Table 1.
Biomarkers of Suicidal Ideation, Attempt, and Death by Suicide
| Category a | Marker | Source | Comparison group | Study design | Reference | Suicidal ideation | Suicide attempt | Death by suicide |
|---|---|---|---|---|---|---|---|---|
| BDNF | BDNF | Blood (serum) | Psychiatric controls, HCs, SA | Case-control | (Eisen et al., 2016) | No association was found between BDNF levels and SA | ||
| BDNF | BDNF | Blood (plasma) | SI (received ketamine) | Pilot | (Zheng et al., 2020) | No changes in BDNF found across patients throughout baseline, infusion, and follow up. No association between BDNF and reported SI | ||
| BDNF | BDNF | Blood (serum) | MDD non-suicidal, HCs, SA | Cross-sectional | (Pedrotti Moreira et al., 2018) | No differences found between MDD non-SA and SA groups | ||
| BDNF | BDNF | Blood (serum and plasma) | Psychiatric controls, SI, and SA | Meta-analysis | (Salas-Magaña et al., 2017) *used suicidal behavior—could be SI or SA | No difference in serum BDNF levels between psychiatric controls and those with suicidal behavior, but plasma levels were lower in patients with suicidal behavior | No difference in serum BDNF levels between psychiatric controls and those with suicidal behavior, but plasma levels were lower in patients with suicidal behavior | |
| BDNF | BDNF | Blood | General population, SA (all women) | Cross-sectional | (Kudinova et al., 2019) | Women with history of SA had lower peripheral levels of BDNF | ||
| BDNF | BDNF | Blood (serum) | MDD non-suicidal, HCs, SI | Cross-sectional | (Khan et al., 2019) | Serum BDNF levels differentiated non-suicidal MDD from MDD with SI, as well as mild-to-moderate SI. Lower BDNF levels were associated with increased SI | ||
| BDNF | BDNF | Blood (serum) | BD treated with ketamine or midazolam, SI | Pilot | (Grunebaum et al., 2017) | Decreased BDNF was associated with reduced SI after ketamine infusion but not midazolam treatment | ||
| BDNF | BDNF, DST suppression | Blood | SA | Cross-sectional | (Ambrus et al., 2016) | Female non-suppressors had lower BDNF levels than suppressors | ||
| BDNF | proBDNF, mBDNF | Blood (serum) | MDD, BD, SA, HCs | Cross-sectional | (Lin et al., 2021) | High serum mBDNF differentiated SA from psychiatric controls, but not from HCs | ||
| Biometals | Biometal profile (over 16 metals) | Cortical tissue | MDD, BD, HCs, death by suicide | Post-mortem | (Dean et al., 2019) | Significant changes of 16 metals in BA. Six of those died by suicide compared with psychiatric controls and HCs | ||
| Biometals | Iron transport (ceruloplasmin, APP, tau, transferrin, prion) | Cortical tissue | MDD, BD, HCs, death by suicide | Post-mortem | (Dean et al., 2020) | Copper containing cerulo-plasmin was lower in suicide, while APP, tau, and transferrin were higher | ||
| Dopa-minergic | HVA | CSF | Psychiatric controls, HCs, SA | Systematic review and meta-analysis | (Hoertel et al., 2021) | HVA levels were significantly lower in SA | ||
| Endo-cannabinoids | AEA, 2-AG | Blood (whole) | Veteran population, SA | Cross-sectional | (Sher et al., 2020) | AEA levels correlated negatively with SSI scores in SA group, but not others | 2-AG levels were significantly higher in SA group | |
| Endo-cannabinoids | AEA, 2-AG, PEA, OEA | Blood (serum) | Psychiatric controls, SA | Cross-sectional | (Herranz-Herrer et al., 2020) | AEA and PEA expression was higher in SA | ||
| Endo-cannabinoids | CB1 Receptor Density | Cortical tissue | AUD controls | Post-mortem | (Colino et al., 2018) | Significant increases in CB1 receptor density in those who died by suicide | ||
| Gluco-corticoid | GR-α mRNA | Blood | SI, SA, HCs | Cross-sectional | (Melhem et al., 2017) | Higher GR-α mRNA in SI than SA | Lower GR-α mRNA in SA than SI | |
| Gluco-corticoid | Cortisol | Saliva | Suicide Risk Behavior (SRB) (preparation, interruption, ideation), non-suicidal, HCs | Cross-sectional, after SA—sample taken after the TSST | (Melhem et al., 2016) | Pre-task cortisol higher in SRB compared with all other groups | Pre- and post-task cortisol lower in SA compared with all other groups | |
| Gluco-corticoid | Cortisol | Hair | SI, SA, HCs | Cross-sectional | (Melhem et al., 2017) | Higher cortisol levels in SI than SA | Lower cortisol levels in SA than SI | |
