Suicide attempt predictors among adolescents exhibiting non-suicidal self-injury: A six-week follow-up open study

Abstract

BACKGROUND

Non-suicidal self-injury (NSSI) in adolescents is a strong predictor of suicide and a significant mental health problem worldwide. Previous studies have identified various risk factors for NSSI. However, studies have not explored the association between inflammatory factors and NSSI in adolescents.

AIM

To investigate inflammatory marker changes post-antidepressant treatment and their association with suicide risk in NSSI adolescents.

METHODS

The study enrolled 68 adolescents with NSSI behaviors. The participants were divided into high and low suicide risk groups (n = 38 and n = 30, respectively) based on their scores on the Suicide Risk Factors Assessment Scale. Symptom severity was assessed at baseline and after six weeks of treatment. Blood samples were obtained to monitor for inflammatory factors.

RESULTS

The high suicide risk group exhibited higher levels of interferon (IFN)-α and interleukin (IL)-10 than the low suicide risk group. Scores on the Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Insomnia Severity Index decreased significantly post-treatment. Tumor necrosis factor-α, IL-10, IL-6, IL-1, and IL-12 levels decreased, whereas IFN-γ, IL-4, and IFN-α levels increased. IL-10 levels were correlated with the severity of suicide risk factors.

CONCLUSION

Adolescents with NSSI exhibit distinct inflammatory markers based on suicide risk, which change following treatment. Moreover, IL-10 levels are associated with suicide risk. These biomarkers may help assess suicide risk in clinical settings.

Key Words: Adolescents; Non-suicidal self-injury; Inflammatory factors; Suicide risk; Antidepressant treatment

Core Tip: This observational study explores the link between inflammatory markers and suicide risk in Chinese adolescents with non-suicidal self-injury, alongside antidepressant treatment effects. Key findings reveal distinct inflammatory profiles stratified by suicide risk levels, with specific cytokines correlating to risk severity. Critically, antidepressant intervention modulates inflammatory expression while improving clinical symptoms. The study identifies a potential inflammatory biomarker for suicide risk assessment in non-suicidal self-injury adolescents, offering a novel biological perspective for clinical risk stratification and treatment monitoring.

INTRODUCTION

Non-suicidal self-injury (NSSI) involves deliberate injury to one's body tissue without suicidal intent and for purposes not socially sanctioned[1]. A study that employed an online survey of a community sample of adults through Amazon Mechanical Turk platform revealed that 23% of participants reported a lifetime history of NSSI[2]. In 2013, Diagnostic and Statistical Manual of Mental Disorders recognized NSSI as a distinct clinical phenomenon, labeling it as NSSI-disorder, and called for systematic research. Another global meta-analysis conducted between 1989 and 2018 found that the aggregate lifetime and 12-month prevalence of NSSI was 22.1% [95% confidence interval (CI): 16.9%-28.4%] and 19.5% (95%CI: 13.3%-27.6%) in children and adolescents, respectively[3].

NSSI is a complex and multifaceted behavior that has gained significant attention in recent years due to its high prevalence among individuals struggling with mental health issues. The rates of NSSI have been steadily increasing over the past few decades, particularly among adolescents and young adults[4]. NSSI is often accompanied by severe suicidal behavior, further underscoring the urgency of understanding and addressing these intertwined phenomena. Among individuals with NSSI, suicidal ideation was the second most frequent, with a lifetime prevalence of 18% and a 12-month prevalence of 14.2%. NSSI and deliberate self-injury have been known to predict future suicide attempts[5]. Studies have shown that adolescents with NSSI behaviors are more likely to develop suicidal ideation and behavior than their peers who display no NSSI behaviors. Moreover, 33%-70% of adolescents with NSSI behaviors were found to have experienced suicidal ideation at least once[6,7]. This alarming prevalence highlights the need for comprehensive prevention and intervention strategies to minimize the potential long-term consequences associated with this behavior.

