Acute coronary syndrome (ACS) is a major cause of morbidity and mortality globally [1]. Patients with this life-threatening condition are at a high risk for suicidality [2]. Suicidal ideation (SI) is a precondition of more serious suicidal behavior, including suicidal attempt or completion, but could be a treatment target upon proper detection [3,4]. Unfortunately, individuals at risk often do not disclose their suicidal thoughts [5]. Introducing objective biomarkers would help in identifying those with suicidal risk.

Many biomarkers relevant to the pathophysiology of suicidal behaviors based on stress-diathesis models have been evaluated [6,7]. The serotonergic system is involved in both stress and diathesis models [8], and low blood serotonin levels have been found to be related to increased suicidality [9]. Immunologic dysfunction has connections to neurotransmissions, and aberrant levels of pro-inflam-matory cytokines have been reported in patients with suicidal behaviors [10]. In ACS patients, roles of serotonergic and immune systems have been investigated, focused only on depression [11,12] but rarely on suicidal behaviors.

Recently, there has been accumulating data on the biological link between the serotonergic and immune systems [13]. Serotonin has immune-regulatory functions and modu-lates cytokine secretions [14], and inflammatory cytokines regulate serotonergic transmission [15]. It has been postulated that serotonergic and immune systems have interactive effects on suicidal behaviors [6]. However, this hypothesis has not been tested in ACS patients at high risk for suicidality. We aimed to investigate individual and interactive effects of the serum levels of serotonin and interleukin 18 with SI evaluated both in the acute and chronic phases.

Study Outline and Participants

This study was conducted as part of a parent research project investigating psychological sequelae after ACS, the design of which was previously published [16]. In brief, all participants presenting with recent ACS from 2006 to 2012 were recruited (see online supplement for eligibility criteria) within the Department of Cardiology of Chonnam National University Hospital, Gwangju, South Korea. Assessments were made within 2 weeks (baseline) in hospitalized patients and at 1 year (follow-up) as outpatients thereafter, to investigate consequences of the disease in both acute and chronic phases. Serum serotonin and interleukin 18 levels were estimated at baseline, and SI was evaluated in both phases. The study was approved by the Chonnam National University Hospital Institutional Review Board (IRB no. 06-026). All participants provided written informed consent.

Serum Biomarkers

Participants were instructed to fast overnight and were asked to sit quietly for 25−45 minutes before blood samples were drawn. Serum serotonin levels were measured using a ClinRep high-performance liquid chromatography kit (Recipe) at GreenCross LabCell. Serum interleukin 18 levels were calculated using solid-phase sandwich enzyme-linked immunosorbent assay kits (Invitro-gen). As there were no designated cut-offs for abnormal serum serotonin and interleukin 18 levels, participants were divided into higher and lower groups by the median values.

Suicidal Ideation

SI was identified using the “suicidal thoughts” item of the Montgomery–Åsberg Depression Rating Scale [17]. This item assesses the feeling that life is not worth living and the existence of plans for suicide, with scores ranging between 0 (life satisfaction) and 6 (explicit plans for suicide). SI was considered if the patient scored ≥ 2 (fleeting suicidal thoughts) on this item, as in previous studies [18, 19].

Baseline Covariates

Socio-demographic characteristics of age, sex, duration of education, living status (living alone or not), housing (owned or rented), and current occupation (employed or not) were obtained. For the depression-related characteristics, previous and family histories of depression and the presence of Diagnostic and Statistical Manual of Mental Disorders IV depressive disorder [20] were ascertained. The following vascular risk factors were evaluated: previous and family histories of ACS or stroke, diagnosed hypertension and diabetes mellitus, hypercholesterolemia by fasting serum total cholesterol level (> 200 mg/dl), obesity by measured body mass index (> 25 kg/m²), and reported current smoking status. Cardiac status was established based on the ACS severity via the Killip classification [21], left ventricular ejection fraction estimated using echocardiography, and the results obtained from serum cardiac biomarkers troponin I and creatine kinase-MB measurements.

Statistical Analysis

Baseline potential covariates were compared by the presence of SI at baseline and at follow-up using ttests or c² tests, as appropriate. Covariates for further adjusted analyses were selected from the characteristics signifi-cantly associated with SI (p < 0.05) and other variables with potential effects on suicidal behaviors and serotonin [3,22] and by considering the collinearity between the variables. Correlations between serum serotonin and interleukin 18 levels were estimated by Spearman’s rho. The individual associations of the serum serotonin (higher vs. lower) and interleukin 18 (lower vs. higher) groups with SI at both baseline and follow-up were analyzed in logistic regression models before and after adjusting for covariates. The interactive effects of serum serotonin and interleukin 18 levels on SI both at baseline and at follow-up were analyzed using multinomial logistic regression tests in the same adjustment model. All statistical tests were two-sided with a significance level of 0.05. Statistical analyses were performed using SPSS 27.0 software (IBM Co.).

