α −308G>A polymorphism may be considered an independent risk factor for SA in MDD.
Vargas et al. (2013) [41]	342 subjects divided into those with (N = 141) and without (N = 201) a history of SA	Cross-sectional case-control study	CRP Fibrinogen ESR IL-6 TNF-α	Subjects with SA had higher nitricoxide metabolites and lipid hydroperoxides levels and reduced plasma total antioxidant potential than those without. Regression analyses showed that unipolar/bipolar disorder, female gender, smoking behavior, and lipid hydroperoxides were linked to a history SA independently of classical risk factors.	1. Participants were recruited from the center for smoking cessation treatment; 2. inflammatory, oxidative/nitrosative stress and metabolic biomarkers were assessed at baseline and correlated with a history of SA (as trait and not state-markers); 3. results may only delineate associations and not causality	Oxidative stress, nitrosative stress, lowered antioxidant levels may play a role in the pathophysiology of suicidal behavior independently from the effects of depression and smoking and classical suicide predictors (e.g., years of education and marital status).
Dunjic-Kostic et al. (2013) [48]	29 melancholic, 18 atypical MDD patients, and 39 healthy controls	Cross-sectional case-control study	TNF-α, IL-6	IL-6 was significantly elevated in MDD-M. Lower TNF-α serum level was found both in melancholic patients and those with atypical depression. We detected a positive correlation between cytokine levels in atypical, but not in melancholic subjects. Clinical parameters (e.g., duration of illness, current episode, age of onset) were related to cytokine levels in atypical depression, while the duration of lifetime exposure to antidepressant treatment correlated to IL-6 serum levels in both patients with melancholic and atypical depression.	1. The cross-sectional study design; 2. the lack of information regarding the association between inflammatory markers and antidepressant treatment over time	The study showed certain differences in pro-inflammatory cytokine serum levels in melancholic and atypical depressed patients than healthy subjects. Importantly, IL-6 elevation might represent a state indicator for acute exacerbation, especially in melancholic patients.
Grassi-Oliveira et al. (2012) [38]	30 female outpatients with recurrent MDD divided in two groups according with the presence/ absence of SI, and 16 healthy controls	Cross-sectional case-control study	MCP-1, CCL2, CCL5, CCL11	MDD patients with suicidal ideation presented lower levels of MCP-1, CCL2 and CCL5 and higher levels of CCL11 compared to healthy controls. These differences remained significant after adjusting for depression severity.	1. Small sample size; 2. participants included in MDD groups were taking antidepressants; 3. nicotine users from the sample were not excluded; 4. only female participants were included.	Findings indicated that the presence of recurrent MDD with suicidal ideation is associated with differences in inflammatory chemokines when compared to those without suicidal ideation.
Isung et al. (2012b) [43]	43 medication-free suicide attempters and 20 healthy male controls	Cross-sectional study	CSF VEGF, CSF IL-8, and IL-6 levels measured with an ultra-sensitive immunoassay system	Suicide attempters showed lower CSF VEGF and IL-8 levels than healthy controls. Also, a significant negative correlation was observed between CSF VEGF and severity of depression. A more severe depressive state was correlated with low CSF levels of VEGF reflecting a lack of trophic support to neurons and down-regulation of hippocampal neurogenesis.	The study was cross-sectional in nature	IL-8 may be crucial in neuroprotection. A role for an impaired innate immunity and dysregulation of neuroprotection has been suggested in both depression and suicidal behavior.
Sublette et al. (2011) [29]	Fourteen subjects with MDD and a history of SA compared with 16 MDD patients without and 31 healthy controls	Cross-sectional case-control study	KYN, TRP, and the cytokine activation marker neopterin were investigated using high performance liquid chromatography	A priori planned contrasts showed that KYN was higher in the MDD SA subgroup compared with MDD non-attempters. KYN but not TRP was associated with attempt status, and only suicide attempters showed a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters.	1. This study did not measure inflammatory indices apart from KYN, TRP, and neopterin levels; 2. the small sample size	These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior. Our findings raise the possibility that pharmacologic manipulation of KYN levels might reduce suicide risk.
