To date, this is the first study to reveal suicide attempts rates and risk factors in middle-aged first-episode untreated patients with IFG. The study found that: (1) suicide attempts rate was 20.98% (174/830) in middle-aged untreated MDD patients, and 38.66% (46/119) in those with IFG, which is significantly higher and 2.87 times higher than the overall middle-aged MDD population. (2) Middle-aged MDD patients with IFG who attempted suicide had longer duration of illness, more depression, anxiety, and psychiatric symptoms, higher blood TSH, TGAb, TPOAb, total cholesterol levels, and higher blood pressure than those without suicide attempts. (3) HAMA, TGAb, and disease duration may act as independent predictors of suicide attempt risk in middle-aged depressed patients comorbid IFG.
Our study indicated that the incidence of suicide attempts in middle-aged untreated depressive patients was 20.9%, which is consistent with previous research on Asian populations. For example, a meta-analysis conducted in Chinese population revealed a lifetime suicide rate of 23.7% and a monthly suicide rate of 20.3%[26]. A study in Thailand reported a suicide rate of 16.9% among MDD patients[27], and In South Korea, Kim reported that 19.8% of MDD patients had attempted suicide once or more[28]. However, in the current study, the suicide rate of depressed patients comorbid IFG increased substantially to 38.66%. This is close to the 35% suicide rate reported by Lalthankimi et al. for patients with severe MDD and the 33.7% suicide rate reported by Azorin JM for patients with unilateral or bilateral disorder[29]. Their findings suggested that the suicide rate related to the severity of the disease. Our study suggested that the suicide attempts rate in middle-aged MDD patients with IFG in China was much higher than that of Asian depressed patients in general, suggesting that the difference in suicide rates may be related to the following reasons. First, IFG or disturbed glucose metabolism directly or indirectly contributes to the increased suicide attempt rate[11]. Second, our study focused on middle-aged adults, who may had a higher rate of somatic diseases compared to the general population. Many somatic diseases, such as chronic pain, thyroid dysfunction, and arthritis, have been associated with increased suicide rates[30, 31]. Third, several other studies had included outpatients and inpatients, a significant proportion of whom were receiving or had received antidepressant treatment, whereas our study focused on untreated patients with MDD. Fourth, differences in the social background, economic status, and medical conditions of the study populations may also contribute to differences in suicide rates[32].
Our findings suggested that among middle-aged patients with MDD, those with longer duration of illness had a higher suicide rate, which is consistent with previous findings on the correlation between the disease duration and patients' risk of suicide. For instance, Fang revealed that the total duration of depression was closely related to suicidal ideation[33]. Kraus et al. found that longer duration of untreated depression were often associated with worse outcomes[34]. Liang et al. reported that recurrent episodes of depression increased the risk of suicide[35]. An analysis of clinical data from 13 psychiatric and general hospitals in China concluded that multiple episodes of depression and a history of suicide attempts were independent risk factors for current suicide attempts[36]. However, there have also been studies that have incorporated disease duration into the selection of suicide risk factors for MDD patients, and the results showed that disease duration did not serve as a predictor for suicide. This inconsistency may be related to age differences and severity of disease among the participants of the studies. We hypothesize that some of the MDD patients who participated in this study did not seek treatment early at the onset of symptoms for social, economic, and cultural reasons. Instead, they sought treatment when their disease progressed to a more severe stage. Thus, the long duration of the disease caused physical or mental harm to untreated MDD patients, increasing the risk of suicide attempts. Our results suggested that early detection and treatment of MDD may reduce the incidence of suicide attempts by shortening the course of the disease. But further research is needed to address this risk factor, and these studies need to quantify the different levels of disease severity.
Our findings revealed a correlation between suicide risk and thyroid autoimmunity in middle-aged MDD patients. We found that blood levels of TGAb, TPOAb, and TSH were significantly elevated in MDD patients with suicide attempts, but without statistically significant differences in FT3 and FT4 levels. Elevated TSH levels with normal FT3 and FT4 levels indicate the presence of subclinical hypothyroidism[37], with a prevalence in the population of 3.8%-4.3%[38, 39]. TGAb and TPOAb play important roles in thyroid autoimmune diseases[40], and TGAb is a marker for autoimmune thyroid disease as is TPOAb[41]. Subclinical hypothyroidism is accompanied by abnormal levels of TGAb and TPOAb, leading to the diagnosis of autoimmune thyroiditis, which is also the main cause of subclinical hypothyroidism[37, 42]. Previous studies have suggested that autoimmune thyroiditis is common in the elderly[43], and TGAb and TPOAb levels are also associated with depressive symptoms[44]. In addition, Our study further suggested that TGAb was also associated with suicide attempts and was a risk predictor of suicide attempts in middle-aged first-episode depressive patients. The mechanism underlying the relevance of abnormal thyroid immune function and suicide attempts in depressed patients may be its effect on neurotransmitters such as serotonin 5-hydroxytryptamine and norepinephrine, which play an important role in suicide attempts[45]. Second, high levels of TGAb and TPOAb indicate that these patients are in an autoimmune state, and autoimmunity has been linked to suicide attempts through the kynurenine pathway and the hypothalamic-pituitary-adrenal axis[46].