| Gluco-corticoid | Cortisol Response | Saliva | SA impulsivity/ aggression subtypes, non-SA | Cross-sectional | (Stanley et al., 2019) | Higher cortisol response differentiated an SA subgroup with high impulsive aggression | ||
| Gluco-corticoid | Cortisol Response | Saliva | SI—brief or long ideation, HCs | Cross-sectional | (Rizk et al., 2018) | After the TSST, higher cortisol response seen in those with brief SI than long SI | ||
| Inflammatory marker | CRP | Blood | SI, SA, HCs | Cross-sectional | (Melhem et al., 2017) | Lower CRP levels in SI than SA | Higher CRP levels in SA than SI | |
| Inflammatory marker | CRP | Blood | MDD, non-suicidal, HCs | Meta-analysis | (Chen et al., 2020) *note: no differentiation between SI, SA, or completed suicide |
Higher CRP levels in suicidal MDD over non-suicidal MDD and HCs | Higher CRP levels in suicidal MDD over non-suicidal MDD and HCs | Higher CRP levels in suicidal MDD over non-suicidal MDD and HCs |
| Inflammatory marker | CRP | Blood | MDD | Cross-sectional | (Köhler-Forsberg et al., 2017) | CRP levels were positively associated with SI in women, but not men | ||
| Inflammatory marker | hsCRP and ESR | Blood | SI, non-suicidal MDD | Cross-sectional | (Chang et al., 2017) | Those with SI had higher levels of hsCRP and ESR than those with non-suicidal MDD. hsCRP levels positively correlated with SI severity | ||
| Inflammatory marker | CRP | Blood | General population | Longitudinal | (Russell et al., 2021) | No association found between CRP levels at baseline and death by suicide | ||
| Inflammatory marker | Cytokine profile (IL-6, IL-10, IFN-γ, TNF-α, and CRP) | Blood | MDD, HCs | Longitudinal | (Choi et al., 2021) | TNF-α at baseline significantly predicted SI over a 12-wk period | ||
| Inflammatory marker | Cytokine profile (IL-6, IL-1β, TNF-α) | Blood | MDD non-suicidal, SI, SA, HCs | Cross-sectional | (Ganança et al., 2021) | SI was not differentiated from non-suicidal group | Compared with those with SI and non-suicidal groups, those with SA had the lowest IL-1β levels | |
| Inflammatory marker | hsCRP | Blood | Psychiatric controls, SA, SI | Retrospective analysis | (Gibbs et al., 2016) | hsCRP levels were higher in those with SI than in controls, but lower in those with SA | As hsCRP level increased, the probability of SA increased from SI and controls | |
| Inflammatory marker | hsCRP | Blood | SI, SA, psychiatric controls, HCs | Cross-sectional | (Park and Kim, 2017) | Higher levels of hsCRP were associated with SI | hsCRP levels were highest in SA, though there were no significant differences between SI and SA | |
| Inflammatory marker | IL-1β | Blood | Depression and anxiety disorders treated with fluoxetine | Longitudinal | (Amitai et al., 2020) | IL-1β levels were not associated with TWSI | ||
| Inflammatory marker | IL-6 | Blood | General population, SI, SA | Cross-sectional | (Knowles et al., 2019) | No genetic correlation between SI and IL-6 | No genetic correlation between SA and IL-6, though BMI may have affected these results | |
| Inflammatory marker | IL-6 | Blood | Depression and anxiety disorders treated with fluoxetine | Longitudinal | (Amitai et al., 2020) | IL-6 levels were increased in youth who developed treatment-associated SI | ||
| Inflammatory marker | IL-8 | Blood | General population, SI, SA | Cross-sectional | (Knowles et al., 2019) | No genetic correlation between SI and IL-8 | Significant genetic correlation observed between SA and IL-8, mainly in females | |
| Inflammatory marker | Inflammatory profile (23 biomarkers) | Blood | MDD non-suicidal, SI, SA | Cross-sectional | (Su et al., 2020) *note: used suicide risk as categorization factor, which can include SI and SA |
Higher levels of inflammatory markers were associated with increased suicide risk, particularly CXCL-1 | Higher levels of inflammatory markers were associated with increased suicide risk, particularly CXCL-1 | |
| Inflammatory marker | Inflammatory profile (CRP, WBC, IgE, DII) | Blood | MDD non-suicidal, MDD SI, non-MDD SI | Cross-sectional | (Bergmans et al., 2019) | MDD SI was indistinguish-able from MDD, but non-MDD SI was associated with DII | ||
