2023; 21(4): 650-664  https://doi.org/10.9758/cpn.22.1046
Peripheral Markers of Suicidal Behavior: Current Findings and Clinical Implications
Hee-Ju Kang1, Ju-Wan Kim1, Sung-Wan Kim1, Jung-Soo Han2, In Kyoon Lyoo3,4, Jae-Min Kim1
1Departments of Psychiatry, Chonnam National University Medical School, Gwangju, Korea
2Department of Biological Science, Konkuk University, Seoul, Korea
3Ewha Brain Institute, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
4Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Korea
Correspondence to: Jae-Min Kim
Department of Psychiatry, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Korea
E-mail: jmkim@chonnam.ac.kr
ORCID: https://orcid.org/0000-0001-7409-6306
Received: December 14, 2022; Revised: December 21, 2022; Accepted: December 22, 2022; Published online: May 22, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Biomarkers of suicidal behavior (SB), particularly peripheral biomarkers, may aid in the development of preventive and intervention strategies. The peripheral biomarkers of SB should be easily accessible, cost-effective, and minimally invasive. To identify peripheral biomarkers of SB, we summarized the current knowledge related to SB biomarkers with a focus on suicidal outcomes (suicidal ideation [SI], suicide risk [SR], suicide attempt [SA], and suicide death [SD]), measured site (center or periphery), and study design (cross-sectional or longitudinal). We also evaluated the central findings to validate the findings of peripheral biomarkers of SB. We found reduced peripheral interleukin (IL)-2 levels in individuals with a recent SA, higher cerebrospinal fluid (CSF) IL-6 levels in patients with a current SR and future SD, higher CSF tumor necrosis factor-α levels for current and future SRs, higher high-sensitivity C-reactive protein levels and lower peripheral total cholesterol levels for recent SAs, lower peripheral 5-HT levels for present SR, and a lower folate level for future SR and SA within 1 year. Previous studies have shown inconsistent associations of low peripheral leptin levels with SR and recent SA; therefore, further study is required. Given the multiple determinants of SB and weak associations with single biological markers, combinations of potential biological markers rather than single markers may improve the screening, diagnosis, and prediction of SB.
Keywords: Biomarkers; Suicide; Cross-sectional studies; Longitudinal studies
INTRODUCTION

Suicide is a serious health and societal problem world-wide. Substantial efforts have been made to understand the mechanism underlying suicide and develop preventive measures [1,2]. However, suicide prevention remains challenging because suicide prediction in the clinical setting relies on self-reported suicidal ideation (SI), suicide attempts (SAs), and past and familial histories [1,3]. The identification of biomarkers for suicidal behavior (SB) may enhance our understanding of the pathological mechan-isms of suicide and aid the development of preventive and intervention strategies [4]. Ideal biomarkers for SB will be peripheral, easily accessible, cost-effective, and minimally invasive.

Several biological factors involved in the patho-mechanisms of SB have been evaluated as potential peripheral biomarkers, including altered serotonergic and neurotrophic systems, dysregulated inflammatory processes and stress-response systems (e.g., cortisol), and an abnormal lipid profile [5,6]. However, no biomarker of SB has been accepted for use because of inconsistent findings in previous studies. There are several reasons for such incon-sistencies. SB is a continuum that ranges from SI to a SA and suicide death (SD); previous studies used different suicidal outcomes. Moreover, biomarkers can be measured using several methods, including changes in gene or protein expression, in the central nervous system or peri-phery. Finally, biomarkers can provide variable informa-tion such as that related to current and future SBs, depending on the study design. We summarized current knowledge on SB biomarkers with a focus on discrepancies among studies in terms of suicidal outcomes (SI, SA, and SD), measured site (center or periphery), and study design (cross-sectional or longitudinal).

INFLAMMATORY MARKERS

Accumulating evidence suggests that inflammation plays an important role in the pathogenesis of SB. Inflammation is associated with cytokine release, leading to neurotoxic effects and breakdown of the blood-brain barrier (BBB), which allows activated immune cells and their products to affect brain function [7]. Therefore, inflammatory cytokines may be key modulators of inflammation. Several meta-analyses and reviews have found altered cytokine levels in suicidal patients [8-10]. A meta-analysis of 18 studies found increased interleukin (IL)-1b and IL-6 levels but decreased IL-2 levels in psychiatric patients with suicidality compared to those without suicidality and healthy controls [7]. Another meta-analysis of 11 studies evaluated IL-2, IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, and transforming growth factor (TGF)-β levels. The IL-2 level was lower in suicidal patients than in non-suicidal patients and healthy controls, wheres the IL-4 level was lower and TGF-β was higher in suicidal patients than in healthy controls [8]. Another meta-analysis found that serum and central nervous system IL-6 levels were increased while the plasma IL-6 level was decreased in individuals with SB [9]. Although previous studies have found roles for abnormal inflammatory cytokine levels in SB, the type of cytokine and direction of association (positive, negative, or none) varied because of the heterogeneity in study design, measured samples, and suicidal outcomes. The associations between individual cytokines and SB are presented according to SB outcomes, measured samples, and study design in Supplementary Table 1 (available online) and Table 1.