Recent estimates suggest that China accounts for approximately 17% of the global mental disorder burden[8]. Over the past 40 years, rapid industrialization and urbanization have profoundly transformed Chinese society, negatively impacting the mental health of children and adolescents. The first national-scale psychiatric epidemiological survey on children and adolescents in China found a 17.5% overall prevalence of psychiatric disorders, the highest ever reported in China. This statistic highlights the significant impact of mental illnesses on the population[9]. A review found that the estimated lifetime prevalence of NSSI among Chinese youth is alarmingly high[10]. The lifetime prevalence of NSSI was found to be 29.3% in primary school children, 25.3% in middle school students, 32.8% in high school students, and 21.2% in college students. Furthermore, the sex-specific lifetime prevalence of NSSI was 26.5% among female students and 27.7% among male students[10]. In a study from China on 394 hospitalized patients from two psychiatric hospitals in Beijing, China, 245 (62.2%) reported NSSI in the past year[11]. This high prevalence rate suggests that mental disorders are not uncommon in Chinese society. This may be attributed to several factors, including increased stress, evolving lifestyles, and rising societal pressures.

A key difference between NSSI and suicide is the underlying motive. Individuals who engage in NSSI often do so as a way to cope with emotional distress, seek emotional relief, or communicate their inner turmoil. NSSI can serve as a maladaptive coping mechanism or a cry for help. In contrast, suicide is typically driven by a desire to end one's life and escape unbearable pain or suffering. Despite these differences, NSSI and suicide are not completely unrelated. Research has shown a significant overlap between individuals who engage in NSSI and those who have attempted or died by suicide. Individuals who engage in NSSI may have suicidal thoughts or be at an increased risk for suicide[5]. Therefore, recognizing NSSI as a warning sign and an indicator of potential suicide risk is important. Addressing NSSI and suicide prevention as distinct yet interconnected issues is crucial. Effective interventions for NSSI emphasize providing alternative coping strategies, fostering emotional regulation skills, and building support networks. By addressing the underlying emotional distress that drives NSSI, professionals can mitigate the risk of further self-injury and potentially reduce the likelihood of suicide. Suicide is the second leading cause of death among youth aged 10 to 19 years. Psychiatric disorders and previous suicide attempt significantly increase the risk of suicide. Depression, in particular, is a critical risk factor for suicidal behavior.

Previous studies on NSSI in adolescents have revealed significant correlations among self-injury, sociological characteristics, and emotions[12,13]. Associations have been observed linking emotional regulation disorder, early traumatic experience, family parenting style, adverse life events, peer relationships, and other factors. However, the relationship between biological factors and non-suicidal NSSI has rarely been explored. Studies have shown that depression, stress, and immune responses are all interrelated, and the immune system affects the central nervous system through cytokines, which regulate brain activities and emotions[14,15]. These observations suggest that neuroinflammation and cytokines may causally contribute to depression or its maintenance, and that they may be useful in the diagnosis and prognosis of depression. Cytokine activation may have some effect on suicidal behavior in susceptible individuals[16]. Inflammation is a promising candidate for modification that may affect suicide risk, as pro-inflammatory states are associated with major depression and suicidal behavior[17,18]. Previous studies on inflammatory factors and depression have produced mixed results, and the effect of antidepressants on inflammatory factors remains unclear[19,20]. Interleukin (IL)-6 was found to be elevated in adolescents with depressive disorders and associated with increased reported depressed mood symptoms[21]. Abnormally elevated pro-inflammatory cytokine levels have been reported to be correlated with suicidal behavior; however, it remains unknown whether, and to what extent, specific inflammatory cytokines abnormalities may contribute to our understanding of the complex pathophysiology of suicide[22].

Previous research on cytokines and adolescent self-injury and suicide suggests that suicidal adolescents with major depressive disorder (MDD) have significantly lower plasma tumor necrosis factor (TNF)-α concentrations than non-suicidal adolescents with MDD[17,23]. Furthermore, both suicidal and non-suicidal adolescents with MDD were found to have higher interferon (IFN)-γ than the control group[17]. The production of IL-6 in non-suicidal patients with MDD is significantly higher than that in suicidal patients with MDD and the normal control group. Conversely, IL-2 is significantly lower in suicidal patients with MDD than in non-suicidal patients and normal controls. In non-suicidal patients with depression, Hamilton Depression Rating Scale (HDRS) scores are significantly positively correlated with IL-6, IFN-γ, and type 1 T helper/type 2 T helper ratio and significantly negatively correlated with IL-4[23]. Moreover, adolescents with MDD at baseline showed significant increases in all pro- and anti-inflammatory cytokines, except IL-1 receptor antagonist and IL-10, compared to healthy volunteers[24].