In the present investigation, it was observed that suicide attempts in depressed patients were associated with anxiety symptoms. Moreover, the HAMA was identified as an independent predictors of suicide attempts in these individuals. In fact, there are three aspects that support this discovery we found. First, Anxiety were identified as major risk factors for suicide by various organizations such as the American Association of Suicidology and the American Foundation for Suicide Prevention[47, 48]. Second, many theories regarding suicide also involved anxiety. For instance, Beck's cognitive-behavioral model of suicide suggests that anxiety is focused attention on the external manifestations of suicide, and interacts with despair to increase suicide risk[49, 50]. Joiner's interpersonal theory of suicide states that the state of acute anxiety, such as heightened alertness, panic attacks, or agitation, is consistent with the individual's psychological state prior to suicide[51]. Fawcett's theory aligns with the above viewpoints, suggesting that anxiety/agitation is a determining factor in suicide[52]. Riskind et al. propose that patients with anxiety, if experiencing feelings of hopelessness, may exhibit an impulse to escape the reality of pain, thus increasing the risk of suicide[53]. Suicide attempts are the avoidance response to intense emotions, similarly, the hallmark characteristic of anxiety is behavioral avoidance, which shares common features with suicide attempts[54]. Patients with anxiety also employ other avoidance strategies such as suppression, which further weakens positive self-awareness and increases suicide attempts[55]. Third, many other clinical studies have confirmed the link between anxiety and suicide attempts. A comprehensive retrospective analysis demonstrated a significant association between depression comorbid with an anxiety disorder and suicide[56]. Furthermore, certain studies have indicated that MDD patients with comorbid anxiety exhibit a higher propensity for suicide compared to those without anxiety[7, 57]. Additionally, one retrospective study found that 79% of depressed individuals with anxiety symptoms before suicide[58]. However, some reports show no relationship between anxiety and suicide attempts[59]. Instead, they found lower suicide rates in MDD patients with anxiety symptoms, suggesting that anxiety symptoms may be a protective factor against suicide risk[60]. These conflicting results may be interpreted as follows: the presence of anxiety in MDD patients is often interpreted as a reflection of a more serious illness and emotional instability, leading to increased suicide attempts. Some causal relationship between anxiety and substance abuse may also explain the relationship between anxiety and suicide[60]. On the other hand, an alternative explanation is that anxiety symptoms indicate an individual's worry and fear of illness and death, which were protective against suicide attempts[60]. There may be several reasons for the differing findings on whether anxiety is a risk factor for suicide attempts in MDD patients. First, our study population included MDD patients aged 35–60 years, many of whom were perimenopausal women. The suicide rate among perimenopausal women was relatively higher compared to premenopausal and postmenopausal women[61]. Therefore, our study results may be biased compared to studies with a lower proportion of perimenopausal women in the research population. Second, some of the studies come from different countries and ethnic groups with different social and cultural backgrounds. Suicide attempts may vary according to the religious and moral values of these societies. Third, our study population was untreated MDD patients, whereas some of other studies involved patients who were hospitalized or had been treated or were being treated, which may affect the results. Therefore, more randomized controlled studies should be conducted on the relationship between anxiety and suicide attempts.
Some limitations need to be mentioned. First, although we identified suicide attempts and associated risk factors (e.g., clinical characteristics and metabolic indicators) in middle-aged MDD patients with IFG, It's difficult to determine a causation because this was a cross-sectional study. Longitudinal studies need to be conducted to determine the causal relationship between them. Second, no healthy control group was set and clinical information and biochemical indicators for statistical analysis were from MDD patients. Third, the study samples we chose were from a single center's psychiatric clinic, and there may be selection bias due to sample source limitations. Fourth, our study excluded patients with substance abuse and personality disorders, many of whom had comorbid depressive disorders and high suicide rates, so the results may be biased. In consequence, our research outcomes should be regarded as preliminary and need to be further confirmed in future large-sample and multicenter longitudinal studies.