We reviewed the studies that investigated IL-1, including those that investigated IL-1α, IL-1β, and both. Although few studies have evaluated the IL-1 level as a whole, the peripheral (plasma) IL-1 level was associated with recent SA [11] and the central (cerebrospinal fluid, CSF) IL-1 level with lifetime SA [12]. No significant association was found between CSF IL-1 level and SI [12]. Few studies have investigated the association between peripheral IL-1α level and SB. An increased IL-1α level was found to be assoiated with lifetime SA [13] and suicidal risk (SR) measured by SI and/or SAs [14]. No significant association was found between IL-1α level and subsequent SD over 13 years of follow-up in patients with SAs [15]. There is a lack of evidence regarding the association between IL-1β level and SB. It is unclear whether there is an association between SR and peripheral IL-1β level. Two studies found an increased IL-1β level in patients with SR [14], whereas no association was found in 4 studies [16-18], including a study in which the significant association was no longer significant after correction for multiple comparisons [19]. The association between peripheral IL-1β level and lifetime SA is also unclear because of an increased serum IL-1β level in one study [20] and decreased serum and plasma IL-1β levels in 2 studies [21]. Meanwhile, no association was found between IL-1β level and recent SA in 2 studies that used the peripheral level [22,23] and 1 study that used the CSF level [24]. Peripheral (plasma) and CSF IL-1β levels were not associated with subsquent SD [15,25]. However, the IL-1β level may be a marker of SD according to the measured brain region. In SDs, the IL-1β levels were increased in the prefrontal cortex (PFC) [26], decreased in the choroid plexus [27], and unchanged in the orbitofrontal cortex (OFC), dorsal anterior cingulate cortex (dACC), and frontal cortex [28]. Briefly, an increased peripheral IL-1 level was associated with recent SA, but not with SI. This was supported by the finding of increased CSF IL-1 levels in individuals with a lifetime SA. An increased peripheral IL-1α level was associated with SR and lifetime SA but not with subsequent SD. Meanwhile, peripheral IL-1β level was not associated with SB; however, differential associations between the IL-1β level in various brain regions and SD were identified. Further research is needed to confirm the associations of IL-1 level as a whole and IL-1α level with SB.

A previous meta-analysis found consistently reduced IL-2 levels in SB [8,9]. In line with the previous meta-analysis, we found that reduced IL-2 level was associated with recent SA in 2 studies [29]. However, no significant association was found between IL-2 level and SR in three cross-sectional studies [17,18,30] or subsequent SD in a longitudinal study [15].

A meta-analysis found no association between the anti-inflammatory cytokine IL-4 and SB [8], whereas another meta-analysis found reduced IL-4 levels with SB [9]. In our review, only one study found an association between low plasma IL-4 [18] and SR, whereas three studies found no association between peripheral IL-4 level and SR [16, 17,30]. A single study of recent SAs [29] and subsequent SDs [15] found no association. By contrast, an increased central IL-4 level in the OFC was associated with SD, particularly in females [28]. Considering the inconsistency between the central and peripheral findings, and the lack of association in most studies, the IL-4 level is not associated with SB.

A previous meta-analysis included 5, 2, and 2 studies that evaluated IL-6 levels in the plasma, serum, and CSF, respectively. The results showed that a low plasma IL-6 level and high serum and CSF IL-6 levels are potential biomarkers of SB [10]. Although we did not find evidence supporting the association of serum, plasma, and CSF IL-6 levels with SB, we have summarized the studies of IL-6 levels according to the suicidal outcomes and measured site. Increased peripheral IL-6 was associated with increased SR in 5 studies [14,17,31], while no association was found in 5 other studies [16,18,19]. Four studies reported an association between increased peripheral IL-6 and recent SA [32], whereas one study reported a reduced plasma IL-6 level [29] and 3 studies reported no association [11,23]. None of the studies found a significant association of peripheral IL-6 level with lifetime SA [21,32, 33]. In one study, the plasma IL-6 level measured at the index SA was not associated with future SD during 13 years of follow-up [15].

Similar to the studies of peripheral IL-6 levels, studies of the associations of central CSF IL-6 levels with recent and lifetime SAs reported inconsistent results. Patients with a recent SA had increased CSF IL-6 levels [24]; however, there was no association of CSF IL-6 level with recent SAs including violent attempts [34]. No association was found [12] between CSF IL-6 level and lifetime SA, whereas a high CSF IL-6 level was associated with lifetime violent SAs [25]. By contrast, a higher CSF IL-6 level was associated with severe SR in 2 studies [25]. In individuals with SD, the IL-6 level was increased in the PFC, hippocampus, and frontal region [26,35], but not in the OFC [28] or choroid plexus [27]. Additionally, the central CSF IL-6 level was associated with future SD during 15 ± 4 years of follow-up [25].

In summary, the association between IL-6 level and recent SA is unclear, whereas there was no association between lifetime SA and peripheral and central IL-6 levels. The CSF, but not the peripheral, IL-6 level predicted future SD. Similarly, the association between peripheral IL-6 level and SR was inconclusive; however, CSF IL-6 level was significantly associated with SR. Thus, an increased central, but not peripheral, IL-6 level was associated with SR and subsequent SD. Additional large-scale studies with longitudinal designs are required to verify these findings.

Few studies have evaluated the association of IL-5, IL-8, IL-10, IL-12, and IL-13 with SB. No significant association was identified between the peripheral [30] and SR or the OFC [28] IL-5 level and SD. Furthermore, there was no association between peripheral IL-12 level and SR [17]. Studies have reported inconsistent results regarding the association between plasma IL-8 level and SR. A decreased plasma IL-8 level was associated with high SR in a study of patients with mood disorders [17] but not in another study of adolescent and young patients with major depressive disorder [18]. By contrast, increased CSF IL-8 level was associated with high suicidal intent [25]. Two studies found no association of central IL-8 level with recent SA [24], whereas another study found an association between low CSF IL-8 level and recent SA [34]. Addition-ally, plasma IL-8 level was not associated with future SD within 13 years [15], and no association was found between central IL-8 level in the PFC and depression in suicidal victims [26]. No association was found between the peripheral IL-10 level and SR [17,18,30], recent SA [22], or future SD [15]. Decreased central IL-10 in the PFC was associated with SD in 1 study [26], but no association was identified with the IL-10 level in the dACC, frontal cortex, or choroid plexus [27]. A single study found no association between plasma IL-13 level and SR [17]. However, an increased IL-13 level in the OFC [28], but not in the PFC [26], was associated with SD. In summary, considering these scarce studies and their inconsistent or negative results, the roles of IL-5, IL-8, IL-10, IL-12, and IL-13 as biomarkers for SR, SA, and SD are unclear.

