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Peripheral blood cellular immunophenotype in suicidal ideation, suicide attempt, and suicide: a systematic review and meta-analysis

Abstract

Previous meta-analyses have documented the association of immune-inflammatory pathways with the pathophysiology of Major Depressive Episode (MDE), as reflected by alterations in peripheral blood immune cell counts. However, it remains unclear whether these immunological changes are distinct in individuals experiencing suicidal ideation (SI) or suicidal behavior (SB), beyond the context of an MDE. This systematic review and meta-analysis aimed to examine peripheral immune cell profiles across samples with SI/SB and compare them to healthy controls or patients with MDE. A systematic literature search was conducted in MEDLINE, Embase, and PsycINFO for articles published from inception until June 12, 2023. Two independent reviewers screened the articles for inclusion, extracted data, and assessed the risk of bias using the Newcastle-Ottawa scale. Meta-analyses were performed using a random-effects model to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs) for immune cell counts or ratios between groups with and without SI/SB. Heterogeneity across studies was assessed using the restricted maximum-likelihood estimator for tau statistic and I2-statistic and tested by the Q test. Publication bias was evaluated using the Egger´s test and funnel plots. Meta-regression analyses were conducted to explore the potential moderating effects of age, gender, current or lifetime SI/SB, and the type of self-harming behavior (SI or SB). The study was registered with PROSPERO (CRD42023433089). The systematic review included 30 studies, with data from 19 studies included in the meta-analyses comprising 139 unique comparisons. Eleven different cell populations or ratios were included, comprising 1973 individuals with SI/SB and 5537 comparison subjects. White blood cell (WBC) and neutrophil counts were higher in individuals with SI/SB than in controls (WBC: SMD = 0.458; 95% CI = 0.367–0.548; p value  0.001; I2 = 0.002% and; Neutrophils: SMD = 0.581; 95% CI = 0.408–0.753; p < 0.001), indicating an inflammatory process. The neutrophil-to-lymphocyte ratio (NLR) emerged as a potential marker, demonstrating a notable elevation in individuals with SI/SB (SMD = 0.695; 95% CI = 0.054–1.335; p value = 0.033; I2 = 94.281%; Q test p value  0.001). The elevated NLR appears to be primarily driven by the increase in neutrophil counts, as no significant differences were found in lymphocyte counts between groups. Comparisons among participants with and without SI/SB and depression revealed similar trends with increased NLR, monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) observed in depressed individuals with SI/SB compared to those without SI/SB. Broad alteration in the peripheral immune cell populations and their ratios were observed in individuals with SI/SB, indicating an immune activation or dysfunction. Notably, these immunological changes were also evident when comparing MDE individuals with and without SI/SB, suggesting that such immune dysfunction associated with suicidality cannot be solely attributed to or explained by depressive symptoms. The NLR, MLR, and PLR ratios, in combination with novel immune cellular and protein biomarkers, open new avenues in understanding the immunological underpinnings of SI/SB. These findings highlight the potential utility of immune markers as part of a multi-modal approach for risk stratification and therapeutic monitoring in SI/SB.

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Fig. 1: PRISMA flow diagram illustrating the study selection process.
Fig. 2: Comparison of mean values of leukocytes between participants with suicidal ideation or suicide behavior (SI/SB) and control groups.
Fig. 3: Peripheral blood immune cell comparison between participants with SI/SB and control groups.
Fig. 4: Peripheral blood immune cell comparison between participants with SI/SB and control groups.
Fig. 5: Peripheral blood immune cell comparison between participants with si/sb and control groups.
Fig. 6: Peripheral blood immune cell comparison between participants with SI/SB and control groups.
Fig. 7: Comparison of mean values of leukocytes between depressive participants with and without suicidal ideation or suicide behavior (SI/SB).
Fig. 8: Comparative analysis of peripheral blood immune cells in depressive participants with and without SI/SB.
Fig. 9: Comparative analysis of peripheral blood immune cells in depressive participants with and without suicidal ideation/suicidal behavior.
Fig. 10: Comparative analysis of peripheral blood immune cells in depressive participants with and without suicidal ideation/suicidal behavior.
Fig. 11: Comparative analysis of peripheral blood immune cells in depressive participants with and without suicidal ideation/suicidal behavior.

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Acknowledgements

We wish to thank Hilde Iren Flaatten, medical librarian at the University of Oslo, for performing the literature search.

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The study was funded through internal resources at the affiliated institutions.

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FMD and SPN conceived the research theme and contributed equally to this article. All authors jointly designed, screened and extracted data, analyzed and interpreted or wrote manuscript. Analyses were performed by LCC. Initial drafts were prepared by FMD and SPN. Revising the draft critically for important intellectual content by all authors. Final approval of the version to be submitted by all authors. Agreed by all authors to be accountable for all aspects of the work.

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Correspondence to Federico M. Daray.

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Daray, F.M., Chiapella, L.C., Grendas, L.N. et al. Peripheral blood cellular immunophenotype in suicidal ideation, suicide attempt, and suicide: a systematic review and meta-analysis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02587-5

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