Recruitment and Descriptive Data

Participants’ recruitment and prevalence rates of SI are summarized in Supplementary Figure 1 (available online). The baseline sample was comprised of 969 ACS patients who met the eligibility criteria and agreed to offer a blood sample. Of these, 711 (73%) were re-evaluated 1 year later as the follow-up sample.

SI was present in 195 (20%) and 87 (12%) ACS patients at baseline and at follow-up, respectively. The baseline characteristics of those with and without SI at baseline and at follow-up are summarized in Supplementary Table 1 (available online). SI at baseline was significantly associated with female sex, lower education, rented housing, current unemployment, and previous and present depression; and SI at follow-up was significantly associated with female sex, family history, and present depression. Con-sidering the present and previous findings [3,22] and the collinearity between the variables, nine covariates were selected for the later adjusted analysis: sex, education, housing, current employment, previous and family history of depression, present clinical depression, family history of ACS, and serum troponin I levels.

Effects of Serum Serotonin and Interleukin 18 Levels with Suicidal Ideation

Serum serotonin and interleukin 18 levels were negatively correlated (Spearman’s rho = −0.091; p = 0.005); the individual associations with SI are described in Table 1. There were no significant associations before or after adjustment. The interactive effects of the serum serotonin and interleukin 18 groups on SI are displayed in Figure 1. The associations between the higher interleukin 18 group and SI at both baseline and follow-up were significant in the lower group but not in the higher serotonin group, with significant interaction terms after adjustment.

In this longitudinal study of ACS patients, associations between serum interleukin 18 and SI were significant in the lower serotonin group but not in the higher group, with significant interaction terms after adjustment for relevant covariates.

Serotonin deficiency has been linked to decision making and impulsive aggressive traits related to suicidal intent [23]; accordingly, low blood serotonin levels have been associated with suicidal behavior [9]. However, no such associations were found in the current study. Differ-ences in the study population (general population vs. ACS patients) and the suicidality definition (suicidal attempt vs. SI) may account for this discrepancy. Pro-inflammatory cytokines interleukin 1-b and interleukin 6 have shown strong associations with suicidal behavior [10]. Interleukin 18, one of the pro-inflammatory cytokines, has roles in various inflammatory disorders [24]. This cytokine has not been previously evaluated as a marker for suicidal behavior, and no individual effects on SI were found in this cohort. Given that our study is the first to investigate this issue, further studies are needed to examine this hypothesis.

Despite lacking information on individual effects, significant interactive effects of serum serotonin and interleukin 18 levels were found on SI during both the acute and chronic phases of ACS. The possible link between serum serotonin and interleukin levels may account for the observations. The two blood markers were significantly negatively correlated in this study, in line with previous literature on the connections between the serotonergic and immune systems [14,15]. Hence, the unfavorable status of both markers may have synergistic effects on sui-cidality.

The main limitation was the outcome was SI and no data on suicidal attempt or completion were obtained, whereas almost all clinical ACS studies used SI as a phenotype, as more severe types of suicidal behavior are rare [18,22]. The strengths were that evaluations were made at similar time points (within 2 weeks and at 1 year after ACS diagnosis) which increased the homogeneity and generalizability of the study, and our study is the first to report on the interactive effects of serum serotonin and interleukin 18 levels on suicidality.

Our findings have several implications. Regarding the pathophysiology, present findings suggest a possible biological link between serotonergic and immune systems on suicidality, thus an interactive role. From a clinical perspective, the prediction of suicidality can be improved by evaluating both serum biomarkers during the acute phase of ACS. This is particularly important in cardiovascular clinics, as interviewing for suicidality evaluation is difficult for untrained clinicians. Future multi-center studies in different settings are required to confirm the generaliz-ability.

Jae-Min Kim declares research support in the last 5 years from Janssen and Lundbeck. 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 interest.

The study was funded by a grant of National Research Foundation of Korea Grant (NRF-2020M3E5D9080733) and (NRF-2020R1A2C2003472).

Concenptualization: Jae-Min Kim. Methodology: Ju-Wan Kim, Hee-Ju Kang, Sung-Wan Kim. Project administra-tion: Hee-Ju Kang, Jung-Chul Kim, Wonsuk Choi. Valida-tion: Byung Jo Chun, Youngkeun Ahn, Myung Ho Jeong. Data acquisition and curation: Ju-Wan Kim, Hee-Ju Kang, Sung-Wan Kim, Jae-Min Kim. Formal analysis: Ju-Wan Kim, Hee-Ju Kang, Jae-Min Kim. Writing-original article: Hee-Ju Kang, Jae-Min Kim. Writing-reviewing and editing: Hee-Ju Kang, Wonsuk Choi, Byung Jo Chun, Youngkeun Ahn, Myung Ho Jeong, Jae-Min Kim.