This study identified the metabolic pathways associated with BD (NSSI) and assessed the important diagnostic and predictive indices of NSSI in BD. To the best of our knowledge, this is the first study to identify the differential metabolites of BD (NSSI) and BD (non-NSSI).
NSSI is a characteristic manifestation of BD. The highest rates of NSSI are observed during adolescence; due to its rapidly increasing prevalence, NSSI requires more clinical attention (26). In a previous study, 5.1% to 24% of people who inflict self-injury reported that they had initiated this behavior before age 11–13 years (27). In this study, we observed that the onset age of patients in the BD (NSSI) group was lower than that of those in the BD (non-NSSI) group, which is consistent with previous results. Cutting, scratching, burning, hitting, and biting are some of the most commonly used methods of inflicting NSSI. Most self-injurers cut themselves using a sharp object, such as a knife or blade, mainly on the forearms, legs, and/or abdomen(28), which was consistent with our research. In a previous study, a multivariate regression analysis revealed that young age, unemployment, a higher monthly family income, single status, impulsivity, long duration of illness, and life stressors were risk factors for NSSI in patients with depression and BD (29). In addition, adverse family life events may expose an individual to a greater degree of stress throughout their lifespan and may serve as triggers for NSSI. Studies confirmed that life stressors and adverse interpersonal experiences are associated with an increased risk of NSSI (30, 31) , which is consistent with the present result. In the present study, we also found that sleep problems were most common in the BD (NSSI) group than in the BD (non-NSSI) group or healthy group. Previous research suggests that multiple sleep variables, including poor sleep quality and frequent nightmares, are associated with and are independent risk factors for NSSI(32, 33) . Therefore, we suspect that interventions that improve sleep quality and sleep duration or reduce life stress may concomitantly decrease the risk of NSSI.
A series of studies of BD demonstrated abnormalities of energy metabolism in patients with BD(34). Several studies have confirmed that lipid metabolic disorders or abnormalities is concerned with neuropsychiatric disorders, such as BD, schizophrenia, and major depressive disorder. Previous studies confirm that there is a high prevalence of elevated triglycerides, cholesterol, low-density lipoprotein, and glucose levels and low high-density lipoprotein (HDL) level in patients with BD(35). In this study, we found that HDL is a common differential metabolite in the BD (NSSI) and BD (non-NSSI) groups, which suggested the importance of lipid metabolism in BD, that is consistent with previous studies (35, 36). Results showed that sphingolipids and glycerolipids were increased, whereas glycerophospholipids were decreased, in serum samples from patients with BD. Moreover, studies also showed that elevated lipid level is associated with smaller brain structures in patients with BD(37). Future research is needed to verify the changes in the HDL levels of BD patients compared with those of healthy individuals and the specific mechanisms of lipid changes in the pathogenesis of BD.
The results of the present study indicate that 3-hydroxybutyric acid, pyruvic acid, oxidized glutathione, glyceryl, citrulline, creatinine, and β-glucose are characteristic markers of bipolar NSSI. Patients in the BD (NSSI) group showed higher lipid, 3-hydroxybutyric acid, pyruvic acid, citrulline, and creatinine levels and lower oxidized glutathione, glyceryl, and β-glucose levels than the healthy controls. Kamonwad et al. reported that patients with BD have increased salivary levels of glutathione and oxidized glutathione compared to controls (38). Rosa et al. (39) documented decreased levels of glutathione and increased levels of glutathione disulfide in the plasma of patients with BD. Previous studies have also revealed higher serum levels of pyruvate and N-acetyl glutamate in patients with BD than in healthy controls (34, 40), which is consistent with the findings of this study. However, previous studies have insufficiently focused on correlation between the abovementioned metabolites and NSSI in patients with BD.
This study showed that the urea cycle and the glutamate metabolism pathway are significant metabolic pathways in BD (NSSI). The urea cycle is a metabolic pathway for the disposal of excess nitrogen, which primarily starts from the removal of ammonia from the blood. For the urea cycle, also known as the ornithine cycle, when amino acids are metabolized in the body, ammonia is produced and subsequently synthesized into urea through. Studies have suggested that an abnormality in the urea cycle (or arginine metabolism) is associated with BD (41, 42). The results of this study indicated that an abnormal urea cycle is associated with BD (NSSI). Lan et al. (43) reported that glutamate levels are increased in the post-mortem brains of patients with BD. This is consistent with the results of the BD (NSSI) group in the present study. Glutamate is the most abundant excitatory neurotransmitter in the mammalian brain; glutamate metabolism is involved in the synthesis of gamma-aminobutyric acid (GABA), and abnormalities in the GABAergic system contribute to the pathophysiology of mood disorders(44). As such, changes in glutamate neurotransmission may be involved in the etiology of BD. Xu et al. reported that state-related abnormalities in oxidative and glutamate metabolism are associated with BD(45). Increasing evidence suggests that changes in inflammatory mediators are involved in the pathogenesis of mood disorders(46, 47). Meanwhile, studies have demonstrated links between alterations in inflammation and glutamate metabolism in mood disorders(48, 49). This indicates that inflammatory mediators, glutamate metabolism and oxidative stress are closely related to the pathogenesis of BD(NSSI). Thus, therapeutic strategies targeting amino acid metabolism such as glutamate may be effective in patients with BD (NSSI), and increased inflammation as reflected in C-reactive protein levels may be helpful in the diagnosis of BD (NSSI).