Several studies of the associations between TNF-α level and SB have reported inconsistent findings, and a meta- analysis found no significant association between them [8,9]. Most studies have not reported an association between peripheral TNF-α level and SR [13,17-19], although a single study found an association between decreased peripheral TNF-α and highly lethal SR [16]. In contrast to cross-sectional studies of peripheral TNF-α levels, the CSF TNF-α level was associated with SI in a cross-sectional study [25] and in a 12-month longitudinal study [36]. Five studies did not find an association between peripheral TNF-α and lifetime SA [13,21,33], although a single study found an association between increased peripheral level and lifetime SA [32]. Meanwhile, 2 studies reported the association between increased peripheral TNF-α and recent SA [23], whereas 3 studies found no significant association [11,22,32]. Additionally, previous studies found no significant association of the central TNF-α level with recent [24] or lifetime SA [12]. Five studies did not identify any significant association of SD with TNF-α expression levels in the OFC, dACC, hippocampus, frontal cortex, and choroid plexus [27,28,35], whereas 2 studies found increased TNF-α expression in the PFC and DLPFC of teenage and adult depressed SDs [26]. Summing up, the CSF, but not peripheral, TNF-α level was associated with SR. By contrast, the role of peripheral TNF-α as a biomarker for SA and SD is unclear with the findings of no association of central TNF-α level with SA and only a limited increase in the TNF-α level in the PFC with SA.

Only 2 studies evaluated the association of peripheral TGF-β with recent SA [29] and SI [31], and found no significant association. Two studies found no association of peripheral IFN-γ level with recent SA [29], whereas 4 studies found no association with SR [14,16-18] and a single study found increased peripheral IFN-γ with SR [30]. A longitudinal study found no association between plasma IFN-γ level and subsequent SD, although there was a statistically insignificant trend toward an increased level [15]. Additionally, a study found no significant association between the central IFN-γ level in the hippocampus and SD [35]. The aforementioned studies suggest that the peripheral TGF-β level was not associated with recent SA or SI, whereas central and peripheral IFN-γ levels were not associated with SR, recent SA, or SD.

C-reactive protein (CRP) is a potential biomarker of SB. It is an inflammatory protein that is produced in response to increased proinflammatory cytokines (e.g., IL-6, IL-1, and TNF-α) [37]. It is easily detected in peripheral blood and is widely used as an inflammatory marker [37]. Al-though few studies have evaluated the association between central CRP levels, 2 previous meta-analyses found increased peripheral CRP levels in suicidal patients with depressive disorders [38], as well as in psychiatric patients with high SI and in those with SAs compared to non-suicidal individuals [39]. The medium-sized magnitude of high sensitivity measurements was significantly associated with suicidality compared to the large-sized mag-nitude of regular measurements [39]. Similarly, we summarized previous studies of CRP level according to suicidal outcomes and CRP detection methods (Table 2).

No association was found between regularly measured CRP levels and SR in 8 studies [17-19], whereas higher levels were associated with SR in 3 studies [40,41]. No association was found between high-sensitivity CRP (hsCRP) and SR in 2 studies [32,42], whereas a higher level was associated with SR in 3 studies [31]. Previous studies reported inconsistent results regarding the association between regularly measured CRP and recent SA: higher regularly measured CRP levels were associated with SA in 4 studies [23] but not in 4 other studies [7,43,44], whereas 1 longitudinal study reported no association between regularly measured CRP levels and future suicide reattempt within 6 months [45]. Four studies found a significant association between high hsCRP level and recent SA [42], whereas 2 other studies found no significant association [32,46]. No association was found between lifetime SA and regularly measured CRP or hsCRP: no association was found between the CRP level and SA in 3 cross-sectional [21] and 2 longitudinal studies [47], although 2 studies found an association between high regularly measured CRP level and SA [40]. A study found an association between high hsCRP level and lifetime SA [42], whereas another study found no significant association [32]. In brief, hsCRP, but not CRP, levels are significantly associated with recent SA, although previous studies are not longitudinal and have reported contradictory findings. Additional large-scale studies with a longitudinal design are needed to verify these results.

LIPID PROFILES

Peripheral lipids have received substantial attention as promising biomarkers of suicide, based on biological evidence showing that a low peripheral cholesterol level reduces the cholesterol/phospholipid ratio in neuronal mem-branes, leading to altered membrane viscosity and function that affects synaptic plasticity, enhances inflamma-tion, and reduces serotonergic neurotransmission, which are associated with mood dysregulation and SB [48]. A previous meta-analysis found lower total cholesterol (TC) and low-density lipoprotein levels in suicidal patients than in non-suicidal patients and healthy controls [49]. Similarly, the TC and low-density lipoprotein levels were lower in major depressive patients with SAs [50], whereas the TC level was lower in patients with schizophrenia spectrum disorders and SAs [51]. Although the BBB prevents the transit of cholesterol molecules, studies have provided support for the association between low central cholesterol level and suicidality. A study found a significantly decreased cholesterol content in the frontal cortex of individuals with violent SD [52] and increased level of the eliminated form of oxycholesterol in the PFC of individuals with SD [53].

Consistent with this, we found that the serum lipid level can be a biomarker of SB, as shown in Supplementary Table 2 (available online). Low peripheral TC level was associated with recent SA in most cross-sectional studies of patients with various psychiatric disorders [7,46] and with suicide reattempt within 6 months in a longitudinal study [45]. However, there was no significant association between other lipid profile parameters and SR, lifetime SA, or SD, given the inconsistent or negative findings of previous studies, except for a few studies of the association between low central cholesterol level and SD [53].

