Interleukin-6 Levels in Serum,Plasma,and Cerebral Spinal Fluid in Individuals with Suicide Behavior: Systematic Review and Meta-Analysis with Meta-Regression
Restricted accessResearch articleFirst published online July, 2021
Interleukin-6 Levels in Serum,Plasma,and Cerebral Spinal Fluid in Individuals with Suicide Behavior: Systematic Review and Meta-Analysis with Meta-Regression
Evidence suggests that interleukin-6 (IL-6) concentrations have an important role in suicide behavior (SB) as they are usually increased in these individuals, although no conclusive outcomes have been attained. The purpose of this study was to evaluate the IL-6 levels in plasma, serum, and cerebral spinal fluid (CSF) to determine through a meta-analysis if these levels are increased in individuals with SB in comparison to a group. We calculated the standardized mean difference and 95% confidence intervals (95% CIs). In the systematic review, 21 studies were included, while in the meta-analysis, we included nine studies. The results of our meta-analysis indicated that individuals with SB had reduced levels of IL-6 in plasma (d − 0.189, 95% CI: −0.274 to −0.103, Z, P (Q) = 0.339, I2= 7.478), but increased levels of IL-6 in serum (d − 1.14, 95% CI: 0.658 to 1.630, Z, P (Q) = 0.26, I2= 7.47) and CSF (d 0.64, 95% CI: 0.245 to 1.035, Z, P (Q) = 0.163, I2= 44.80). The meta-regression analysis showed an association between males and high IL-6 levels in plasma (P = 0.003) and serum (P = 0.010), but not the central nervous system (CNS), while age was not associated with IL-6 levels in any of the samples evaluated (plasma, serum, or CNS). The present meta-analysis indicates that serum and CNS IL-6 levels are increased in individuals with SB, while plasma IL-6 levels are decreased, highlighting the importance of the biological sample at the moment of selecting IL-6 as biomarker. However, we need more studies performed in different populations that measure IL-6 and also consider gender when these measures are performed.
Get full access to this article
View all access options for this article.
References
1.
AhmedST, IvashkivLB. 2000. Inhibition of IL-6 and IL-10 signaling and Stat activation by inflammatory and stress pathways. J Immunol, 165(9):5227–5237.
2.
Bay-RichterC, LinderholmKR, LimCK, SamuelssonM, Träskman-BendzL, GuilleminGJ, ErhardtS, BrundinL. 2015. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav Immun, 43:110–117.
3.
BergmansRS, KellyKM, MezukB. 2019. Inflammation as a unique marker of suicide ideation distinct from depression syndrome among U.S. adults. J Affect Disord, 245:1052–1060.
4.
BrøndumL, SørensenBS, EriksenJG, MortensenLS, LønbroS, OvergaardJ, AlsnerJ. 2016. An evaluation of multiplex bead-based analysis of cytokines and soluble proteins in archived lithium heparin plasma, EDTA plasma and serum samples. Scand J Clin Lab Invest, 76(8):601–611.
5.
BrundinL, BrylevaEY, Thirtamara RajamaniK. 2017. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacology, 42(1):271–283.
6.
CácedaR, GriffinWST, DelgadoPL. 2018. A probe in the connection between inflammation, cognition and suicide. J Psychopharmacol, 32(4):482–488.
7.
CoccaroEF, LeeR, Coussons-ReadM. 2015. Cerebrospinal fluid inflammatory cytokines and aggression in personality disordered subjects. Int J Neuropsychopharmacol, 18(7):pyv001.
8.
ConejeroI, JaussentI, CazalsA, ThouvenotE, MuraT, Le BarsE, GuillaumeS, SqualliS, CourtetP, OliéE. 2019. Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder. Psychoneuroendocrinology, 99:236–242.
9.
CoryellW, WilcoxH, EvansSJ, PandeyGN, Jones-BrandoL, DickersonF, YolkenR. 2020. Latent infection, inflammatory markers and suicide attempt history in depressive disorders. J Affect Disord, 270:97–101.
