Table 2.

Most relevant longitudinal studies showing the association between inflammatory cytokines and suicidal behavior.

Author (s), Year	Sample Characteristics	Study Design	Inflammation Measurement	Main Findings	Limitations	Conclusions
Bay-Richter et al. (2014) [28]	30 subjects (43% MDD) with SA; 36 healthy controls	2-year longitudinal study	IL-6; CSF kynurenic acid; CSF quinolinic acid	Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients vs. healthy controls. A significant association between lower kynurenic acid and severe depressive symptoms as well as a link between higher IL-6 levels and more severe suicidal symptoms were reported.	1. The study is correlational in nature and does not test direct causality in the patients; 2. Most patients were on psychoactive medications; 3. gender and age of both controls and patients were not matched; 4. repeated lumbar punctures are carried out only on suicide attempters and not healthy controls	A long-term dysregulation of the kyn pathway in the CNS of SA was demonstrated. An increased load of inflammatory cytokines was coupled to more severe symptoms.
Li et al. (2013) [49]	64 first-episode drug-naïve MDD patients and 64 matched healthy controls	8-week case-control study	TNF-α	Plasma TNF-α levels were significantly decreased after venlafaxine treatment. Compared to non-responders, responders had a greater reduction in TNF-α levels which was linked to the greater reduction rate of HDRS-17. The plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients relative to healthy controls on admission.	1. The naturalistic observation design may not completely control confounding factors such as selective bias; 2. the levels of serotonin and norepinephrine were not detected; 3. the dexamethasone/CRH test was not performed; 4. the long-term effects of venlafaxine on plasma TNF-α levels have been not evaluated.	MDD but not per se suicide was associated with the increased plasma TNF-α levels that may be inhibited using venlafaxine
O’Donovan et al. (2013) [37]	76 MDD and 48 healthy controls	Follow-up study	TNF-α; IL-6; IL-10; CRP	Patients with MDD and higher SI had higher inflammatory index scores than both controls and MDD patients with lower SI. Patients with lower SI were not different from controls on the inflammatory index as well. Follow-up analyses indicated that differences between MDD patients with high vs. lower SI were independent of depression severity and recent SA.	1. The cross-sectional study design; 2. The small sample size; 3. The assumption of antidepressants and other medications; 4. the use of a structured interview measure of depression severity (HDRS) and not self-report measure; 5. The inclusion of a small number of patients with SA in the previous month.	SI may be uniquely linked to inflammation in depressed patients.
Janelidze et al. (2013) [40]	41 patients with SA, 22 non-suicidal psychiatric patients, 43 healthy controls	12 year follow-up study	CCL11; IP-10; CXCL10; MIP-1β, CCL4; MCP-1, CCL2; MCP-4,CCL13; TARC,CCL17	CSF eotaxin-1, MIP-1β (CCL4), MCP-1 (CCL2), MCP-4 (CCL13), and TARC (CCL17) were significantly lower in SA. Lower chemokine levels were specifically linked to psychotic symptoms and pain.	1. The mismatch in gender distribution in the CSF Index study; 2. differences in the recruitment time between suicide attempter and healthy control groups in the CSF Index study; 3. multiple analyses were performed on the present data.	When compared to non-attempters, abnormally reduced chemokine levels in suicide attempters, both in the acute suicidal setting and after the long-term period, were reported.
Isung et al. (2012a) [42]	58 suicide attempters	13 year longitudinal study	IL-1α; IL-1β; IL-2; IL-4; IL-6; IL-8; IL-10; IFN-γ; TNF-α; MCP-1; EGF; VEGF	Significantly lower VEGF levels were found in the seven patients after a mean follow-up of 13 years before completing suicide. VEGF also showed a trend for negative correlation with the planning subscale of SIS. A trend might be shown for lower IL-2 and higher IFN-γ levels in suicide victims.	1. Degradation of several cytokines has been observed after 4 years of storage at –80 °C; 2. the data on smoking habits and exercise were not available.	Further support for a role of inflammation in the pathophysiology of suicidal behavior has been provided. VEGF may be significantly related with suicide risk.
Nassberger and Trask- man- Bendz (1993) [44]	Medication-free suicide attempters with depressive disorders	Follow-up study	Urine and CSF soluble IL-2 receptor concentration presumably reflecting an activation of T-lymphocytes	A median soluble IL-2 receptor concentration far above the range of healthy controls was found. High levels of the soluble IL-2 receptor concentration were also reported at follow-up. There was a tendency of an association between soluble IL-2 receptor concentration and the ratio of norepinephrine-epinephrine in 24-h urine, as well as plasma and CSF 4-hydroxy-3- methoxymethyl-glycol.	1. The small sample size limits the generalization of the present findings; 2. the study lacks of a placebo group.	Psychiatric patients investigated after a suicide attempt showed an imbalance of the immune system.

Note: CCL11 = eotaxin-1; COBY = course and outcome of bipolar youth; CXCL10 = C-X-C motif chemokine 10; CNS = central nervous system; CRH = corticotropin releasing hormone; CRP = c-Reactive protein; CSF = cerebrospinal fluid; EGF = epidermal growth factor; HDRS = Hamilton Depression Rating Scale; IFN-γ= interferon gamma; IL = interleukine; IP-10 = interferon gamma-induced protein 10; KYN = kynurenine; MCP-1, CCL2 = monocyte chemoattractant protein-1, chemokine (C-C motif) ligand 2; MCP-4, CCL13 = monocyte chemoattractant protein 4, C-C motif chemokine ligand 13; MDD = major deprerssive disorder; MIP-1b, CCL4 = macrophage inflammatory protein, chemokine (C-C motif) ligands 4; SA = suicide attempts; SI = suicide ideation; SIS = Suicide Intent Scale; TARC, CCL17 = thymus and activation regulated chemokine (C-C motif) ligand; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor.