Major depressive disorder (MDD) is a widespread mental health disease clinically defined by significant and persistent low mood, declining role functioning, a poor quality of life, a high risk of medical comorbidity and mortality, and even a propensity for suicide (1). The 2015 Global Disease Burden Study included 310 illnesses and injuries for study, and depression was identified as the third most common disability cause globally (2). Around 17.3 million people in the United States had at least one major depressive episode in 2017, while 260 million people globally suffered from depression (3). Depression’s disability-adjusted life years (DALYs) have increased by 36.5% in China during the past ten years, moving it up from 15th place in 1990 to 10th place in 2017 (4). Additionally, several investigations have revealed that depression is closely related to cardiovascular diseases, metabolic diseases, diabetes, all-cause mortality, and suicide behaviors (5–8).

The most severe outcome of untreated MDD is suicide. Even after receiving treatment for depression, a previous study found that 15% of patients with MDD died by suicide (9). Suicide rates have been increasing both in China and worldwide, presenting a growing public health issue. In 2019, over 700,000 individuals worldwide died by suicide, which accounted for nearly 1% of all deaths (10). The World Health Organization (WHO)’s Mental Health Action Plan 2013–2030 and the United Nations Sustainable Development Goals 2030 have set an aim to reduce suicide rates by one-third by 2030 (11). It is disturbingly common for people with MDD to attempt suicide, with estimates ranging from 16% to 33.7% having done so at least once in their lifetime (12–16). In addition, suicide attempts (SA) are also known to be the strongest predictor of eventual death by suicide (17). Despite this, the reasons behind SA in patients with MDD are still unclear, highlighting a need for further investigation into associated risk factors.

Reduced insulin responsiveness is referred to as insulin resistance (IR), which is a typical hallmark of type 2 diabetes, hypertension, lipid metabolic problems, and even cardiovascular disease (18). A number of observational studies on the general population have shown that IR-related diabetes is associated with depression (19–21). Epidemiological studies and meta-analyses repeatedly show that people with mental problems are more likely to develop type 2 diabetes mellitus (T2DM) and vice versa, reiterating the reciprocal relationship (22). T2DM has been linked to increased treatment resistance, chronicity, and the occurrence of more severe depressive symptoms, whereas depression exacerbates the negative health outcomes, micro- and macrovascular problems, and death rates among patients with T2DM (22). Interesting research by the European Group for the Study of Resistant Depression (GSRD) links a high body mass index (BMI) to higher rates of suicidality, protracted psychiatric hospitalizations over the course of a person’s lifetime, an earlier onset of major depressive disorder (MDD), and the presence of comorbidities (23). Clinical and genomic studies have revealed a polygenic risk that unites disorders connected to IR and MDD, suggesting overlapping etiopathological processes (24). As likely common pathways, immune-inflammation dysregulation, hypothalamic-pituitary-adrenal axis dysfunction, changes in gut microbiome, and disruptions in brain insulin signaling are identified (25). Notably, insulin can cross the blood-brain barrier and is produced centrally by the choroid plexus. Insulin receptors are found on neurons and glia in the nucleus accumbens, amygdala, and hippocampus, which are involved in mood regulation and cognition (26). Within these areas, neuroprotection, neurogenesis, neurotransmission, and synaptic plasticity are all significantly influenced by the complex network of insulin signaling. Additionally, several antidepressants and diabetes medicines have the potential to improve insulin sensitivity indicators and lessen depressed symptoms (27).

In recent years, a brand-new marker of IR has been discovered: the triglyceride-glucose (TyG) index, which is created by adding fasting plasma glucose and triglycerides. According to research, TyG index is connected to depression, cardiovascular disease, and illness prognosis (21, 28). Shi et al. discovered, for instance, that persons with higher TyG index scores are more prone to have depressed symptoms (29). IR may raise the risk of SA as well as depression. To our knowledge, however, no research has looked at the relationship between TyG index and SA in patients with MDD, particularly in the Chinese community. Therefore, the aim of this study was to evaluate the association between TyG index and SA in a sizable Chinese sample of patients who were first-episode and drug-naive (FEDN) MDD.

To the best of our knowledge, this is the first study to examine the relationship between TyG index and SA in a moderately large sample size of patients with FEDN MDD in China. Even after correcting for any confounding factors, our results show a strong correlation between TyG index and SA. Various stratification and sensitivity analysis revealed the connection to be constant. Additionally, TyG index and SA also showed a non-linear connection, with an inflection point of 9.29. No significant relationship was observed on the left side of the inflection point, whereas on the right side of the inflection point, there was a notable positive association between each incremental unit increase in TyG index and a substantial 247% rise in the risk of SA. These results provide novel insights into the link between TyG index and SA in patients with MDD. However, further investigation is required to comprehend the processes underlying this link, and a number of possibilities may be present.

First off, IR has been linked to suicidal behavior and is often associated with blood glucose issues in depressed people. For instance, cross-sectional research in South Korea with over 160,000 participants found that IR was linked to a greater risk of depression, with an increase in incidence of 4% and 17% for young adults and non-diabetics, respectively (35). Furthermore, it has been shown that changes in IR and glucose metabolism are linked to suicidal attempts and ideation in depression (36). On the other side, suicidal thoughts can also cause metabolic problems and impaired lipid synthesis, which can aggravate IR and raise blood sugar levels in type 2 diabetes (37). Excessive fluctuations and uncontrolled blood sugar levels may impair patient awareness of self-management, which is linked to suicidal ideation (38). Our study demonstrated a positive relationship between SA and TyG index, which remained stable even after controlling for relevant confounders and across multiple subgroup analyses. The mechanisms underlying the association between TyG index and SA in patients with MDD require further investigation.