Besides biological factors, psychological and social dimensions also play a pivotal role in adolescent self-harm and suicidality. Self-esteem refers to an individual's overall evaluation of their own worth and abilities, and it plays a critical role in adolescents' mental health. Childhood trauma and dysfunctional family communication can negatively impact self-esteem, thereby increasing the risk of suicide. Enhancing self-esteem in adolescents can effectively reduce the incidence of depression and lower the risk of suicide. The social support system has also been found to have a significant impact on adolescent suicidal thoughts and behaviors[25]. The quality and accessibility of the social support system are important for reducing the risk of suicide[26]. Social support can be in the form of emotional support, practical help, informational support, and a sense of companionship, fostering resilience as primary suicide prevention among youth[27].

Studies have mainly focused on the relationship between inflammatory factors and depression, as well as the association between inflammatory factors and suicide risk. However, the link between inflammatory factors and NSSI in adolescents has not been examined heretofore. Since adolescents who engage in NSSI are also at risk of exhibiting suicidal behavior, investigating the suicide risk factors among individuals with NSSI is crucial[28,29]. Therefore, in this study, this study examined the relationship between NSSI and inflammatory factors in adolescents, in the hope that the results may assist practitioners in identifying adolescents with high risk of future suicide attempts, so that targeted prevention and intervention strategies may be enhanced.

MATERIALS AND METHODS

Participants

The participants of this study are 68 adolescents with NSSI behaviors. Among them, 61 completed the 2-week follow-up assessment, and 57 were retained through the 6-week follow-up period. All participants were between 13 and 18 years of age at the time of enrollment. They were hospitalized in the Department of Mental Health of the First Affiliated Hospital of Xi'an Jiaotong University in Xi'an, China, and all of them met the diagnostic criteria for NSSI based on the 5^th edition of the American Diagnostic and Statistical Manual of Mental Disorders. The participants had not taken any psychiatric medication and were diagnosed as requiring antidepressant medication by child and adolescent psychiatrists. They were not allowed to use antibiotics, non-steroidal anti-inflammatory drugs, or other medications that could affect serum inflammatory factors in the three months prior to enrollment. The exclusion criteria were the following: (1) A history of manic or hypomanic episodes; (2) A history of cerebral brain diseases or severe brain trauma; (3) Any heart disease, liver disease, kidney disease, diabetes, or other strenuous physical disease; (4) A history of substance dependence or abuse of tobacco, alcohol, cocaine, or drugs; and (5) Intellectual disabilities.

Clinical procedures

At least two independent, experienced psychiatrists diagnosed the patients using Diagnostic and Statistical Manual of Mental Disorders as the diagnostic standard. General data collection, blood sample collection, and clinical symptom scale assessment were performed at baseline, and clinical symptom scale assessment and blood sample collection were performed again after 6 weeks of treatment. General data collection included information about age, smoking and drinking habits, physical illness, being an only child or not, place of birth, parents' marital status, parents' educational background, and family history of mental illness. All participants received psychological scale assessments on the HDRS, Hamilton Anxiety Rating Scale (HAMA), Suicide Risk Assessment Scale, Insomnia Severity Index[30], Rosenberg Self-Esteem Scale, Social Support Assessment Scale, and Automatic Thoughts Questionnaire[31,32]. Before the study, the personnel conducting the clinical scale evaluation were trained to ensure consistency of the scale and subsequently passed a consistency assessment test. Blood samples were also collected at the time of enrollment to measure cytokine levels. Following psychological testing and blood sampling, the participants were treated with antidepressants (sertraline or fluoxetine). Psychological assessments were repeated at 2-week and 6-week intervals, and blood sampling was repeated at the 6-week interval.

Measurement of cytokines

After reviewing the relevant literature and integrating previous research findings, 10 inflammatory cytokines were selected for measurement: TNF-α, IL-6, IL-10, IL-1, IFN-γ, IL-4, IL-17, IL-2, IFN-α, and IL-12[22]. For cytokine analysis, fasting venous blood samples were centrifuged to separate plasma and stored at -80 °C. Enzyme-linked-immunosorbent serologic assay was performed to detect serum cytokine levels.

