Major depressive disorder (MDD) is a mental disorder in which low mood and anhedonia persist for at least two weeks to a distressing or disabling degree (1). According to the World Health Organization (WHO) reports, MDD was one of the top 10 leading causes of disability-adjusted life years (DALYs) among people aged 10-49 in 2019 (2). Suicidal behaviors, an intentional self-inflicted act that ends in death, are one of the recognized diagnostic criteria for MDD in the DSM-5 (3). Suicide is the most severe symptom of MDD patients and may or may not be fatal (4, 5). Up to 50% of people with MDD report suicidal thoughts or suicide attempts (3, 6). People with MDD have a 20-fold higher risk of suicide attempts (7), and they are three times more likely to suicide (8).

A number of factors have been recognized as possible risk factors for suicide. According to a meta-analysis, various confounding factors such as low age, female, underweight or obesity, a longer duration of illness, and comorbid psychiatric or somatic symptoms were identified as risk factors for suicide attempts (9–11). Studies have also shown that a history of suicide attempts increases the risk of suicide, and serves as one of the strongest factors of impending suicide attempts (12–15). Therefore, it is critical to explore the first-time suicide attempt (FSA).

It is estimated that up to 13% of people with MDD who have made a non-fatal suicide attempt later die by suicide (3). 1.6% of suicide attempters die by suicide within 12 months, and 3.9% of them die by suicide within five years (16). In the first month following an emergency department visit for a psychiatric problem, 12.9% of people with MDD have attempted suicide (17). Approximately 40% of those who die by suicide have visited a physician one month before death. Of these, 20% have visited a physician one week before death (18, 19). According to a recent meta-analysis of suicide risk studies over the past 50 years, they mostly focused on predicting suicide attempts in the next 12-24 months, with less than 1% on predicting suicide attempts in the next 30 days (20). Risk factors for suicide attempts have been explored over a long term (i.e., over a lifetime or the past year), but clinicians are still frequently asked to assess the suicide risk in the near term (17).

In recent decades, researchers have attempted to identify biomarkers associated with suicide attempts, such as cholesterol levels, thyroid hormones, and impaired fasting glucose (21–23). The median time from the last psychiatric outpatient visit to the death is 18 days (24). Therefore, identifying possible biomarkers of FSA within 14 days of MDD onset is critical to prevention and treatment. In this study, different from previous studies, FSA was focused on the past 14 days.

To the best of our knowledge, this study was the first to explore FSA in the past 14 days in patients with first-episode drug-naïve (FEDN) MDD. Notably, investigating FEDN MDD patients offers distinct advantages of minimizing confounding factors such as antidepressant effects, long-term medication use, and associated medical and psychiatric complications. The objectives of this study were to (1) comprehensively analyze the occurrence and clinical characteristics of FSA in FEDN MDD patients over 14 days, and (2) identify key factors significantly associated with FSA in the past 14 days in patients with FEDN MDD.

A total of 1718 patients with FEDN MDD were recruited, with a mean age of (34.9 ± 12.4) years and a mean duration of illness of (6.4 ± 4.7) months, of whom 588 were males and 1130 were females. Of these, 138 had a history of suicide, and 1,580 had no history of suicide in the time frame prior to the past 14 days. The most recent suicide attempt occurred the day before the interview, while the most distant suicide attempt occurred more than a year ago. The largest number of suicide attempts was four.

This study is the first to investigate the prevalence of FSA in the past 14 days and its associated factors in patients with FEDN MDD. Identifying individuals at risk of short-term suicide poses a significant challenge for clinical professionals and is of paramount importance. This study aimed to identify variables that differentiate between FEDN MDD patients with FSA in the past 14 days and those who did not attempt suicide. It was found that (1) 20.1% (346/1718) of FEDN MDD patients attempted suicide, of which 13.68% (235/1718) occurred in the past 14 days and 12.11% (208/1718) were FSA; (2) MDD patients with a history of suicide attempts were approximately 11 times more likely to attempt suicide in the past 14 days than those without a history of suicide attempts; (3) more severe anxiety symptoms, higher levels of TC, and TSH in patients with FEDN MDD were associated with a higher risk of FSA in the past 14 days. The combination of HAMA score, TC, and TSH level was the most effective in differentiating FSA in the past 14 days (AUC = 0.82).