In clinical practice, identifying specific diagnostic markers of NSSI in patients with BD will provide a strong basis for the recognition and treatment of NSSI. Thus, we also compared the metabolic differences between BD (NSSI) and BD (non-NSSI) groups. Five endogenous differential metabolites, including xanthine, niacinamide, adenosine, hypoxanthine, and histidine, were significantly higher in the BD (NSSI) group than in the BD (non-NSSI) group. Adenosine, a purine nucleoside, may contribute to the pathophysiology of mental disease by interacting with dopamine and glutamate receptors through A1 and A2A receptors; thus, modulating dopaminergic and glutamatergic neurotransmission (50, 51). Zhang et al. reported that levels of the purines guanine and guanosine are decreased in the brains of patients with BD (52). However, assessments of changes in purine and adenosine metabolism levels are lacking. This study shows that the important metabolic pathways associated with BD (NSSI) are the purine and methylhistidine metabolism pathways. The purinergic system is a critical neurotransmitter system with uric acid (UA) as its end-product. Recent studies have shown that the patients with BD have the highest UA levels among healthy controls and those with other mental disorders (53, 54) , which is involved in the occurrence and development of mental illnesses such as BD and MDD(55, 56) . A series of studies have demonstrated a direct association between UA levels and associated purinergic dysfunction. The purinergic system is involved in the neurodevelopment and pathophysiological processes of psychotic disorders, such as the genesis, differentiation of neurocytes and inflammation of neuroglial cells (57-59). Growing evidence suggests that oxidative stress and the purine/adenosine system play key roles in the development and progression of mental diseases, such as BD(60, 61). We suggest that NSSI in patients with BD is related to an increase in oxidative stress levels. Post-mortem and imaging studies showed an increasingly complex interaction between the mitochondrial, purinergic, and oxidative systems, which are associated with psychiatric disorders(62). These results suggest that an increase in purinergic-UA metabolism and oxidative stress levels may be a significant mechanism underpinning BD (NSSI), which may be related to mitochondrial dysfunction.
It has been hypothesized that gout and BD may share similar pathophysiological mechanisms, such as purinergic dysfunction. Previous research has shown that patients with BD have an increased risk of gout (63, 64). We observed increased purine synthesis in the BD (NSSI) group in this study, indicating that the incidence of gout was higher in patients with BD (NSSI). This suggests that purine-UA metabolism is a potential therapeutic target in the treatment of BD (NSSI). As xanthine and hypoxanthine levels are elevated in BD (NSSI), allopurinol, an inhibitor of xanthine oxidase, is used to treat and prevent gout. Allopurinol and febuxostat(65), two potent inhibitors of UA accumulation, have demonstrated antimanic and antidepressant effects in clinical and preclinical studies, and may be used as add-on therapy for BD (NSSI) to reduce rates of self-injury. Tomoya et al. suggested that adenosine modulator adjuvant therapy is more beneficial than a placebo in treating manic episodes of BD (66). As adenosine levels were altered in this study, we suspect that adenosine modulator adjuvant therapy may be effective for BD (NSSI). These drugs can be used as potential therapeutic options for patients with BD (NSSI).
In this study, purine and amino acid metabolism were found to be altered in patients with BD (NSSI) compared to that in healthy controls, which is consistent with the findings of a previous study(67). As the final metabolite of purine, UA acts on neurons presynaptically and postsynaptically, and on specific receptors in the glial cell membrane that can affect activities of other neurotransmitters involved in the pathophysiological process of mood disorders, including dopamine, GABA, glutamate, and serotonin(68). It has been suggested that purinergic-UA metabolism is associated with glutamate metabolism, further affecting oxidative stress and is involved in the pathogenesis of NSSI, all of which are related to mitochondrial dysfunction(69-71). This provides important evidence for the diagnosis and treatment of BD (NSSI). These findings provide a basis for further research on the pathogenesis of NSSI, and are highly significant with regard to the diagnosis, recognition, and treatment of NSSI.
This study has some limitations. First, we did not control for the effects of psychotropic medications, which may affect plasma metabolite profiling. Second, the sample size was limited. Adequately powered studies are warranted in the future to confirm our preliminary conclusions. Third, although we controlled for main clinical characteristics, blood metabolites may be influenced by additional factors that we did not consider, including cardiovascular health and dietary patterns.