Statistical analysis

Statistical analyses were conducted using SPSS version 20. First, the mean ± SD of the demographic and clinical data were calculated. To investigate the relationship between inflammatory markers and suicide risk factors, all patients were categorized into two groups based on their suicide risk factor assessment. Participants who scored 30 or higher were classified into a high suicide risk group (n = 38), whereas those who scored below 30 were classified into a low suicide risk group (n = 30). A normality test was conducted. The Student's t-test was used for continuous variables, and the Mann-Whitney test was used for non-normally distributed variables. Paired t-tests were also performed to measure cytokine levels before and after treatment. Finally, logistic regression analysis was used to explore the effects of various biomarkers and psychosocial factors on suicide risk. Exp(B), or the odds ratio, represents the exponential value of the regression coefficient, indicating the relative change in the odds of the outcome occurring for each one-unit increase in the risk factor. Values > 1 indicated an increased risk, whereas values < 1 indicated a decreased risk.

RESULTS

Participants and demographic data

Participant characteristics are presented in Table 1. No significant differences were observed in basic characteristics between the two groups. Therefore, the two groups were comparable in the basic characteristics.

Table 1 Demographic and clinical data, n (%).

	Low risk	High risk	χ2/t	P value
Age (years, mean ± SD)	14.83 ± 1.82	14.6 ± 1.516	0.564	0.575
Gender (men/women)	5/25	4/34	0.146	0.703
Smoking/drinking	9 (30.00)	17 (44.74)	1.542	0.214
Have physical illnesses	2 (6.67)	9 (23.68)	2.435	0.119
Only child	16 (53.33)	15 (39.47)	1.298	0.255
Urban household registration	16 (53.33)	27 (71.05)	2.264	0.132
Single parent family	9 (30.00)	13 (34.21)	0.136	0.712
Father with education above high school	16 (53.33)	21 (55.26)	0.025	0.874
Mother with education above high school	18 (60.00)	17 (44.74)	1.564	0.211
Family history of mental illness	3 (10.00)	4 (10.53)	0.005	1.000

Categorical variables (e.g., gender and smoking/drinking status) were analyzed using χ² tests, while continuous variables (e.g., age) were assessed via independent samples t-tests.

Comparison of clinical scale scores between the two groups

Patients in the high suicide risk group had significantly higher scores on HDRS, HAMA, Automatic Thoughts Questionnaire, and Insomnia Severity Index, and significantly lower scores on Rosenberg Self-Esteem Scale and Schizophrenia Suicide Risk Scale than those in the low suicide risk group (Table 2).

Table 2 Comparison of clinical scale scores between the two groups, mean ± SD.

	Low risk	High risk	t	P value
HDRS	44.17 ± 10.58	52.16 ± 9.06	-3.355	0.001
HAMA	29.00 ± 9.91	36.24 ± 9.60	-3.042	0.003
RSES	20.53 ± 5.83	16.37 ± 4.39	3.362	0.001
ATQ	106.37 ± 28.62	128.79 ± 15.81	-4.106	0.000
SSRS	50.33 ± 14.47	36.76 ± 13.47	3.993	0.000
ISI	14.27 ± 5.42	19.55 ± 5.94	-3.786	0.000

HDRS: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; RSES: Rosenberg Self-Esteem Scale; ATQ: Automatic Thoughts Questionnaire; SSRS: Schizophrenia Suicide Risk Scale; ISI: Insomnia Severity Index.

Differences in inflammatory cytokine levels in plasma between the two groups of adolescents with depression

IL-10 (P < 0.05) and IFN-α (P < 0.05) levels were significantly higher in the high suicide risk group than in the low suicide risk group (Table 3), suggesting a potential biomarker or biological link to suicide risk. However, further investigation is required to confirm causality and elucidate the underlying mechanisms.

Table 3 Comparison of inflammatory cytokines between the two groups.

Inflammatory cytokine	Low risk	High risk	Z	P value
TNF-α	3.46 (2.65, 4.09)	3.84 (3.10, 5.35)	-1.561	0.118
IL-6	1.91 (1.28, 3.03)	1.77 (1.52, 3.78)	-0.669	0.503
IL-10	0.94 (0.63, 1.14)	1.12 (0.95, 1.27)	-2.522	0.012
IL-1	2.68 (2.59, 3.40)	2.99 (2.59, 3.40)	-1.280	0.201
IFN-γ	11.25 (10.57, 13.06)	10.90 (10.90, 12.32)	-0.330	0.742
IL-4	3.32 (2.02, 3.32)	3.32 (2.02, 3.32)	-0.252	0.801
IL-17	3.46 (3.27, 3.90)	3.46 (2.69, 4.38)	-0.329	0.742
IL-2	6.18 (4.35, 7.54)	5.88 (5.03, 7.06)	-0.334	0.738
IFN-α	1.85 (1.70, 2.00)	2.00 (1.96, 2.00)	-2.033	0.042
IL-12	129.96 (110.96, 150.45)	145.24 (117.95, 150.45)	-0.847	0.397

Mann-Whitney U test (non-parametric) was used to compare inflammatory cytokine levels between the low- and high-risk groups. Data are presented as median, with Z and P values reported. TNF: Tumor necrosis factor; IL: Interleukin; IFN: Interferon.