| Inflammatory marker | Inflammatory profile (IL-6, IL-1β, TNF-α, IL-1ra, CRP) | Blood | MDD non-suicidal, SA | Cross-sectional | (Coryell et al., 2018) | Low levels of IL-1β, but no other cytokines, were associated with SA | ||
| Inflammatory marker | Inflammatory profile, including 45 immuno-biological factors | Blood | Neuro-psychiatric population | Cross-sectional | (Keaton et al., 2019) *note: used suicide risk, which includes SI and SA |
IL-6, lymphocytes, WBC count, and polymorphonuclear leukocyte count were positively associated with significant suicide risk. IL-8 was negatively associated with suicide risk | IL-6, lymphocytes, WBC count, and polymorphonuclear leukocyte count were positively associated with significant suicide risk. IL-8 was negatively associated with suicide risk. | |
| Inflammatory marker | NLR and PLR, SIII | Blood | MDD non-suicidal, SA | Retrospective | (Meydaneri and Meydaneri, 2018) | No measures were significantly different in SA | ||
| Inflammatory marker | NLR | Blood | Non-violent and violent SA | Cross-sectional, after SA | (Capuzzi et al., 2020b) | NLR was significantly lower in violent SA compared with non-violent SA | ||
| Inflammatory marker | NLR, PLR, and MLR | Blood | MDD non-suicidal, SA | Cross-sectional | (Velasco et al., 2020) *note: also included suicidal behavior, which can include SI and SA |
Those with a history of SA had significantly higher NLR and PLR ratios. NLR was significantly associated with suicidal behavior | ||
| Inflammatory marker | TNF-α | Blood | General population, SI, SA | Cross-sectional | (Knowles et al., 2018) | No genetic correlation between SI and TNF-α | No genetic correlation between SA and TNF-α | |
| Inflammatory marker | TNF-α | Blood | Depression and anxiety disorders treated with fluoxetine | Longitudinal | (Amitai et al., 2020) | TNF-α levels were not associated with TWSI | ||
| Inflammatory marker | WBC count | Blood | General population | Longitudinal | (Russell et al., 2021) | Significant association between WBC count at baseline and death by suicide | ||
| Inflammatory marker, lipid | Inflammatory and lipid profile (CRP, TRSF, HCY, AAT, HDL-c, APOA1) | Blood | MDD non-suicidal, HCs, SI | Cross-sectional | (Bai et al., 2021) | A panel of AAT, TRSF, HDL-c, and APOA1 effectively differentiated SI from MDD and HCs. Lipids were more effective than inflammatory markers | ||
| Lipid | AA%, DHA%, EPA% | Blood | MDD non-suicidal, SI, SA, HCs | Cross-sectional | (Ganança et al., 2021) | SI was not differentiated from the non-suicidal group | DHA% had the lowest IL-1β levels from SI and non-suicidal groups | |
| Lipid | Cholesterol | Blood | MDD, non-suicidal | Case-control, after SA | (Eidan et al., 2019) | Lower LDL levels in SA | ||
| Lipid | Cholesterol | Blood | Non-violent SA | Case-control, after SA | (Capuzzi et al., 2020b) | Lower cholesterol levels in violent SA | ||
| Lipid | Esterified cholesterol, unesterified cholesterol, cholesterol efflux capacity | Blood | Mexican-American population, SA | Retrospective/ longitudinal | (Knowles et al., 2018) | Esterified cholesterol shared genetic overlap with SA. The relationship between unesterified cholesterol and SA was mediated bycholesterol efflux capacity (ABCA-1 mediated) | ||
| Lipid | LDL | Blood | MDD, non-suicidal | Case-control, after SA | (Eidan et al., 2019) | Lower LDL levels in SA | ||
| Lipid | LDL | Blood | Non-violent SA | Cross-sectional, after SA | (Capuzzi et al., 2020b) | Lower LDL in violent SA | ||
| Lipid | Leptin | Blood (serum) | Psychiatric controls, HCs, SA | Meta-analysis | (González-Castro et al., 2021) | Lower leptin levels were associated with increased risk of SA | ||
| Lipid | Lipid profile (TC, LDL-c, TGC) | Blood (serum) | BD non-suicidal, SA | Meta-analysis | (Bartoli et al., 2017) | No association between lipid profile and SA | ||
| Lipid | Lipid profile (TC, LDL-c, TGC) | Blood (serum) | Psychiatric controls, SA | Cross-sectional | (Capuzzi et al., 2018) | No association between lipid profile and SA | ||
| Lipid | Lipid profile (TC, TGC, HDL-c, LDL-c) | Blood | MDD non-suicidal, HCs, SA | Cross-sectional | (Messaoud et al., 2017) | TC in plasma was significantly decreased in SA compared with all other groups; no differences in other measures | ||