10.
de JongeE, FriederichPW, VlasukGP, RoteWE, VroomMB, LeviM, van der PollT. 2003. Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects. Clin Diagn Lab Immunol, 10(3):495–497.
11.
de OliveiraJF, WienerCD, JansenK, PortelaLV, LaraDR, SouzaLDM, da SilvaRA, MoreiraFP, OsesJP. 2018. Serum levels of interleukins IL-6 and IL-10 in individuals with posttraumatic stress disorder in a population-based sample. Psychiatry Res, 260:111–115.
12.
Del GiudiceM, GangestadSW. 2018. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun, 70:61–75.
13.
DolsenMR, PratherAA, LamersF, PenninxB. 2020. Suicidal ideation and suicide attempts: associations with sleep duration, insomnia, and inflammation. Psychol Med, 50:1–10.
14.
EidanAJ, Al-HarmooshRA, Al-AmareiHM. 2019. Estimation of IL-6, INFγ, and lipid profile in suicidal and nonsuicidal adults with major depressive disorder. J Interferon Cytokine Res, 39(3):181–189.
FazelS, RunesonB. 2020. Suicide. N Engl J Med, 382(3):266–274.
17.
FrommbergerUH, BauerJ, HaselbauerP, FräulinA, RiemannD, BergerM. 1997. Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission. Eur Arch Psychiatry Clin Neurosci, 247(4):228–233.
18.
GabbayV, KleinRG, GuttmanLE, BabbJS, AlonsoCM, NishawalaM, KatzY, GaiteMR, GonzalezCJ. 2009. A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. J Child Adolesc Psychopharmacol, 19(4):423–430.
19.
GrudetC, MalmJ, WestrinA, BrundinL. 2014. Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood. Psychoneuroendocrinology, 50:210–219.
20.
ImaniMM, SadeghiM, KhazaieH, EmamiM, Sadeghi BahmaniD, BrandS. 2020. Evaluation of serum and plasma interleukin-6 levels in obstructive sleep apnea syndrome: a meta-analysis and meta-regression. Front Immunol, 11:1343.
21.
IsungJ, AeinehbandS, MobarrezF, MårtenssonB, NordströmP, AsbergM, PiehlF, JokinenJ. 2012. Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters. Transl Psychiatry, 2(11):e196.
22.
IsungJ, AeinehbandS, MobarrezF, NordströmP, RunesonB, AsbergM, PiehlF, JokinenJ. 2014. High interleukin-6 and impulsivity: determining the role of endophenotypes in attempted suicide. Transl Psychiatry, 4(10):e470.
23.
JanelidzeS, MatteiD, Westrin Å, Träskman-BendzL, BrundinL. 2011. Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav Immun, 25(2):335–339.
24.
KarlovićD, SerrettiA, VrkićN, MartinacM, MarčinkoD. 2012. Serum concentrations of CRP, IL-6, TNF-α and cortisol in major depressive disorder with melancholic or atypical features. Psychiatry Res, 198(1):74–80.
KhandakerGM, PearsonRM, ZammitS, LewisG, JonesPB. 2014. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry, 71(10):1121–1128.
27.
Kiecolt-GlaserJK, PreacherKJ, MacCallumRC, AtkinsonC, MalarkeyWB, GlaserR. 2003. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A, 100(15):9090–9095.
28.
KimJW, SzigethyEM, MelhemNM, SaghafiEM, BrentDA. 2014. Inflammatory markers and the pathogenesis of pediatric depression and suicide: a systematic review of the literature. J Clin Psychiatry, 75(11):1242–1253.
29.
KimYK, LeeSW, KimSH, ShimSH, HanSW, ChoiSH, LeeBH. 2008. Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Prog Neuropsychopharmacol Biol Psychiatry, 32(2):356–361.
30.
LindqvistD, JanelidzeS, HagellP, ErhardtS, SamuelssonM, MinthonL, HanssonO, BjörkqvistM, Träskman-BendzL, BrundinL. 2009. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry, 66(3):287–292.