Logistic regression analysis of factors associated with NSSI in adolescents with depression

IL-10 Levels were associated with a higher risk of suicide [regression coefficient = 3.06, Wald χ² value = 4.92, P = 0.027, Exp(B) = 21.402]. Other variables, such as IFN-γ, International Staging System, HDRS, HAMA, Rosenberg Self-Esteem Scales, Automatic Thoughts Questionnaire, Schizophrenia Suicide Risk Scale, somatic disorders, and regional factors, had no significant independent effect on health outcomes in this study (Table 4).

Table 4 Factors affecting suicide risk.

Risk factor	Regression coefficient	SE	Wald χ² value	P value	Exp(B)
TNF-α	0.38	0.23	2.81	0.094	1.464
IL-10	3.06	1.38	4.92	0.027	21.402
IFN-γ	-0.03	0.09	0.10	0.757	0.972
ISS	0.10	0.08	1.59	0.208	1.102
HDRS	0.05	0.05	0.75	0.386	1.046
HAMA	-0.05	0.06	0.61	0.435	0.954
RSES	-0.01	0.10	0.02	0.898	0.987
ATQ	0.04	0.03	1.55	0.213	1.037
SSRS	-0.04	0.03	1.55	0.214	0.959
Somatic disorders	-1.43	1.28	1.25	0.263	0.240
Regional factors	-1.44	0.86	2.81	0.094	0.236
Constant	-6.87	5.35	1.65	0.199	0.001

Binary logistic regression analysis was performed to assess the impact of risk factors on the outcome variable. TNF: Tumor necrosis factor; IL: Interleukin; IFN: Interferon; ISS: International Staging System; HDRS: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; RSES: Rosenberg Self-Esteem Scales; ATQ: Automatic Thoughts Questionnaire; SSRS: Schizophrenia Suicide Risk Scale.

Receiver operating characteristic curve analysis

IL-10 demonstrated moderate diagnostic accuracy for suicide risk prediction (area under the curve = 0.679, 95%CI: 0.549-0.808, P = 0.012). The optimal cutoff value of 1.075 was determined by maximizing Youden's index, yielding balanced sensitivity (57.9%) and specificity (70.0%) (Youden's index = 0.279) (Figure 1).

Figure 1 Receiver operating characteristic curve analysis of interleukin-10 for suicide risk prediction. ROC: Receiver operating characteristic.

Comparison of clinical scales before and after treatment in the entire sample

The least significant difference method was used for multiple comparisons of HDRS, HAMA, and International Staging System scores. The results indicate that, compared with baseline, scores on all scales decreased significantly at both the 2-week and 6-week time points. However, no significant changes in these scores were observed between the 2-week and 6-week time points (Table 5).

Table 5 Comparison of clinical scale scores before and after treatment.

Clinical scale	Comparison group	Mean difference	SE	P value	95%CI
HDRS	Baseline vs 2-week time point	-23.00	2.73	< 0.001b	-28.41 to -17.59
	Baseline vs 6-week time point	-23.32	2.73	< 0.001b	-28.73 to -17.92
	2-week time point vs 6-week time point	0.32	2.73	0.906	-5.08 to 5.73
HAMA	Baseline vs 2-week time point	9.00	2.34	< 0.001b	4.37-13.63
	Baseline vs 6-week time point	7.74	2.34	0.001a	3.10-12.37
	2-week time point vs 6-week time point	-1.26	2.34	0.590	-5.90 to 3.37
ISS	Baseline vs 2-week time point	6.56	1.50	< 0.001b	3.60-9.53
	Baseline vs 6-week time point	6.45	1.50	< 0.001b	3.47-9.40
	2-week time point vs 6-week time point	-0.13	1.50	0.932	-3.09 to 2.83

^aP < 0.01.