CORTISOL AS A NEUROENDOCRINE MARKER

The stress-diathesis model has been suggested as being involved in SB based on the finding that suicide is triggered by stressful events in individuals with predisposing diathesis [54]. Thus, biological markers of a dysregulated stress response system, such as the hypothalamus-pituiptary-adrenal axis, may also be biomarkers of suicidality. Of the several biomarkers of the hypothalamus-pituiptary-adrenal axis, including corticotropic-releasing hormone, adrenocorticotropic hormone, and glucocorticoid or mineralocorticoid receptor expression and/or activity, only the association between SB and cortisol, an effector hormone for the hypothalamus-pituiptary-adrenal axis, was reviewed in this manuscript. The cortisol level correlates with the serotonin level, a biological risk factor for SB, via decreased 5-HT1A mRNA expression and increased tryptophan 2,3 dioxygenase (which degrades tryptophan, a precursor of serotonin) [55]. Additionally, the bidirectional association between cortisol and inflam-mation, including cytokine regulation [56], is involved in SB.

A previous meta-analysis found no significant difference in cortisol levels between participants with and without a previous SA, although higher cortisol levels were found in individuals with SAs aged < 40 years [57]. A recent meta-analysis found a possible role for cortisol in SB, with higher cortisol levels in participants with SB compared to healthy controls but lower cortisol levels in those with SB compared to psychiatric controls [58]. In contrast to previous meta-analyses that reviewed suicidal outcomes together, we summarized the findings according to the suicidal outcomes (Supplementary Table 3; available online).

No longitudinal studies have evaluated the associations of cortisol with SR and recent SAs. Moreover, studies of urinary, salivary, and CSF cortisol are rarer than those of blood cortisol. The cross-sectional studies did not find an association between blood cortisol level and SR [19,31, 59], although a study found higher cortisol levels in individuals with SI and borderline personality disorder [60] as well as lower cortisol levels after a dexamethasone suppression test (DST) in individuals with suicidal intent and major depressive disorder [61]. Few studies have investigated the associations of urinary [62] and CSF [59] cortisol with SR, and found no significant association, in line with the findings of studies of blood cortisol. Cross-sectional studies of the association of cortisol level with recent SA have reported inconsistent findings: 8 studies found increased blood cortisol levels [63], 2 found decreased blood cortisol levels [64], and 12 found no association [11,59,64]. Similarly, studies of urinary and CSF cortisol levels reported inconsitent findings, with some studies reporting higher cortisol levels [63] and others reporting no association with recent SA [59,64]. However, studies found lower salivary and hair cortisol levels in patients with SA compared to healthy controls and psychiatric controls [23]. Longitudinal studies have found inconsistent results regarding the associations of blood, urinary, and salivary cortisol levels with lifetime SA and SD. Studies have reported positive, negative, and no associations of blood, urinary, and salivary cortisol levels with lifetime SA and SD [63,65]. In brief, there is no evidence for an association between cortisol level and SR. Addition-ally, studies have reported inconsistent results regarding the association between cortisol level and SB, except for SR.

BRAIN-DERIVED NEUROTROPHIC FACTOR AS A NEUROPLASTICITY MARKER

Brain-derived neurotrophic factor (BDNF) is involved in brain neurogenesis, neuroplasticity, and regeneration [66]. Its relationship with suicidality has received substantial interest. It is easily measured in peripheral blood, and the peripheral BDNF level is a reliable indicator of the central nervous system BDNF level because of its ability to cross the BBB [67]. An altered BDNF level leads to impaired neural maintenance and plasticity, which causes neuropsychological deficits and impairs the ability to adapt to environmental stimuli [68]. Moreover, a reduced BDNF level is associated with reduced serotonin function via the interaction between BDNF and serotonin [69]. Consequently, 3 meta-analyses have evaluated the association of BDNF level with SB, and found no significant association between serum BDNF level and SA [70] as well as lower plasma, but not serum, BDNF levels in individuals with SAs compared to those without SAs [71]. We have summarized the association of BDNF level with SB according to the suicidal outcome (Table 2).

There is a lack of longitudinal studies of the potential of BDNF to predict future suicidality. Moreover, more studies have typically measured the serum rather than the plasma BNDF level. Five studies found no association of peripheral BDNF level with SR, whereas 3 studies found an association between low BDNF level and SR. A single study found a positive correlation of CSF BDNF level with SI severity, which is in contrast to the association identified for the peripheral BDNF level. Based on these inconsistent findings, additional studies of SR are needed. Simi-larly, studies of the association between recent SA and BDNF level reported inconsistent results, with 6 studies reporting a low BDNF level in patients with a recent SA [37,72] and others reporting no association [43,44]. Further-more, no association was identified between BDNF level and lifetime SA in 6 studies [44], although a low BDNF level was identified in 3 studies [73] and a high BDNF level was identified in a single study [74]. Unfortunately, no study has evaluated the associations of central BDNF level with recent and lifetime SAs. However, a reduced BDNF level was noted in the PFC, hippocampus, ACC, and frontal cortex of suicide victims [75], although 2 studies found increased BDNF levels in the PFC and frontal cortex [76]. Overall, there is a lack of evidence regarding the association between peripheral BDNF level and recent or lifetime SAs or SR, although additional longitudinal studies are needed. However, the brain BDNF level is reduced in individuals with SD.

SEROTONIN (5-HT)

Because 5-HT regulates mood, anxiety, aggression, and impulsivity, impaired 5-HT function has been suggested to play a crucial role in SB [55]. Independent studies of SB have demonstrated impaired 5-HT function, as evidenced by increased tryptophan hydroxylase activity, reduced tryptophan (5-HT precursor) or 5-hydroxyindoleacetic acid (5-HIAA; 5-HT metabolite), 5-HT levels and altered 5-HT transporters and receptors [54,55]. Of these, the association between 5-HT levels and suicidality is summarized in Table 3.