The above results suggest that a 14-day window is critical. To date, only a few cross-sectional studies have reported the prevalence of short-term suicide attempts in patients with MDD. For example, Mash et al. reported that 2.6% of soldiers with MDD attempted suicide without suicidal thoughts, 16.2% of which occurred within 30 days. Among soldiers with documented suicidal thoughts, 7.4% attempted suicide, with 46.3% occurring within 30 days (32, 33). In Brazil, Brunon et al. found that 0.67% of participants had suicidal thoughts in the week prior to the interview (34). A China-based meta-analysis revealed that 20.3% of participants had attempted suicide one month before the interview (35). The prevalence of suicide attempts in previous studies varied for several reasons. First, little data are available on specific time windows related to suicidal behaviors (36). Many studies focused on suicide attempts over a long term (i.e., over a lifetime or the past year) (12). Second, there is no universally agreed upon definition of acute or chronic suicide (i.e., subsequent hours, days, weeks, or months) (12). Third, cultural and sample differences may exist. It was found that MDD patients with a history of suicide attempts were approximately 11 times more likely to attempt suicide in the last 14 days than those without a history of suicide attempts. A history of suicide attempts strongly predicts future suicide attempts or suicide deaths (37–43). According to systematic reviews and meta-analyses, adults with a history of suicide attempts have a ten-fold higher risk of suicide compared to normal people (44). MDD patients with a history of suicide attempts have a 4.84-fold higher risk of suicide than those without a history of suicide attempts (19). Sohn et al. predicted the 6-month suicide attempt rates and found that patients with a history of suicide attempts have a higher risk of suicide (OR = 2.99) (45). A history of suicide attempts was also incorporated in the final multivariate model predicting the risk of suicide in adolescents within three months (46). These studies suggest that individuals with a history of suicide attempts are more likely to attempt suicide in the long or short term. Therefore, it is critical to analyze the risk of FSA in patients with MDD.

Among MDD patients without a history of suicide attempts, the risk factors for FSA in the past 14 days were explored. It was found that more severe anxiety symptoms and higher levels of TC and TSH might contribute to short-term suicide (14 days). MDD patients with anxiety symptoms were more prone to suicide attempts, consistent with the results of several previous studies (19, 47–49). Mood disorders strongly predict future suicide attempts (50). MDD and anxiety disorders are common co-occurring psychiatric disorders (48). Patients with mild, moderate, or severe anxiety symptoms are at greater risk of suicide (49), and anxiety symptoms are more prevalent in patients with MDD who attempt suicide (3). Some researchers have suggested that the presence of depressive symptoms influences suicide attempts among patients with anxiety disorders (51). In a population-based survey, Sareen et al. conducted two follow-up assessments one year after baseline and three years after baseline, respectively. They found that a history of anxiety disorders is a unique risk factor for future suicide attempts, and MDD patients with anxiety disorders have a 4.15-fold increased risk of suicide attempts compared to those without anxiety disorders (47). In this study, anxiety remained an independent risk factor for FSA in the past 14 days in patients with MDD.

MDD patients with higher TC levels were more likely to undergo FSA in the past 14 days. In recent years, there have been an increasing number of studies on biomarkers associated with suicidal behavior, and lipid levels have emerged as a potential factor in this regard (52–55). Metabolic syndrome is common in patients with MDD, and it is associated with suicide attempts (56). One theory suggests that serum lipid levels play a crucial role in the pathogenesis of suicide; high levels of serum TC increase the risk of violent suicide (52). Higher levels of TC are associated with a higher risk of suicide in adult women (57, 58), irrespective of menopause status (59). Zhou et al. revealed that TC levels may be discovered as a potential and valuable biomarker for first-episode MDD suicide risk within two weeks (60). A recent study showed that patients with suicide attempts had higher LDL and TC but lower HDL in FEDN MDD patients (10). The underlying association mechanisms between serum cholesterol and suicide are still unclear. Surace et al. reported that higher total cholesterol blood levels may be linked to an increased risk of self-harm through the pro-inflammatory state that directly affects the brain (61). Comings et al. found that higher levels of blood cholesterol were connected to polymorphisms in the serotonin transporter gene (HTT, SLC6A4) (62), which were associated with suicidal behavior (63). Penttinen et al. hypothesized that elevated cytokine production, particularly interleukin-2 (IL-2), contributes to higher total blood cholesterol and reduced HDL cholesterol, subsequently influencing melatonin release and elevating impulsivity and suicide risk (64). Brunner et al. speculated that patients with higher cholesterol may exhibit maladaptive nutritional behaviors (such as binge eating), which was associated with suicide attempts (65).