Secondly, the association between a high TyG score and a greater risk of SA may be explained by reverse causation. In addition to IR, a greater TyG index is associated with a variety of harmful health conditions, including metabolic syndrome, obesity, diabetes, hypertension, cerebrovascular disease, and disturbances of the lipid metabolism (39–41). The illness condition may also be correlated with an increased level of depression and SA. The incidence of suicide fatalities was positively connected with those from ischemic heart disease and stroke, according to a 27 year study’s time series between 1979 and 2005 (42). In addition, Hawkins et al. (43) found that those with cardiovascular illness who also had depression had a higher likelihood of having SA in the previous year. Additionally, there is proof that SA, lipid metabolism issues, and metabolic syndrome are related in people with MDD (44, 45). The concept about the glucose-fatty acid cycle is a potential explanation (46, 47). Depressed people are reported to have lower HDL cholesterol and higher triglyceride levels when compared to healthy controls. Triglycerides are likely causal risk factors for depression (48).

Thirdly, the link between TyG index and SA in depression may be influenced by inflammatory and oxidative stress. According to the monoamine hypothesis, lower serotonin levels are connected to a variety of metabolic and mood-related problems (49, 50) and that depression is related to monoaminergic dysfunction. On the other hand, the pro-inflammatory cytokines and immunological activity that cause tryptophan depletion and serotonergic hypofunction are highlighted by the inflammatory theory of depression (51, 52). It is understood that type 2 diabetes is an immune-mediated condition in which cytokines are crucial for insulin signaling and the eradication of beta cells that produce insulin (53). A potential pathophysiological mechanism underpinning IR and altered glucose metabolism in depression and suicidal behavior may be the interaction between serotonin and pro-inflammatory cytokines (54, 55). According to recent studies, suicidal behavior is linked to inflammation in both the peripheral and central neural systems (56). Especially in those with a history of childhood trauma and high inflammation, targeting inflammatory processes may be a unique therapy option for lowering suicide risk (57). TyG index and inflammatory indicators such white blood cells and C-reactive protein have been linked positively in prior research (58). Inflammation, oxidative stress, and endothelial dysfunction are also associated with a high TyG index. Both oxidative stress and inflammation can harm the vascular endothelium, which aids in the emergence of a number of illnesses, such as dementia and depression (59). Patients with MDD who attempted suicide showed higher levels of IL-6, which may be impacted by traumatic and stressful situations, according to recent research (60). The link between TyG index and SA in MDD in this study was only found to be statistically significant when TyG index was larger than 9.29, indicating a threshold impact that calls for more investigation into the underlying mechanism.

The current study has a number of advantages. First off, it concentrates on a research group of people with FEDN MDD, which reduces the impact of confounding variables including disease duration, lifestyle interventions, drugs, and associated medical conditions. Second, the linear and nonlinear correlations between TyG index and SA were investigated using both multivariable logistic regression analysis and smoothing plots. However, the study also has several limitations. First of all, its cross-sectional design prevents it from proving causality. Future research should use longitudinal designs to more fully explore the causal association between TyG index and SA in patients with MDD. Second, only Han Chinese patients were included in the study’s patient population, which was drawn from the mental outpatient department of a general hospital in Taiyuan, Shanxi Province, China. Confirmation of these results in people with various ethnic and clinical backgrounds is required. Thirdly, SA was identified using interviews and medical records, which are not structured assessment tools for suicidal behavior. In addition, we did not have access to detailed information on the severity, plans, or thoughts behind the SA. Therefore, future studies should employ specific suicide questionnaires to collect data on these aspects of SA. Fourthly, the study’s participants were patients with MDD who were having their first episode and who had not sought therapy for their depressive symptoms. It is not possible to exclude patients whose diagnosis may have changed to bipolar disorder, as the initial depressive episode may have mirrored the MDD episode. Fifth, since the patients with MDD included in this study had depression that was fairly severe—the 17-item HAMD scores are higher than or equal to 24, the mean HAMA is over 20—the findings of this study may not be generalizable to patients who are less seriously afflicted. Finally, a number of confounding variables that may have a major influence on the connection between TyG index and SA were not examined, including smoking, drinking, personality characteristics, family income, social position, and biological variables. To further understand the pathophysiological processes behind the link between TyG index and SA in individuals with MDD, future research should take into account more confounding variables.

In conclusion, TyG index and SA had a nonlinear association in Chinese patients with FEDN MDD, with an inflection point around 9.29. On the right side of the inflection point, but not on the left, there was a positive correlation between TyG index and SA. The findings should be regarded as preliminary and verified by follow-up research employing a longitudinal design and structured evaluation instruments due to the poor knowledge of the underlying processes, the cross-sectional design, and other limitations of this study.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Institutional Review Board (IRB) of Shanxi Medical University (No. 2016-Y27) and performed in accordance with the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.

XyZ, XD, and JL: study design. JL, XmZ, HY, and YL: investigation. JL, XbZ, QW, and ZL: analysis and interpretation of data. JL, XmZ, YL, and FJ: drafting of the manuscript. XD and XyZ: critical revision of the manuscript. JL, XmZ, YL, XD, and XyZ: approval of the final version for publication. All authors contributed to the article and approved the submitted version.

This work was supported by the Gusu Talent Program (nos. GSWS2021052, GSWS2021053, and GSWS2019070), Key Diagnosis and Treatment Program of Suzhou (LCZX202016), the Suzhou Clinical Medical Center for Mood Disorders (Szlcyxzx202109), the Medical Science and Technology Development Foundation, Nanjing Department of Health (nos. YKK21216, YKK20184, and YKK22264). The funding sources of this study had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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