31.
MillerJN, BlackDW. 2020. Bipolar disorder and suicide: a review. Curr Psychiatry Rep, 22(2):6.
32.
NowakW, GrendasLN, SanmarcoLM, EstechoIG, Arena ÁR, EberhardtN, RodanteDE, AokiMP, DarayFM, Carrera SilvaEA, ErrastiAE. 2019. Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces anti-inflammatory M2 macrophages by NMDAR and mTOR. EBioMedicine, 50:290–305.
33.
O'DonovanA, RushG, HoatamG, HughesBM, McCrohanA, KelleherC, O'FarrellyC, MaloneKM. 2013. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depress Anxiety, 30(4):307–314.
34.
OhlssonL, GustafssonA, LavantE, SunesonK, BrundinL, Westrin Å, LjunggrenL, LindqvistD. 2019. Leaky gut biomarkers in depression and suicidal behavior. Acta Psychiatr Scand, 139(2):185–193.
35.
Orlovska-WaastS, Köhler-ForsbergO, BrixSW, NordentoftM, KondziellaD, KroghJ, BenrosME. 2019. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry, 24(6):869–887.
36.
PandeyGN. 2017. Inflammatory and innate immune markers of neuroprogression in depressed and teenage suicide brain. Mod Trends Pharmacopsychiatry, 31:79–95.
37.
PandeyGN, RizaviHS, RenX, FareedJ, HoppensteadtDA, RobertsRC, ConleyRR, DwivediY. 2012. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res, 46(1):57–63.
38.
PandeyGN, RizaviHS, ZhangH, BhaumikR, RenX. 2018a. Abnormal protein and mRNA expression of inflammatory cytokines in the prefrontal cortex of depressed individuals who died by suicide. J Psychiatry Neurosci, 43(6):376–385.
39.
PandeyGN, RizaviHS, ZhangH, RenX. 2018b. Abnormal gene and protein expression of inflammatory cytokines in the postmortem brain of schizophrenia patients. Schizophr Res, 192:247–254.
40.
RinconM. 2012. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol, 33(11):571–577.
41.
RossiJF, LuZY, JourdanM, KleinB. 2015. Interleukin-6 as a therapeutic target. Clin Cancer Res, 21(6):1248–1257.
42.
SchiavoneS, NeriM, MhillajE, MorgeseMG, CantatoreS, BoveM, RiezzoI, TucciP, PomaraC, TurillazziE, CuomoV, TrabaceL. 2016. The NADPH oxidase NOX2 as a novel biomarker for suicidality: evidence from human post mortem brain samples. Transl Psychiatry, 6(5):e813.
43.
SuH, LeiCT, ZhangC. 2017. Interleukin-6 signaling pathway and its role in kidney disease: an update. Front Immunol, 8:405.
44.
SuzukiH, OhgidaniM, KuwanoN, ChrétienF, Lorin de la GrandmaisonG, OnayaM, TominagaI, SetoyamaD, KangD, MimuraM, KanbaS, KatoTA. 2019. Suicide and microglia: recent findings and future perspectives based on human studies. Front Cell Neurosci, 13:31.
45.
TanakaT, NarazakiM, MasudaK, KishimotoT. 2016. Regulation of IL-6 in immunity and diseases. Adv Exp Med Biol, 941:79–88.
46.
VargasHO, NunesSO, Pizzo de CastroM, BortolasciCC, Sabbatini BarbosaD, Kaminami MorimotoH, VenugopalK, DoddS, MaesM, BerkM. 2013. Oxidative stress and lowered total antioxidant status are associated with a history of suicide attempts. J Affect Disord, 150(3):923–930.
47.
ZhouY, LutzPE, IbrahimEC, CourtetP, TzavaraE, TureckiG, BelzeauxR. 2020. Suicide and suicide behaviors: a review of transcriptomics and multiomics studies in psychiatric disorders. J Neurosci Res, 98(4):601–615.