Three cross-sectional studies found an association between low peripheral 5-HT level and SR in psychiatric patients [77]. Five cross-sectional studies found an association between reduced peripheral (whole blood, platelet, or serum) 5-HT level and recent SA [78], whereas 8 studies reported no significant association [59,78], including two longitudinal studies of future SAs within 6−12 weeks [79,80] and one cross-sectional study of CSF 5-HT levels [59]. Studies have reported inconsistent results regarding the association between peripheral 5-HT level and lifetime SA, with 3 studies finding increased peripheral 5-HT levels [81], including one longitudinal study [79], 2 studies finding decreased peripheral 5-HT levels [82], and 4 studies finding no significant association [83], including one longitudinal study [80]. Only a few postmortem studies have evaluated the association between 5-HT level and SD. The CSF 5-HT level was decreased in SD in a single study [84], whereas differential 5-HT expression according to the brain region was identified, with a decreased level in the hypothalamus, increased levels in the globus pallidus, putamen, and temporal cortex, and no change in the occipital and parietal cortices, cerebellum, substantia nigra, dentate and caudate nuclei, and amygdala [85]. In brief, a decreased peripheral 5-HT level was associated with SR, whereas evidence for an association between 5-HT level and other suicidal outcomes, including recent and lifetime SAs and SD, is inconclusive.

OTHER BIOLOGICAL MARKERS

To evaluate potential biomarkers for suicidality, we explored studies of additional markers, including leptin, folate, and homocysteine, which are associated with lipid or 5-HT levels. Leptin, an adipocyte hormone that affects lipid metabolism [86], is a candidate biomarker for SB. Despite limited studies, a meta-analysis found that individuals with SB have a reduced leptin level [87]. We summarized previous findings related to leptin according to the suicidal outcome (Table 4). Two cross-sectional studies found a reduced peripheral leptin level in psychiatric patients with a SR [41], whereas another study found no significant association [19]. Similarly, reduced leptin level was associated with recent SA in 2 studies [88], but not in another study [43]. A single study found decreased leptin levels in individuals with a first episode of psychosis and a SA or SD [89]. Reduced leptin mRNA and leptin receptor levels were found in the hypothalamus and frontal cortex of suicide victims [90]. In summary, cross-sectional studies demonstrated associations of reduced leptin level with SR, recent SA, and SD. However, few studies have evaluated the association between leptin level and SB. Future studies with a longitudinal design are needed to verify these findings.

Folate and homocysteine are involved in the one-carbon transfer (methylation) reaction necessary for the production of monoamine neurotransmitters [72]. Folate, associated with neurotransmitter synthesis [91], and homocysteine, which inhibits neurotransmitter metabolism and causes neurotoxicity [92], may play a role in suicide patho-genesis. Several studies have evaluated the association of folate and homocysteine with SB. Two longitudinal studies investigated the association between peripheral folate level and SA in depressed patients over 1−2 years. In one study, depressed patients who committed a violent SA had similar red cell and serum folate levels compared to non-suicidal depressed individuals and those without psychiatric diseases [93]. Another study found an association of low baseline folate level with lifetime SA and baseline severe SI, as well as increased SI severity and SAs during 1 year of psychopharmacotherapy [94]. No significant association was found between serum homocysteine level and lifetime SA in a single study [33] or with SI in 2 studies [95]. However, a study found higher serum homocysteine levels in individuals with higher SI severity [96]. In brief, the role of folate and homocysteine levels in suicidality should be investigated in longitudinal studies of individuals with various psychiatric diseases.

LIMITATIONS AND FUTURE DIRECTIONS

Substantial efforts have been made to identify biomarkers for the diagnosis and prediction of SB. Although previous meta-analyses identified several potential biomarkers of SB, their results were inconsistent. Based on our extensive review, it is difficult to identify biomarkers with definite diagnostic, screening, and predicting value. Reduced peripheral IL-2 level is associated with recent SA, incrased CSF IL-6 level with present SR and future SD, increased CSF TNF-α level with present and future SR, increased hsCRP level with recent SA, reduced peripheral TC level with recent SA, reduced peripheral 5-HT level with present SR, and reduced folate level with future SR and SA within 1 year. Low peripheral leptin is suggested to be associated with SR and recent SA. However, the associations with peripheral leptin require further study because of the inconsistent results of previous studies.

To overcome the limitations of single peripheral biomarkers, their combinations may be used to evaluate the complex diathesis of suicidality and improve the diagnosis and prediction of SB. Previous studies have combined CSF 5-HIAA with DST non-suppression [65] and serum cholesterol with DST non-suppression [97] to detect suicidality; however, the results were not satisfactory. Recently, a panel-based approach based on serum lipid, CRP, transferring, homocysteine, and alpha-1 antitrypsin levels has been effectively used to distinguish major depressive patients with SI from those without SI [95]. Additionally, in a previous study, we identified that multi-biomarker scoring systems based on serum cortisol, IL-1β, cholesterol, folate, and homocysteine levels predicted increased SI severity and a SA during 1 year of pharamacotherapy in depressed patients [98]. Given the multiple determinants of SB and its weak association with single biomarkers, identification of the best combination of potential biological markers to screen, diagnose, and predict SB is likely to alter clinical practices related to SB and improve our ability to individualize diagnostic and predictive strategies. Moreover, the difficulties of identify the potential biomarker of SB might be due to phenotypical heterogeneity, including not only differential suicidal outcomes but also a magnitude of suicidal intention and severity [99]. Therefore, future investigations to identify the biomarkers of SB with consideration of phenotypical heterogeneity are needed.

Funding

The study was funded by a grant of National Research Foundation of Korea Grant (NRF-2020M3E5D9080733) to Jae-Min Kim and by a grant (BCRI-22072) of Chonnam National University Hospital Biomedical Research Insti-tute to Hee-Ju Kang.

Conflicts of Interest

Jae-Min Kim declares research support in the last 5 years from Janssen and Lundbeck. Robert Stewart declares research support in the last 5 years from Janssen, GSK and Takeda. Sung-Wan Kim declares research support in the last 5 years from Janssen, Boehringer Ingelheim, Allergan and Otsuka. All other authors report no biomedical financial interests or potential conflicts of in-terest.