Janelidze et al. (2011) [9]	47 SA and 17 non-suicidal depressed patients 16 healthy controls.	Cross-sectional study	IL-2 IL-6 TNF-α	Increased levels of IL-6 and TNF-α as well as decreased IL-2 concentrations in SA were found compared to non-suicidal depressed patients and healthy controls.	1. Retrospective data, such as the duration of treatment and disease, were not registered; 2. data on smoking habits were not available; 3. the SA method, which was intoxication in 91% of patients in our sample; 4. storage time between sample collection and cytokine analysis was different for suicide attempters and depressed/healthy control subjects.	These results demonstrate for the first time that suicidal patients display a distinct peripheral blood cytokine profile compared to non-suicidal depressed patients.
Boehm et al. (2010) [45]	40 forensic autopsy cases of burn victims were examined 1 h after fire exposure and compared with 48 autopsy cases divided in post-mortem burns, deaths (e.g., hemorrhagic shock, railway suicide deaths)	Post-mortem study	TNF-α, IL-8, and ICAM-1 measured using immunohistochemical studies of lung tissue probes	Significantly higher extent of intra-alveolar edema was observed in the lungs of burn victims compared to other groups. A distinct expression of TNF-α, but not IL-8 or ICAM-1 was found in macrophages of all groups. A significantly stronger positivity of TNF-α in the group of burn victims was reported in intravascular erythrocytes when compared with other control groups.	1. The survival times (>1 h) of the cohorts may be too short to reach the phase of leukocyte immigration for further morphological changes (no reactive inflammatory cell infiltrates were found); 2. the small sample size limits the generalization of the present findings.	A non-specific immune response to fire-induced inhalation trauma was demonstrated by the positive reaction of TNF-α in erythrocytes of burn victims.
Lindqvist et al. (2009) [8]	63 SA divided in violent or non violent SA and 47 healthy controls	Cross-sectional case-control design	CSF and plasma IL-1β, IL-6, IL-8, TNF-α were measured. The relation between cytokines and monoamine metabolites, 5-HIAA, HVA, and MHPG in CSF was also evaluated	Suicide attempters showed significantly higher CSF IL-6 levels compared to healthy controls. Specifically, violent SA showed the highest IL-6. A significant positive correlation between MADRS scores and CSF IL-6 levels was found in all patients. CSF 5-HIAA and HVA were found to correlate with IL-6 and TNF-α but not with MHPG.	1. In order to test whether IL-6 is directly related to depressive and suicidal symptoms, cytokines should be administered peripherally or into the CNS; 2. the interaction between cytokines, monoamines, and HPA axis was not assessed.	CSF IL-6 plays a crucial role in suicidal behavior presumably through alterations of dopamine and serotonin metabolism.
Gabbay et al. (2009) [30]	12 suicidal adolescents, 18 non-suicidal adolescents with MDD, 15 controls	Cross-sectional case-control study	IFN-γ, TNF-α, IL-6, IL-1β, IL-4	Suicidal adolescents with MDD had significantly decreased plasma TNF-α concentrations compared to non-suicidal adolescents with MDD. IFN-γ was increased in both suicidal and non-suicidal adolescents with MDD compared to controls.	1. The cohort size was relatively modest; 2. a substantial proportion of patients was receiving psychotropic medications, which have been reported to induce negative immunoregulatory effects in adults with MDD; 3. due to the small sample, a multiple comparison correction to preserve statistical power was not carried out.	These preliminary findings suggest that immune system dysregulation may be associated with suicidal symptomatology in adolescent MDD.
Tonelli et al. (2008) [46]	Post-mortem samples from the Brodman area 11 of 34 completed suicides and 17 controls	Post-mortem study	The expression of mRNA species for TNF-α, IL-1β, IL-4, IL-5, IL-6, and IL-13 measured using real-time- CRP	Female suicide victims showed increased expression of IL-4 whereas males suicide victims exhibited increased IL-13. Female suicide victims also showed higher but not significant TNF-α expression.	Controls were not matched for age, toxicology was incomplete in 82% of cases, and limited information were available on psychological diagnosis. In addition, accurate interactions between alcohol on inflammatory processes with the expression of cytokines were not reported.	Increased expression of mRNA transcripts of Th2 cytokines were found in the human orbitofrontal cortex of completed suicides.