^bP < 0.001.

Repeated measures ANOVA was used to evaluate differences in scores of clinical scales (Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, International Staging System) across different time points (baseline, 2-week time point, 6-week time point). Bonferroni correction was applied for multiple comparisons. Results are reported as mean differences, standard errors, P values, and 95% confidence intervals. HDRS: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; ISS: International Staging System; CI: Confidence interval.

Changes in inflammatory cytokine levels in adolescents with NSSI after treatment

Among the 10 cytokines analyzed, significant decreases were observed in TNF-α (P < 0.01), IL-6 (P < 0.01), IL-10 (P < 0.01), IL-1 (P < 0.01), and IL-12 (P < 0.05) at 6 weeks post-treatment compared to baseline. Conversely, INF-γ (P < 0.05), IL-4 (P < 0.01), and INF-α (P < 0.01) showed significant increases after 6 weeks of treatment (Table 6).

Table 6 Pre- and post-treatment cytokine levels in the whole sample.

Inflammatory cytokine	Pre-treatment	Post-treatment	Z	P value
TNF-α	4.05 (3.10, 4.67)	2.98 (2.11, 3.53)	-4.72	< 0.001b
IL-6	3.43 (1.28, 3.58)	1.42 (1.11, 1.62)	-4.615	< 0.001b
IL-10	1.04 (0.87, 1.21)	0.85 (0.56, 1.04)	-4.082	< 0.001b
IL-1	4.00 (2.59, 3.40)	2.58 (2.36, 2.77)	-4.306	< 0.001b
IFN-γ	12.43 (10.90, 13.03)	25.41 (9.30, 12.17)	-2.561	0.010a
IL-4	3.13 (2.02, 3.32)	7.02 (4.80, 8.87)	-5.401	< 0.001b
IL-17	3.42 (2.69, 3.79)	3.34 (3.05, 4.05)	-0.657	0.511
IL-2	5.82 (4.39, 7.24)	5.44 (4.37, 6.76)	-1.570	0.116
IFN-α	1.95 (1.70, 2.00)	2.27 (2.00, 2.46)	-4.814	< 0.001b
IL-12	137.66 (129.96, 150.45)	127.03 (111.56, 132.41)	-2.219	0.026a

^aP < 0.05.

^bP < 0.001.

Wilcoxon signed-rank tests (non-parametric) were used to compare inflammatory cytokine levels before and after treatment. Data are presented as median, with Z and P values reported. TNF: Tumor necrosis factor; IL: Interleukin; IFN: Interferon.

DISCUSSION

The study findings reveal that the more severe the depression, the higher the risk of suicide in patients, consistent with the results of most previous research. Active antidepressant treatment has been shown to effectively reduce the risk of suicide in patients. Patients in the high suicide risk group had more insomnia than those in the low suicide risk group, which might lead to poor prognosis and an increased risk of depression relapse in the former. Sleep disturbance is associated with broadband measurements of emotion regulation, which are in turn associated with psychiatric outcomes, including adolescent suicidal ideation and attempts. Insomnia symptoms are common in patients with MDD[33-35]. Improving insomnia can effectively reduce the risk of suicide in adolescents[36].

Suicidal ideation may be uniquely associated with inflammation in depressed patients[37]. Patients with MDD who attempt or commit suicide have elevated inflammation compared to patients with MDD and NSSI. Preclinical and clinical studies also suggest that IL-6 and TNF-α are associated with anhedonia, and higher levels of TNF-α predict more severe depressive symptoms[38]. Higher risk of suicide was associated with higher levels of TNF-α and IL-10, which is consistent with previous findings[39]. In this study, it was found that patients in the high suicide risk group had significantly higher levels of IFN-α compared to those in the low suicide risk group, which is consistent with previous research indicating that IFN-α can induce depressive mood in individuals[40], and that similar depressive symptoms are observed in patients receiving IFN-α treatment[41,42].

After including all potential risk factors associated with an elevated risk of suicide in a regression analysis, a positive correlation was observed between higher IL-10 Levels and increased suicide risk. Specifically, patients with elevated IL-10 Levels exhibited heightened depressive symptoms[43], whereas the association between elevated IL-10 Levels and anhedonia significantly escalated suicide risk[44]. This underscores the potential of IL-10 Levels as a biomarker for assessing suicide risk in patients. The use of anti-inflammatory agents should be considered for patients at a high risk of suicide. Studies have shown that medications such as minocycline, etanercept, and celecoxib have demonstrated efficacy in alleviating symptoms of depression[45,46].