Author Contributions

Conceptualization: Hee-Ju Kang, Jae-Min Kim, In Kyoon Lyoo. Data acquisition: Hee-Ju Kang. Formal analysis: Hee-Ju Kang, Jae-Min Kim. Funding: Jae-Min Kim, In Kyoon Lyoo. Writing—original draft: Hee-Ju Kang, Jae- Min Kim. Writing—review & editing: Ju-Wan Kim, Sung- Wan Kim, Jung-Soo Han, In Kyoon Lyoo, Jae-Min Kim.

Tables

The association between CRP and suicidal behaviors

Suicidal outcomes Increased level No association
SR-CRP Gambi, 2005 (Italy) [S94]: SR/lifetime SA, serum, suicidal MD, non-suicidal MD
De Berardis, 2013 (Italy) [S57]: SR, serum, high-suicidal > low-suicidal-drug-naïve FEP > control
Gohar, 2019 (Norway) [S61]: SR, serum, schizophrenia spectrum disorders		 Karlović, 2012 (Croatia) [S29]: SR, serum melancholic (ns) atypical (ns)
Loas, 2016 (France) [S60]: Recent SA/SI, serum, high SI: non-suicidal
Keaton, 2019 (USA; women) [S11]: SR, plasma, suicidal mod., non-suicidal mod.
Jha, 2020 (USA) [S10]: SR (SA + SI), plasma, suicidal MD, non-suicidal MD, control
Cáceda, 2018 (USA) [S34]: SI, plasma, suicidal MD, non-suicidal MD
Su, 2020 (China) [S13]: SR, serum, suicidal MD, non-suicidal MD
Huang, 2022 (Taiwan) [S142]: SI/lifetime SA, serum, suicidal BD, non-suicidal BD > control
Dolsen, 2021 (Netherlands) [S28]: SI/lifetime SA, plasma, suicidal D/Anx, non-suicidal D/Anx
SR-hsCRP O’Donovan, 2013 (Ireland) [S27]: SI, plasma, high suicidal MD > low suicidal MD, control
Chang, 2017 (Taipei) [S110]: SI, serum, current SI(+) lifetime SB(−) D > lifetime SI(−) lifetime SB(−) D
Priya, 2016 (India) [S30]: SR, serum, SR of SA and control		 Courtet, 2015 (France) [S143]: SR/lifetime SA, plasma, high vs. lower SR
Goldstein, 2015 (USA) [S31]: Lifetime SI (ns), lifetime SA (ns), SA (ns), and SI (tr) within preceding 6 mo (ns), serum, suicidal BD, non-suicidal BD
Recent SA-CRP Loas, 2016 (France) [S60]: Recent SA/SI, serum, suicidal mod. > non-suicidal mod.
Ekinci, 2017 (Turkey) [S88]: Recent SA, serum, suicidal MD > non-suicidal MD, control (after adjustment; ns after regression)
Melhem, 2017 (USA) [S15]: Recent SA, WB mRNA, SA > SI(+) SA(−), control
Aguglia, 2019 (Italy) [S79]: Recent SA, serum, highly > low lethal SA, control		 da Graça Cantarelli, 2015 (Brazil) [S86]: Recent SA, serum, suicidal mod., non-suicidal mod.
Ventorp, 2015 (Sweden) [S144]: Recent SA, plasma, SA (irrespective of diagnosis) > MD, control, (ns after multiple comparison correction)
Al-Amarei, 2019 (Iraq) [S78]: Recent SA, plasma, suicidal MD, non-suicidal MD, control
Kim, 2019 (USA) [S145]: Mod. with recent SA vs. SI (ns), plasma
Aguglia, 2020 (Italy) [S80]: Suicide reattempt (6 mo FU), serum, suicide reattempt > no reattempt (ns after regression)a
Recent SA-hsCRP Priya, 2016 (India) [S30]: Recent SA, serum, SA > control
Kumar, 2021 (India) [S193]: Recent SA, serum, SA > control D/Anx-SA > control
Gibbs, 2016 (USA) [S104]: Recent SA, serum, SA > SI, control, CRP↑→ SA↑
Courtet, 2015 (France) [S143]: Lifetime SA, plasma: A risk in dose dependent manner but ns (SA more vs. less than 7 days)		 Peng, 2018 (China) [S76]: Recent SA, serum, suicidal MD, non-suicidal MD
Goldstein, 2015 (USA) [S31]: Lifetime SI (ns)/SA (ns), SA (ns)/SI (tr) within preceding 6 mo, serum, suicidal BD, non-suicidal BD
Lifetime SA-CRP Gambi, 2005 (Italy) [S94]: SR/lifetime SA, serum, suicidal MD > non-suicidal MD
Cáceda, 2018 (USA) [S34]: Lifetime SA, plasma, suicidal MD > non-suicidal MD		 Huang, 2022 (Taiwan) [S142]: SI/lifetime SA, serum, suicidal BD, non-suicidal BD > control
Dolsen, 2021 (Netherlands) [S28]: SI/lifetime SA, plasma, suicidal D/Anx, non-suicidal D/Anx
Coryell, 2020 (USA) [S8]: Lifetime 2 + SA, plasma, suicidal mod., non-suicidal mod.
Russell, 2021 (Taiwan) [S147]: SA (15.1−15.8 yr FU), periphery (not specified)a
Oh, 2020 (USA) [S146]: SA (retrospective electroninc medical records review), periphery (not specified at 0−6 mo, 6 mo−2 yr, 2−5 yr preceding SA) suicidal D > non-suicidal D (ns after adjusting physical illness)a
Lifetime SA-hsCRP Courtet, 2015 (France) [S143]: Lifetime SA, plasma: SA risk in dose dependent manner but ns (SA more vs. less than 7 days) Goldstein, 2015 (USA) [S31]: Lifetime SI (ns), lifetime SA (ns), SA (ns), and SI (tr) within preceding 6 mo (ns), serum, suicidal BD, non-suicidal BD

CRP, C-reactive protein; Anx, anxiety disorder; BD, bipolar disorder; D, depressive disorder; FU, follow-up; MD, major depressive disorder; mod., mood disorder; ns, no significance; FEP, first episode psychosis; SB, suicidal behaviors; SI, suicidal ideation; SR, suicidal risk; SA, suicidal attempt; 2 + SA, 2 and more SA; tr, trend level of significance; WB, whole blood.

aLongitudinal studies.

