Major depressive disorder (MDD), one of the most prevalent mental illnesses, is characterized by major depressive episodes and includes symptoms such as weight loss, weariness, insomnia, depressed mood, reduced interest or pleasure, and recurrent thoughts of suicide (1). MDD constitutes a notable societal and individual burden, involving substantial medical and financial costs. According to the World Health Organization, depression is predicted to be the primary cause of worldwide illness burden by 2030, overtaking cardiovascular and respiratory diseases, ranking third in terms of disability-adjusted life years (2). A recent comprehensive study suggests a global lifetime prevalence of MDD ranging from 2 to 21% (3). The National Comorbidity Replication Survey conducted in America using the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria revealed a 12-month estimate of 6.6% and a lifetime prevalence of 16.2% for MDD (4). Particularly in mainland China, the estimated lifetime prevalence of depression was 3.3% overall, with rural individuals appearing to be more susceptible to depression than urban ones (5). The impact of MDD on patients’ lives and society at large was enormous, as evidenced by the correlations between depression and suicidality, increased work loss and disability, worse quality of life, and increased financial and familial burden (6). Despite its substantial impact, the psychopathological mechanisms of MDD remain poorly understood.

A severe subtype of MDD, known as MDD with psychotic characteristics or psychotic depression, is characterized by major depressive episodes accompanied by tactile, somatic, paranoid, auditory, and guilt-related hallucinations (7). This subtype is linked to poorer outcomes in comparison to individuals with MDD without psychotic symptoms, regarding depressive episodes, suicide, hospitalizations, financial support, and social functioning (8, 9). Psychotic symptoms are used as an assessment of MDD severity in both the DSM-V and the International Classification of Diseases (ICD)-10, the current worldwide categorization and diagnostic systems for mental diseases. Epidemiological studies indicate that the prevalence of psychotic depression can range from 0.4 to 0.6% in general populations and from 25.3 to 44.7% in patient groups suffering from major depressive illness (9–11). Recent systematic review and meta-analysis findings show that the presence of psychosis during a major depressive episode doubles the likelihood of lifetime and acute phase suicide attempts, while also increasing the risk of developing psychosis in subsequent episodes (12). These results substantiate the distinction between psychotic and nonpsychotic depression. According to earlier research, individuals with MDD experiencing psychotic symptoms also exhibited more severe depressive symptoms, a higher risk of suicidality, a worse course of the illness, a higher rate of relapse, a greater impairment in social function, and a worse response to depression treatment. These findings suggest that co-occurring psychotic and MDD symptoms are predictive of poor clinical outcomes (9, 13). There are significant differences in the clinical appearance, diagnosis, therapy, and prognosis of depression with and without psychotic symptoms (14). Nonetheless, psychotic symptoms in depression are often overlooked, receiving inadequate research and identification, underscoring the critical need for further investigation.

Insulin resistance (IR), also known as reduced insulin responsiveness, is a common marker of type 2 diabetes, hypertension, lipid metabolic issues, and even cardiovascular disease. Research has found that the TyG index, which was used to assess IR with 84.0% sensitivity and 45.0% specifcity, can act as a reliable and easy-to-use stand-in marker for IR (15). Compared to the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), the gold standard method to measure IR, the TyG index performed better in detecting patients with IR than the HOMA-IR index. Depression and insulin resistance-related diabetes have been linked to a number of observational studies conducted on the general population (16–18). The reciprocal association between type 2 diabetes mellitus (T2DM) and mental health disorders is consistently supported by epidemiological studies and meta-analyses (19). Depression worsens the already compromised health outcomes, amplifies micro- and macrovascular issues, and elevates death rates among individuals with T2DM. Simultaneously, T2DM has been associated with greater treatment resistance, chronicity, and the onset of more severe depressive symptoms (19). Brain regions involved in mood regulation and cognition, such as the hippocampus, amygdala, and nucleus accumbens, contain neurons and glia with insulin receptors (20). Within these areas, the intricate network of insulin signaling plays a major role in regulating neuroprotection, neurogenesis, neurotransmission, and synaptic plasticity. High body mass index (BMI) is associated with long-term psychiatric hospitalizations across an individual’s lifetime, an earlier onset of MDD, and the presence of comorbidities, according to the European Group for the Study of Resistant Depression (GSRD) (21). Moreover, emerging research suggests that patients with psychotic disorders may display varying degrees of insulin resistance in the early stages of the disorder, exhibiting greater fluctuations in glucose, insulin, and lipid parameters compared to the healthy control group (22). At this stage, cumulative effects of drugs and lifestyle factors are relatively limited. In light of these findings, researchers should promptly investigate the pathophysiology underlying this two-way connection.