| Lipid | TC | Blood | Veterans: non-suicidal, SI, SA | Retrospective/ longitudinal | (Reuter et al., 2017) | TC was significantly lower in SI or SA veterans. In the available data, TC was significantly decreased in these populations from an earlier visit | TC was significantly lower in SI or SA veterans. In the available data, TC was significantly decreased in these populations from an earlier visit | |
| Lipid | VLDL | Blood | Non-violent SA | Cross-sectional, after SA | (Capuzzi et al., 2020b) | Lower VLDL levels in violent SA | ||
| Lipid | Androgens (testosterone, andro-stenedione, DHEAS) | Blood (plasma) | Psychiatric population, healthy population | Longitudinal | (de Wit et al., 2020) | No androgen levels at baseline were implicated in SI or SA after a nine-year follow up | ||
| Nora-drenergic | MHPG | CSF | Psychiatric controls, HCs | Systematic review and meta-analysis | (Hoertel et al., 2021) | No differences in MHPG levels between groups | ||
| Serotonergic | 5-HIAA | CSF | Psychiatric and healthy controls | Systematic review and meta-analysis | (Hoertel et al., 2021) | 5-HIAA levels were significantly lower in attempters | ||
| Serotonergic | Kynurenine/ tryptophan ratio | Blood | Non-suicidal MDD, HCs | Cross-sectional, after SA | (Messaoud et al., 2019) | Kynurenine/ tryptophan ratio was higher in suicidal MDD than non-suicidal and HCs | ||
| Serotonergic | Serotonin | Blood | BD type I non-attempters | Cross-sectional, after SA | (Giurgiuca et al., 2016) | Lower levels in attempters compared with non-attempters, and lower levels in those who used a high-lethality method compared with low-lethality | ||
| Serotonergic | SERT, 5-HTR1A, and 5-HTR2A binding | Brain Tissue | MDD, non-suicide, AUD | Post-mortem | (Underwood et al., 2018) | SERT binding was lower, and 5-HT1A binding was greater in suicides independent of MDD diagnosis | ||
| Serotonergic | Tryptophan | Blood | Non-suicidal MDD, HCs | Cross-sectional, after SA | (Messaoud et al., 2019) | Tryptophan levels were lower in suicidal MDD than non-suicidal and HC | ||
| MicroRNA | miR-3688 and miR-5695 | Blood | TWSI | Longitudinal | (Belzeaux et al., 2019) | Both miRNA significantly predicted TWSI | ||
| Uric Acid | Uric acid levels | Blood (serum) | SA, MDD non-suicidal | Cross-sectional | (Peng et al., 2018) | No differences in uric acid levels between MDD controls and those with a previous SA |
a 2-AG, 2-Arachidonoylglycerol; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTR1A, 5-Hydroxytryptamine Receptor 1A; 5-HTR2A, 5-Hydroxytryptamine Receptor 2A; AA%, arachidonic acid %; AAT, alpha 1-antitrypsin; AEA, anandamide; APOA1, Apolipoprotein A1; APP, amyloid precursor protein; AUD, alcohol use disorder; BA, Brodmann’s area; BDNF, brain derived neurotrophic factor; BD, bipolar disorder; BMI, body mass index; CB1, cannabinoid receptor type 1; CRP, C-reactive protein; CSF, cerebrospinal fluid; CXCL-1, CXC ligand-1; DHA%, docosahexaenoic acid %; DII, dietary inflammatory index; DHEAS, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; EPA%, eicosapentaenoic acid %; ESR, erythrocyte sedimentation rate; GR-α, glucocorticoid receptor alpha; HCs, healthy controls; HCY, homocysteine; HDL-c, high-density lipoprotein cholesterol; hsCRP, high-sensitivity CRP; HVA, homovanillic acid; IFN-γ, interferon gamma; IgE, immunoglobulin E; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IL-1β, interleukin 1 beta; IL-1ra, Interleukin 1 receptor antagonist; LDL, low-density lipoprotein; LDL-c, low-density lipoprotein cholesterol; mBDNF, mature brain derived neurotrophic factor; MDD, major depressive disorder; MHPG, 3-methoxy-4-hydroxyphenylglycol; MLR, mixed lymphocyte reaction; mRNA, messenger ribonucleic acid; NLR, neutrophil-lymphocyte ratio; OEA, oleoylethanolamide; PBMC, peripheral blood mononuclear cell; PEA, palmitoylethanolamide; PLR, platelet lymphocyte ratio; proBDNF, BDNF precursor; SA, suicide attempt; SERT, serotonin transporter; SI, suicidal ideation; SIII, systemic immune inflammatory index; SRB, suicide risk behavior; SSI, Scale for Suicide Ideation; TC, total cholesterol; TGC, triglycerides; TNF-α, tumor necrosis factor alpha; TNFAIP3, TNF alpha induced protein 3; TRSF, transferrin; TSST, Trier Social Stress Task; TWSI, treatment-worsening suicidal ideation; VLDL, very-low-density lipoprotein; WBC, white blood cell.