The association between BDNF and suicidal behaviors

Suicidal outcomes Decreased level Increased level No association
SR-peripheral Pinheiro, 2012 (Brazil) [S148]: SR/lifetime SA, serum, suicidal- < non-suicidal-postpartum
Ai, 2019 (China) [S149]: SI/lifetime SA, plasma, suicidal < non-suicidal MD
Khan, 2019 (USA) [S150]: SI, serum, suicidal < non-suicidal MD, control (tr)		 Park, 2014 (Korea) [S151]: Lifetime SA/SI in moderate to severe D, serum
Priya, 2016 (India) [S30]: Recent SA/SR, serum, SR predictor of SA (ns)
Kavurma, 2017 (Turkey) [S152]: SR/lifetime SA, serum adolescents Psy
Su, 2020 (China) [S13]: SR, serum, MD
Bilgiç, 2020 (Turkey) [S153]: SR, serum, adolescents MD > control, SR severity (ns)
SR-central Martinez, 2012 (Sweden) [S2]: SI/lifetime SA, CSF
Recent SA- peripheral Kim, 2007 (Korea) [S154]: Recent SA, plasma, suicidal < non-suicidal MD, control
Lee, 2007 (Korea) [S155]: Recent SA, plasma, suicidal < non-suicidal MD, control
Deveci, 2007 (Turkey) [S156]: Recent SA, serum, suicidal Psy, non-suicidal MD < control
Grah, 2014 (Croatia) [S157]: Recent SA, serum, MD (ns) suicidal < non-suicidal PD/AD
Priya, 2016 (India) [S30]: Recent SA/SR, serum, suicidal Psy inpatients < control
Lee, 2021 (Korea) [S158]: Recent SA, plasma, suicidal < non-suicidal MD, control		 Lee, 2009 (Korea) [S159]: Recent SA, platelet, suicidal MD, non-suicidal MD < control
da Graça Cantarelli, 2015 (Brazil) [S86]: Recent SA, serum, mod.
Eisen, 2016 (Canada) [S160]: Recent SA, serum, SA, Psy/community control
Kim, 2019 (USA) [S145]: Recent/lifetime SA, plasma, mod. with SA vs. SI vs. control
Pasyk, 2020 (Canada) [S161]: Recent SA, serum, inpatients SA vs. Psy/healthy control
Yilmaz, 2021 (Turkey) [S162]: Recent SA, BDNF expression, adolescents, control
Lifetime SA- peripheral Ai, 2019 (China) [S149]: SI/lifetime SA, plasma, suicidal < non-suicidal MD < control
Kudinova, 2019 (USA) [S163]: Lifetime SA, plasma, suicidal < non-suicidal women in the community with SA
Mamtani, 2022 (India) [S164]: Lifetime SA, serum, suicidal < non-suicidal schizophrenia, control		 Sher, 2022 (USA) [S165]: Lifetime SA, plasma, suicidal > non-suicidal veterans Huang, 2006 (Taiwan) [S166]: Lifetime SA, serum, schizophrenia control
Pinheiro, 2012 (Brazil) [S148]: SR/lifetime SA, serum, postpartum women
Park, 2014 (Korea) [S151]: Lifetime SA/SI, serum, MD
Kavurma, 2017 (Turkey) [S152]: SR/lifetime SA, serum adolescents Psy
Pedrotti Moreira, 2018 (Brazil) [S167]: Lifetime SA, serum, suicidal MD, non-suicidal MD < control
Kim, 2019 (USA) [S145]: Recent SA/No. lifetime SA, plasma, mod.
SD-central Dwivedi, 2003 (USA) [S168]: SD, mRNA/protein in PFC (BA9), hippocampus, mRNA in PFC/hippocampus: SD < control
Karege, 2005 (Switzerland) [S169]: SD, protein in ventral PFC, hippocampus/entorhinal cortex, SD < non-suicidal death in ventral PFC, hippocampus
Banerjee, 2013 (India) [S170]: SD, mRNA/protein hippocampus, SD < noPsycontrol
Youssef, 2018 (USA) [S171]: SD, protein, DLPFC (BA9), ACC (BA24), brainstem adv(−) SD(−) > adv(+) SD(+) > adv(+) SD(−) > adv(−) SD(+) in ACC
Erbay, 2021 (Turkey) [S172]: SD, protein/mRNA in hippocampus, SD < control
Misztak, 2020 (Poland) [S173]: SD, protein in frontal (BA10)/hippocampus: SD < control both in BA10/hippocampus		 Gadad, 2021 (USA) [S174]: SD, plasma, CSF, PFC (BA10), only BDNF level in PFC was SD > non-suicidal death
Ropret, 2021 (Slovenia) [S175]: SD, mRNA in BA9, hippocampus, SD > control in BA9 but not hippocampus		 Ropret, 2021 (Slovenia) [S175]: SD, mRNA level in BA9, hippocampus mRNA of BDNF: hippocampus

AD, adjustment disorders; ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; D, depressive disorder; DLPFC, dorsolateral prefrontal cortex; MD, major depressive disorder; mod., mood disorder; ns, no significance; PD, personality disorder; Psy, psychiatric patients; SI, suicidal ideation; SR, suicidal risk; SA, suicidal attempt; SD, suicidal death; BA, Broadman area; adv, early life adversity.