Kim et al. (2008) [31]	36 MDD patients with recent SA, 33 non-suicidal MDD patients, and 40 normal controls	Cross-sectional case-control study	IL-6, IL-2, IFN-γ, IL-4, TGF-β1, Th1/Th2 ratio	Non-suicidal MDD patients had higher IL-6 levels than suicidal MDD patients and normal controls, while suicidal MDD patients had lower IL-2 than non-suicidal patients and normal controls. Both MDD groups, with or without attempted suicide, had lower IFN-γ and IL-4 and higher TGF-β1 levels. HDRS scores had positive correlations with IL-6, IFN-γ, Th1/Th2 ratio and negative correlations with IL-4 in non-suicidal depression patients. Suicidal MDD patients had no significant correlations between the LSARS or RRR scores and cytokine release.	1. The effects of various confounding factors from these data cannot be excluded; 2. the existence of potential differences between those who agreed to participate and those that did not; 3. only in vitro mitogen-stimulated cytokine production (and not in vivo serum or plasma levels of cytokines) before the MDD treatment was measured.	The immune response has distinct differences between non-suicidal patients and suicidal patients.
Lee and Kim (2006) [32]	48 suicidal MDD patients, 47 non-suicidal MDD patients, 91 controls	Cross-sectional case-control study	In vitroTGF-β1 levels were investigated	In vitro TGF-β1 levels were significantly higher in suicidal MDD patients and non-suicidal MDD patients than controls.	1. In vitro but not CSF TGF-β1 levels were measured; 2. methods of suicide attempt were not controlled; 3. the fact that blood for the quantification of the TGF was drawn after fasting for controls and 2 h later from the admission for suicidal depressive patients may represent a bias.	In vitro TGF-β1 levels may play a relevant role in MDD but not in suicidal behavior.
Mendlovic et al. (1999) [36]	9 patients with MDD that lasted 2–12 weeks and 9 age- and sex- matched controls	Cross-sectional case-control study	IFN-γ, IL-2, IL-4, IL-5, IL-10 secretion measured from PHA-stimulated lymphocytes	The stimulated lymphocytes of suicidal depressed patients secreted significantly more IFN-γ than those of healthy controls. Non-suicidal depressed patients secreted significantly less IFN-γ as compared with controls. Also, suicidal depressed patients secreted less IL- 4 and IL-5 as compared with non-suicidal depressed patients (although the difference was not statistically significant).	The small sample size limits the generalization of the present findings	Th1 activation in suicidal depression might reflect a unique form of autoimmune suicide.

Note: 5-HIAA = 5-hydroxyindoleacetic acid; BMI = body mass index; CCL5, RANTES = chemokine (C-C motif) ligand 5, regulated on activation, normal T cell expressed and secreted; CCL11 = eotaxin-1; CNS = central nervous system; CRP = c-Reactive protein; CSF = cerebrospinal fluid; dlPFC = dorsolateral prefrontal cortex; ESE = explicit social exclusion; ESR = erythrocyte sedimentation rate; HDRS = Hamilton Depression Rating Scale; INC = social inclusion conditions; GR = glucocorticoid; HCC = hair cortisol concentration; HPA = hypothalamic pituitary adrenal; HVA = homovallinic acid; KYN = plasma kynurenine; IBA1 = ionized calcium binding adaptor molecule 1; IBA1-IR = IBA1-immunoreactive; ICAM-1 = intercellular adhesion molecule 1; IFN = interferon; IL = interleukine; IL-1ra = interleukine-1 receptor antagonist; LSARS = Lethality Suicide Attempt Rating Scale; MADRS = Montgomery-Asberg Depression Rating Scale; MCP-1, CCL2 = monocyte chemoattractant protein-1, chemokine (C-C motif) ligand 2; MHPG = 3-methoxy-4-hydroxy-phenylglycol; mRNA = messenger ribonucleic acid; MDD = major depressive disorder; MDD-M = major depressive disorder-melancholic; PHA = phytohaemagglutinin; RRR = Risk-Rescue Rating; SA = suicide attempt; SI = suicidal ideation; TGF = transforming growth factor; Th1 = T helper 1; Th2 = T helper 2; TNF = tumor necrosis factor; TRP = tryptophan; VEGF = vascular endothelial growth factor.