However, different findings have been reported in other studies. For example, an association has been observed between depressive symptoms and low plasma TC levels, and low levels of TC are associated with suicide and violent death (66). Additionally, low levels of TC lead to an increased risk of suicide in patients with mental illness (67). A meta-analysis revealed that individuals with lower serum TC levels are more prone to suicidal behavior (53). A follow-up study showed that lower total cholesterol levels were significant predictors of suicide re-attempts (68). Some studies reported no association between serum cholesterol and recent suicide attempts (occurring within 72 hours before hospital admission), either violent or nonviolent (69, 70). Research including 11,653 Korean participants found that men’s depression was associated with higher triglycerides. However, there was no obvious effect of the blood lipid variables on suicidal thoughts (71). It’s important to note that drugs were used in these studies, which may have impacted the results. We recruited first-episode and drug-naïve young MDD patients to avoid the influence of many confounding factors, and this may partially explain the differences between our findings and other studies. Several other factors may account for these differences. First, different populations, genders, and ages in each study may lead to differences in findings. Cho et al. suggested that the relationship between lipids and suicide varies by age (72). Second, lipid levels fluctuate across different stages of illness. Lipid levels are lower during acute episodes of depression but increase during periods of remission (73). Some previous studies on suicide did not consider the time window, so the relationship between lipid levels and suicide appeared to vary greatly depending on the stage of MDD. Third, serum TC levels are not a reliable marker of lipid content in the brain (74). Finally, further study is needed to determine the association between TC and suicide attempts.

This study showed that elevated TSH levels in patients with MDD were associated with an increased prevalence of FSA in the past 14 days, consistent with many previous studies (75–78). A China-based study involving FEDN MDD patients found that the levels of serum TSH and TC are statistically higher in suicide attempters than in non-suicide attempters (76). Another study reported that 179 adolescents with MDD who attempted suicide had higher TSH levels, consistent with our findings, and that TSH levels are a significant predictor of suicide attempts, with an adjusted OR of 5.14 (77). Among participants with suicide attempts, there was a substantial correlation between suicide attempts and higher TSH levels (79). Furthermore, a systematic review and meta-analysis confirmed the association between higher TSH levels and suicidal behavior (75). However, some studies reported no difference in TSH levels between individuals with and without suicidal behavior (80, 81). There are several possible explanations for the inconsistency among previous studies. First, the sample sizes varied widely, ranging from 179 to 1279 subjects. Second, the sampling time was different. Some studies collected blood samples within 24 hours after suicide attempts (80), whereas some did not mention the specific time of blood collection. Therefore, future investigations are needed.

This study exhibits several strengths. First, this study used a relatively large sample size to minimize the impact of extreme data on trial results. Second, this study recruited drug-naïve MDD patients who were first-episode. Compared to previous studies, our study can relatively reduce the interference of confounding variables on FSA, such as drugs, course of disease, and comorbidities. Third, we focused on first-time suicide attempts, which made the correlation results more accurate and avoided the impact of the duration from suicide attempt to blood sampling.

However, it’s essential to acknowledge the limits of this research. First, the patients in this study were all Han people recruited from outpatient clinics; hence, it is imperative to validate our findings across diverse populations, encompassing distinct ethnicities and clinical profiles. Second, this case-control study could not determine the causal relationship between associated factors and suicide attempts in patients with MDD. Prospective cohort studies are needed to confirm our results. Third, suicide attempts were determined by interview, rather than a structured assessment tool. In addition, the data collected focused solely on suicide attempts without capturing information regarding suicidal thoughts or ideation. Despite these limitations, this study is the first to evaluate suicide attempts over a brief period of time (in the past 14 days), thereby providing valuable insights into the precise association.

In summary, the results of this study are essential for identifying at-risk populations for suicide attempts and making timely and appropriate clinical decisions and interventions. More severe anxiety and higher levels of TC and TSH may be risk factors for FSA in the past 14 days in patients with MDD. Future studies should focus on the changes in variables involved in the transition from no suicide risk to suicide attempts and create predictive algorithms as clinical aids to better identify patients with MDD who are at high risk of suicide. By analyzing data from a variety of sources, we hoped to provide clinicians with more valuable information for decision-making and improve prognosis. Understanding the factors contributing to FSA is critical to developing effective interventions for patients with MDD.

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

The protocol of this cross-sectional study was approved by the Institutional Review Board (IRB) of the First Hospital of Shanxi Medical University (ID No. 2016-Y27). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

XC: Conceptualization, Data curation, Formal Analysis, Investigation, Writing – original draft, Writing – review & editing, Methodology. XZ: Resources, Supervision, Writing – review & editing. TZ: Data curation, Investigation, Writing – review & editing. RB: Data curation, Investigation, Writing – review & editing. YL: Investigation, Writing – review & editing. JL: Funding acquisition, Supervision, Writing – review & editing.