The association between serotonin (5-HT) and suicidal behaviors

Outcome Measure site Increased level Decreased level No association
SR Peripheral Bråunig, 1989 (Germany) [S176]: SR/lifetime SA, blood, suicidal < non-suicidal female schizophrenia
Marcinko, 2007 (Croatia) [S177]: SR, platelet, suicidal < non- suicidal psychosis, control
Kovacic, 2008 (Croatia) [S178]: SR, platelet 5-HT, suicidal-PTSD, suicidal-non-PTSD < non- suicidal-PTSD/non-PTSD, control
Recent SA Peripheral Mann, 1992 (USA) [S179]: Recent SA, WB/platelet, platelet: suicidal < non-suicidal MD; WB (ns, tr)
Rilke, 1998 (Germany) [S180]: Recent SA, WB, impetuous, desperate & ambivalent SA < appealing SA, non-suicidal-subjects
Alvarez, 1999 (France) [S181]: Recent SA, platelet, inpatients SA < control
Almeida-Montes, 2000 (Mexico) [S84]: Recent SA, serum, suicidal < non-suicidal MD
Spreux-Varoquaux, 2001 (France) [S182]: Recent SA, plasma/platelet, platelet: SA < control plasma (ns)		 Mann, 1992 (USA) [S179]: Recent SA, WB/platelet, platelet: suicidal < non-suicidal MD WB (ns, tr)
Verkes, 1997 (Netherlands) [S184]: Suicide reattempt (6, 52 wk FU), platelet, suicide reattempt (6 wk FU), no suicide reattempt (ns)a
Pfeffer, 1998 (USA; prepubertal) [S183]: Recent SA, WB/platelet, Psy inpatients with SA, SI, no SB, control (ns)
van Heeringen, 2000 (Belgium) [S131]: Recent + lifetime SA, WB, inpatients SA, no SA, recent vs. lifetime SA (ns)
Spreux-Varoquaux, 2001 (France) [S182]: Recent SA, plasma/platelet, platelet: SA < control plasma 5-HT (ns)
Brunner, 2002 (Germany) [S109]: Recent SA, CSF/plasma, D inpatients, control
Roaldset, 2011 (Norway) [S90]: SA + selfharm (3/12 mo FU), platelet, Psy inpatients (ns)a
Tripodianakis, 2002 (Greece) [S65]: Recent SA, urine, inpatients SA, control
Central Brunner, 2002 (Germany) [S109]: Recent SA, CSF/plasma, D inpatients, control
Lifetime SA Peripheral Verkes, 1997 (Netherlands) [S184]: Suicide reattempt (6, 52 wk FU), platelet, suicide reattempt (52 wk) > no suicide reattempta
Grah, 2010 (Croatia) [S185]: Lifetime SA, platelet, non-suicidal < suicidal female PTSD, control
Ruljancic, 2011 (Croatia) [S72]: Recent SA, thrombocyte, non- suicidal < suicidal D, control		 Bråunig, 1989 (Germany) [S176]: SR/lifetime SA, blood, suicidal < non-suicidal female schizophrenia
Giurgiuca, 2016 (Romania) [S186]: Lifetime SA, platelet, suicidal < non-suicidal BPD high lethality < low lethality		 van Heeringen, 2000 (Belgium) [S131]: Recent + lifetime SA, WB, inpatients SA, no SA, recent vs. lifetime SA (ns)
Nenadic-Sviglin, 2011 (Croatia) [S187]: Lifetime SA, platelet, alcoholism, control
Roaldset, 2011 (Norway) [S90]: SA + selfharm (3/12 mo FU), platelet, Psy inpatients (ns)a
Messaoud, 2019 (Tunisia) [S130]: Lifetime SA, plasma, MD, control
SD Central Korpi, 1986 (USA) [S189]: SD, GP/putamen/ temporal/hypothalamu suicidal SD > control Dogan, 2016 (Turkey) [S188]: SD, CSF, SD < non-suicidal death
Korpi, 1986 (USA) [S189]: SD, hypothalamus, SD < control		 Korpi, 1986 (USA) [S189]: SD, various brain region except globus pallidus, putamen temporal cortex hypothalamus SD, control (ns)

BPD, borderline personality disorder; D, depressive disorder; FU, follow-up; MD, major depressive disorder; ns, no significance; PTSD, post- trumatic stress disorder; Psy, psychiatric patients; SI, suicidal ideation; SR, suicidal risk; SA, suicidal attempt; SD, suicidal death; tr, trend level of significance; WB, whole blood; CSF, cerebrospinal fluid; GP, globus pallidus.

aLongitudinal studies.

The association between leptin and suicidal behaviors

Outcome Measured site Decreased level No association
SR Peripheral Atmaca, 2002 (Turkey) [S190]: SR, SI + lifetime SA, serum, borderline personality disorder with SR < without SR
Gohar, 2019 (Norway) [S61]: SR, serum, schizophrenia spectrum diagnosis, low leptin is predictor in logistic regression		 Su, 2020 (China) [S13]: SR, serum, MD with SR, MD without SR (ns)
Recent- SA Peripheral Atmaca, 2003 (Turkey) [S66]: Recent SA serum, schizophrenia with SA < schizophrenia without SA; schizophrenia < control
Atmaca, 2008 (Turkey) [S70]: Recent SA serum, violent SA < non-violent SA < control		 da Graça Cantarelli, 2015 (Brazil) [S86]: Recent SA, serum, mood disorder with SA, without SA (ns)
Lifetime- SA Peripheral Ayesa-Arriola, 2018 (Spain) [S100]: SA + SD, serum, FEP with SB < FEP without SB but ns in regression
SD Central Eikelis, 2006 (Austrailia) [S191]: SD, hypothalamus, suicidal death < natural death
Lalovic, 2010 (Canada) [S101]: SD, leptin receptor expressed level in frontal (BA8/9, 11, 47) down regulated in suicide completer

BA, Broadman area; MD, major depressive disorder; ns, no significance; SI, suicidal ideation; SR, suicidal risk; SA, suicidal attempt; SD, suicidal death; SB, suicidal behaviors; FEP, first episode psychosis.
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