In recent years, the triglyceride-glucose (TyG) index produced by adding fasting plasma glucose and triglycerides, has emerged as a novel indicator of IR (23). TyG index has been linked to depression, heart disease, and prognosis of sickness (24). For example, Shi et al. found that people with higher TyG index scores are more likely to have symptoms of depression. In addition to sadness, IR may increase the likelihood of psychotic symptoms (25). Consequently, we hypothesized that the TyG index could serve as a useful marker for detecting psychotic symptoms in MDD patients. However, to our knowledge, no study has investigated the connection between the TyG index and psychotic symptoms in MDD patients, especially in the Chinese community. Hence, this study aims to assess the association between the TyG index and psychotic symptoms in a large Chinese patient population with first-episode and drug-naive MDD (FEDN).

To our knowledge, this study marks the first investigation in China exploring the connection between psychotic symptoms and the TyG index within a reasonably large sample of individuals diagnosed with FEDN MDD. Our results demonstrate that the TyG index and psychotic symptoms are strongly correlated, even after adjusting for potential confounding variables. Moreover, there was a non-linear relationship between the TyG index and psychotic symptoms, with an inflection point of 8.42. On the right side of the inflection point, there was a significant 142% increase in the likelihood of psychotic symptoms for every unit increase in TyG index, yet no significant association was found on the left side of the inflection point. These findings shed new light on the relationship between the TyG index and psychotic symptoms in MDD patients. However, a comprehensive understanding of the underlying mechanisms necessitates further research, considering that alternative hypotheses may exist.

In our study, the prevalence of psychotic symptoms in MDD patients was found to be 9.95%, a lower prevalence compared to the range of 27 to 42% reported in most prior studies (11, 13, 31, 32), with only one indicating a prevalence of 5.3% (9). Numerous reasons could be contributing to this disparity. First, differences in psychiatric illness prevalence across studies could stem from the use of different diagnostic approaches (33). Second, the majority of the study participants in earlier investigations were long-term patients who were inpatients, outpatients, and members of the community. Of note, psychotic symptoms are more common in MDD inpatients, reaching 42% in a most recent study (11), compared to 14 to 20% in MDD outpatients (10, 31). Third, our study focused on individuals experiencing their first episode without prior drug usage. It is conceivable that as MDD progresses, certain patients may experience psychotic symptoms during their illness, resulting in a higher prevalence of MDD in chronic patients. Lastly, factors such as sample size, age, ethnicity, and gender ratio might also impact prevalence rates. Psychiatric symptoms are among the most prevalent symptoms in MDD patients, and while previous studies in various populations have shown varying prevalence of psychiatric symptoms, nearly all of them have shown that psychiatric symptoms require special attention in their management and treatment.

Clinically, insulin resistance refers to the inability of a known amount of endogenous or exogenous insulin to raise an individual’s absorption and utilization of glucose to the same extent as it does in the normal population (34). In our study, the TyG index, an indicator of insulin resistance, showed a positive correlation with psychotic symptoms, a correlation that persisted even after considering relevant confounding factors. In addition to being frequently connected to blood glucose problems in depressed individuals, IR has been related to psychotic symptoms. For example, a cross-sectional study conducted in South Korea involving over 160,000 participants discovered that IR was associated with a higher risk of depression, showing a 17 and 4% rise in incidence among young adults and non-diabetics, respectively (35). Moreover, it has been demonstrated that suicidal conduct in depression is associated with alterations in glucose metabolism and insulin resistance (36). Few studies have investigated the relationships between psychotic symptoms, insulin resistance, glucose levels, and depression. However, prior research indicates that dysthymia and recurrent or psychotic depression are related to higher glucose levels and higher HbA1c concentrations, respectively (37). Furthermore, interventions aimed at addressing depressive symptoms in adults with T2DM and/or significant depression have demonstrated improvements in indicators of insulin resistance or glucose impairment in adults, even without changes in body weight or adiposity (38).

