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. 2025 Mar 25;28(4):112290.
doi: 10.1016/j.isci.2025.112290. eCollection 2025 Apr 18.

Peripheral biological correlates of suicidality in children and adolescents: A systematic review and meta-analysis

Thomas K Pak  1 , Emine Rabia Ayvaci  1   2 , Thomas Carmody  1   3 , Limi Jamma  1 , Zihang Feng  1 , Arya Nekovei  1 , Graham Emslie  1   2 , Madhukar H Trivedi  1
Affiliations

Peripheral biological correlates of suicidality in children and adolescents: A systematic review and meta-analysis

Thomas K Pak et al. iScience. .

Abstract

A systematic review and meta-analysis were conducted to identify peripheral biological correlates of suicidality in children and adolescents. The review was pre-registered through PROSPERO (CRD42023417128) and included four databases (PubMed, Cochrane Library, Embase, and PsycINFO). From 27,977 non-duplicated articles, 102 full-text studies were selected. Studies investigated suicide attempts (n = 52), suicidal ideation (n = 42), or individuals with suicidal ideation or attempts grouped together (n = 22). Seropositive toxoplasmosis, cortisol, neutrophil, and neutrophil to lymphocyte ratio (NLR) exhibited significant effect size after Bonferroni correction. Effect sizes for biological correlates of suicidality were pooled using Cohen's d (effect size = -0.04, 95% confidence interval [CI]: -1.36 to 1.27) and odds ratio (effect size = -0.31, 95% CI: -1.06 to 0.42). Meta-regression analysis revealed that type of suicidality, type of control, means collected, and sample size significantly impacted the pooled effect size. Analysis showed significant publication bias and heterogeneity, as well as notable moderators and potential biomarkers for future research.

Keywords: Psychology; Public health.

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Conflict of interest statement

T.K.P., E.R.A., D.C., L.J., Z.F., and A.N. report no conflicts of interest. G.E. is a consultant for Lundbeck and Neuronetics. G.E. receives research support from American Foundation for Suicide Prevention (AFSP), Janssen Pharmaceuticals, Janssen Research & Development, the National Institutes of Health, Patient-Centered Outcomes Research Institute (PCORI), and the State of Texas. M.H.T. has received research funding from NIMH, NIDA, NCATS, the American Foundation for Suicide Prevention, the Patient-Centered Outcomes Research Institute, and the Blue Cross Blue Shield of Texas. He has served as a consultant or advisor for ACADIA PHARMACEUTICALS INC., Akili Interactive, ALKERMES INC (Pub Steering Comm-ALKS5461), Allergan Sales LLC, Alto Neuroscience, Inc. , Applied Clinical Intelligence, LLC (ACI), Axome Therapeutics, Boehringer Ingelheim, Engage Health Media, Gh Research, GreenLight VitalSign6, Inc., Heading Health, Inc., Health Care Global Village, Janssen – Cilag.SA, Janssen Research and Development, LLC (Adv Committee Esketamine), Janssen Research and Development, LLC (panel for study design for MDD relapse), Janssen - ORBIT, Legion Health, Jazz Pharmaceuticals, LUNDBECK RESEARCH U.S.A, Medscape, LLC, Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Myriad Neuroscience, Neurocrine Biosciences Inc, Navitor, Pharmaceuticals, Inc., Noema Pharma AG, Orexo US Inc., Otsuka Pharmaceutical Development & Commercialization, Inc. (PsychU, MDD Section Advisor), Otsuka America Pharmaceutical, Inc. (MDD expert), Pax Neuroscience, Perception Neuroscience Holdings, Inc., Pharmerit International, LP, Policy Analysis Inc., Sage, Therapeutics, Rexahn Pharmaceuticals, Inc., Sage Therapeutics, Signant Health, SK Life Science, Inc., Takeda Development Center Americas, Inc., The Baldwin Group, Inc., and Titan Pharmaceuticals, Inc. M.H.T. also received editorial compensation from Oxford University Press. Disclaimer: The Intellectual Property of VitalSign6 belongs to the University of Texas Southwestern Medical Center (Principal Investigator, M.H.T.) and is now licensed to GLVS6 for future distribution.

Figures

None
Graphical abstract
Figure 1
Figure 1
PRISMA flow diagram for systematic review
Figure 2
Figure 2
Forest plot of effect size (Cohen’s d) of biological correlates of suicidality (A) Forest plot for cortisol (p < 0.0001). (B) Forest plot for dexamethasone suppression test (non-suppressors) (p = 0.013). (C) Forest plot for neutrophil (p < 0.0001). (D) Forest plot for platelet (p = 0.025). (E) Forest plot for platelet to lymphocyte ratio (p = 0.046). (F) Forest plot for neutrophil to lymphocyte ratio (p = 0.0023). (G) Forest plot for seropositive toxoplasmosis (p < 0.0001). (H) Forest plot for tryptophan (p = 0.045). The Black Diamond at the bottom is the pooled effect size. Each horizontal line represents a specific biomarker from a specific study. The study number and biomarker are listed on the left of the forest plot. The study numbers reflect the study numbers in Table 1 and are not reference numbers. The dots and whiskers at the center represent the effect size and 95% confidence interval. The right of the forest plot is the numerical data of the effect size and the 95% confidence interval. Cortisol, neutrophil, neutrophil to lymphocyte ratio, and seropositive toxoplasmosis remained significant after Bonferroni correction. Some study numbers are listed multiple times since different study characteristics were utilized for assessing biological correlates of suicidality (different types of suicidality and control). DST; dexamethasone suppression test. RE, random effect.
Figure 3
Figure 3
Funnel plot of effect size (Cohen’s d) of biological correlates of suicidality (A) Funnel plot for cortisol. (B) Funnel plot for dexamethasone suppression test (non-suppressors). (C) Funnel plot for neutrophil. (D) Funnel plot for platelet. (E) Funnel plot for platelet to lymphocyte ratio. (F) Funnel plot for neutrophil to lymphocyte ratio. (G) Funnel plot for seropositive toxoplasmosis. (H) Funnel plot for tryptophan. Each dot represents an individual biological correlate from a study. The x axis is the effect Size (Cohen’s d) and the y axis is the standard error. DST, dexamethasone suppression test.
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