After systematic treatment, patients showed significant improvement in depression and improved sleep, and most importantly, significant changes were seen in inflammatory factors. Immune dysregulation has been implicated in depression and other psychiatric disorders[17]. A previous review evaluated evidence from 22 Longitudinal studies involving a total of 827 patients and found inconsistent findings[47]. But the most consistent observation was an elevation in TNF-α, IL-6, IL-10, and C-reactive protein[39,48-50]. These results are consistent with our findings. Higher risk suicide was associated with higher IL-10 Levels, which may be related to anhedonia[48]. This is a common problem in adolescents with NSSI. These findings indicate that antidepressants decreased several markers of peripheral inflammation.

The existing literature suggests that IFN-γ levels are lower in patients with depression compared to healthy controls[51]. IFN-γ levels are also a significant positive predictor of sleep quality deterioration[52]. In this study, after treatment with systemic antidepressants, participants showed improvements in both depression and sleep quality, accompanied by increased levels of IL-4 and IFN-γ. Elevated IL-4 post-depression treatment exerts anti-inflammatory effects by activating M2 macrophages and inhibiting pro-inflammatory factors (IL-1β, IL-6, and TNF-α)[53]. It also promotes neuroprotection and improves depressive behavior and cognition by reprogramming microglia (arginase 1-positive) and inducing astrocytic brain-derived neurotrophic factor/nerve growth factor production[54]. This aligns with the findings of most prior research. In a similar study on depressed adolescents, maresin-1 and IL-4 Levels increased after antidepressant treatment, whereas IL-6 and IL-1β levels decreased significantly[55]. In some studies, cytokine inhibitor therapies, such as anti-IL-6 biologics, TNF-α inhibitors, and IL-12 and IL-23 antagonists were found to be efficacious in depression[56,57], which suggests that cytokine inhibitors may be a potential therapeutic enhancer for depression.

This pioneering study, in exploring the relationship between suicide risk and inflammatory markers in adolescents who engage in NSSI, found that heightened IL-10 concentrations may be linked to increased suicide risk among adolescents deemed to be at high risk of suicide. Hence, these biomarkers could potentially serve as predictive tools for assessing suicide risk in clinical settings. Certain inflammatory markers are associated with the severity of depression in adolescents, particularly in those exhibiting self-harming behaviors. Monitoring the levels of these inflammatory factors may help predict disease progression and outcomes. Furthermore, targeted therapies aimed at modulating inflammatory markers could represent a novel approach to treating depression. For instance, inhibiting the inflammatory response or adjusting the levels of inflammatory factors may improve depressive symptoms and reduce self-harming behaviors. However, research in this area is still in the nascent phase, and more clinical evidence is needed to support these findings.

Limitations and future directions

Although the findings of the study are useful, this study has several limitations as well. First, the inclusion criteria focused exclusively on adolescents, a demographic characterized by ongoing growth and development, which may have introduced a bias into the results. Second, the dietary habits and nutritional status of the participants were not considered; these factors could potentially influence the measurement of biological markers. Third, the investigation was conducted at a single center with a small sample size, potentially limiting the generalizability of the findings. Future research should aim to increase the sample size and incorporate multi-center, randomized controlled trials to enhance the robustness of the conclusions. Moreover, recruiting adolescents with depression presents challenges, as it requires authorization from parents or guardians, which further limits the sample size.

CONCLUSION

In summary, this study demonstrates that elevated IL-10 and IFN-α levels are associated with increased suicide risk in adolescents with NSSI, suggesting their potential utility as clinical biomarkers. Antidepressant treatment significantly reduced pro-inflammatory markers (e.g., TNF-α and IL-6) while ameliorating depressive symptoms, further supporting the involvement of immune dysregulation in depression pathogenesis. These findings indicate that adjunctive anti-inflammatory therapies may benefit high-risk cases, although these conclusions are limited by the single-center design, restricted sample size, and unaccounted dietary confounders. Future multi-center studies with expanded cohorts are warranted to validate these observations and explore their translational applications.

ACKNOWLEDGEMENTS

We would like to especially thank all the adolescents who participated in the clinical assessment and blood sample collection.