The interaction between dyslipidemia and depression, leading to mental symptoms, primarily occurs through the inflammatory system. Multiple inflammatory cytokines have been robustly demonstrated to be positively correlated with depression and schizophrenia (39). Specifically, young adults with elevated IL-6 levels during childhood exhibit a higher likelihood of experiencing psychotic symptoms, while adolescents with increased C-reactive protein (CRP) levels tend to display subclinical psychotic symptoms (40). The trans-diagnostic impact of inflammation might be attributed to the correlation between CRP and symptoms that are common to both mood and psychotic illnesses, such as auditory hallucinations and anhedonia (40). Additionally, there was a positive correlation found between inflammatory markers (hs-CRP, MCP-1, TNF-alpha, and PAI-1 levels), lipid profiles (LDL-c, TG, and TC levels), and insulin resistance (fasting glucose level, fasting insulin level, and HOMA-IR) (41). These interactions may potentially exacerbate psychotic symptoms in MDD patients. Moreover, brain anatomy can be impacted by blood lipids, as higher TC levels cause a reduction in hippocampal volume (42). Of note, a recent study found that patients with bipolar disorder and higher levels of lipids displayed smaller brain structures than healthy controls (42). Additionally, it has been observed that compared to patients with less severe depression, those with psychotic depression had decreased hippocampus sizes (43). Consequently, the development of psychotic symptoms could potentially be mediated by TC-induced alterations in brain volume. In our study, statistical significance between the TyG index and psychotic symptoms in MDD was only found when TyG index was higher than 8.42, suggesting a threshold effect. Other recent research also disclosed a threshold impact with a turning point value of 9.29 between the TyG index and suicide attempts in MDD patients (44). While the threshold inflection points differ between these studies, they collectively indicate that exceeding the TyG index threshold significantly increases the risk of psychiatric symptoms and suicide attempts. As mentioned above, prior research has established links between psychiatric symptoms and inflammatory cytokines, which in turn are associated with lipid profiles. In turn, these lipid profiles have been correlated with brain anatomical anomalies. With the confirmed positive correlation between the TyG index and psychiatric symptoms, as shown in this study, it becomes crucial to comprehensively understand the intricate interplay among these factors to unravel the underlying pathological mechanisms.

The prevalence of MDD and conditions associated with IR, such as obesity, T2DM, and metabolic syndrome, is rapidly escalating and stands as the primary cause of disability in the world (45). Multiple epidemiological studies have demonstrated that individuals with MDD have an increased risk of IR-related disorders, with up to a 4-fold increased risk of MDD in those affected by T2DM and obesity (45). Additionally, a reduction in life expectancy of 10 to 20 years has been connected to MDD (46), where somatic disorders related to IR could be a contributing factor. Moreover, IR-related comorbidities in MDD have been linked to greater depression intensity, chronicity, and less favorable treatment outcomes (47, 48). The coexistence of depression in T2DM patients escalates mortality risk by 54%. In addition to environmental risk factors, genomic research has revealed a polygenic risk that is shared by disorders connected to IR and MDD, implying overlapping etiopathological pathways (49). Of note, dysregulations of immunological inflammation, gut microbiota, brain insulin signaling, and the hypothalamic-pituitary-adrenal axis are among the hypothesized common causes (50). Specifically, insulin signaling influences neurotransmission, synaptic plasticity, neuroprotection, and neurogenesis, with its receptors expressed in both neurons and glia in brain regions related to mood regulation and cognition, including the hippocampus, amygdala, and nucleus accumbens (20). Indeed, an altered brain insulin signaling has been described to impact the dopaminergic mesolimbic circuit (51), a significant pathway in the limbic system where dopamine acts as a major neurotransmitter. In addition, insulin levels were found to influence dopamine and other crucial neurotransmitters related to the phenomenology and management of major depressive disorder (52). For instance, insulin-resistant animal models show increased dopamine concentration in limbic and striatal regions, indicating a potential role for insulin resistance in the initiation or maintenance of psychotic symptoms through the enhancement of mesolimbic dopaminergic transmission (53).

Nonetheless, there has been some evidence that certain antidepressant and antidiabetic medications can improve insulin sensitivity measures or alleviate depressive symptoms. Particularly, selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, have been shown in short-term studies to improve glycemic control in individuals with comorbid MDD and T2DM, with no negative long-term effects on glycemic homeostasis (50). Due to these positive effects, SSRIs are typically regarded as first-line treatments for those with concomitant IR. In humans, the norepinephrine-dopamine reuptake inhibitor bupropion induces weight loss by modifying the mesolimbic reward circuit. In rats subjected to a high-fat diet, bupropion improved insulin sensitivity and glycolipid indicators (54). Consequently, bupropion might be especially intriguing for people with comorbid MDD and IR. In contrast, monoamine oxidase inhibitors and tricyclic antidepressants cause weight gain and upset glycemic homeostasis, making them less suitable for patients with IR (55). Furthermore, several oral hypoglycemic agents including biguanides (e.g., metformin), peroxisome proliferator-activated receptor-γ (PPAR- γ) agonists (e.g., rosiglitazone, pioglitazone), and glucagon-like peptide 1 receptor agonists (GLP1RA; e.g., liraglutide) have been tested as potential adjunctive therapies for depression (56). Specifically, metformin was shown to not be more effective than controls in reducing depressive symptomatology in a recent meta-analysis (57).

To lower the population’s risk of IR and, consequently, the chance of depression and cardio-metabolic disorders, clinicians must work to promote healthier lifestyles. Physical exercise could help mitigate IR and constitutes an effective depression therapy (58). Adopting a Mediterranean diet has shown protective effects against insulin resistance and the onset of depression while alleviating depressive symptoms and enhancing cognitive function in individuals with T2DM (59). Furthermore, prebiotics play a role in supporting cognitive and antidepressant effects, as well as improving insulin sensitivity by maintaining the homeostasis of the gut microbiota (60, 61). Therefore, implementing more tolerable and tailored treatment approaches alongside promoting healthier lifestyles can serve as vital prevention interventions. Given their significant impact, physicians should prioritize these interventions to effectively reduce potential risk factors associated with both IR-related conditions and psychiatric multimorbidity.

The present investigation offers several advantages. Firstly, it eliminates the impact of confounding variables such as disease duration, lifestyle modifications, medication, and concomitant medical problems by focusing on a research group of individuals with FEDN MDD. Secondly, multivariable logistic regression analysis and smoothing plots enable exploration of both linear and nonlinear relationships between the TyG index and psychotic symptoms. However, certain limitations warrant attention. Namely, the cross-sectional nature of this study precludes it from establishing causation. Thus, employing longitudinal methods in future investigations can better explore the causal relationship between the TyG index and psychotic symptoms in MDD patients. Second, the study’s exclusive focus on Han Chinese patients recruited from a general hospital’s mental outpatient department in Taiyuan (Shanxi Province, China) emphasizes the need to validate the present findings in individuals with different clinical backgrounds and ethnicities. Third, the inclusion of MDD patients who had not sought previous therapy for their depressed symptoms and were experiencing their first episode does not exclude those whose diagnosis later shifted to bipolar disorder. Fourth, as the study focused on individuals with severe MDD (HAMA mean > 20, 17-item HAMD scores ≥ 24), its findings might not apply to individuals with milder pathology. Fifth, the HOMA-IR, or revised quantitative insulin sensitivity check index (QUICKI), is the most widely used surrogate measure of insulin resistance. It is calculated using fasting insulin and glucose measurements. Unfortunately, relevant indicators were not assessed in this study. Lastly, a variety of confounding factors, such as diet, physical activity, drinking, smoking, personality traits, family income, social standing, and biological factors, were not investigated and could have a significant impact on the relationship between the TyG index and psychotic symptoms. Future studies should include a wider array of confounding variables to better understand the pathophysiological mechanisms behind the association between the TyG index and psychotic symptoms in people with MDD.

In conclusion, our study identified a nonlinear relationship between the TyG index and psychotic symptoms in Chinese patients with FEDN MDD, with an inflection point at approximately 8.42. Notably, we observed that psychotic symptoms were positively correlated with TyG index on the right side of this inflection point, while no significant correlation surfaced on the left side. Specifically, there was a considerable 142% rise in the probability of experiencing psychotic symptoms with each incremental elevation in the TyG index. Due to the cross-sectional methodology, limited understanding of the underlying mechanisms, and other study limitations, these results constitute a valuable preliminary report. Subsequent research employing a longitudinal design and structured evaluation tools is imperative to fully validate these findings, enhance our understanding of this correlation, and offer valuable insights into potential therapeutic strategies.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by the Institutional Review Board of the First Hospital, Shanxi Medical University (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.

JL: Investigation, Methodology, Writing – original draft. YW: Investigation, Writing – original draft. WM: Investigation, Writing – review & editing. LY: Formal Analysis, Investigation, Writing – original draft. RT: Investigation, Methodology, Writing – original draft. ZLu: Conceptualization, Data curation, Investigation, Writing – original draft. HY: Investigation, Writing – original draft. FJ: Investigation, Methodology, Software, Writing – original draft. XBZ: Validation, Writing – review & editing. ZLi: Funding acquisition, Resources, Validation, Writing – original draft. WY: Funding acquisition, Investigation, Visualization, Writing – original draft. XD: Supervision, Validation, Writing – review & editing. XYZ: Supervision, Validation, Writing – review & editing.