The purinergic system is involved in neurodevelopment and pathophysiological processes of psychotic disorders, such as the process of genesis, differentiation on neurocyte and inflammation of neuro-glial cell, and so on [21–24]. Purinergic receptors can be divided into P1 and P2 receptors according to their biochemical and pharmacological properties [25]. P1 receptors can regular plasticity of synapse and the release of neurotransmitters [23, 24, 26, 27], while P2 receptors are closely related to embryonic neural development [28]. The dysfunction of the purinergic system result from any causes may lead to psychotic disorders. UA, as the end product of the purinergic system, is in connection with some physiological functions, including sleep, motor, cognitive function, appetite, and social activities, as well as the pathophysiology of mood disorders [6, 12]. Additionally, UA is also related to specific traits, including driving and disinhibition, which is very common in BD. It is also noticed that the peripheral UA levels are consistent with that in the central nervous system [29, 30].
In the study, UA levels in the BD group were higher than UD and HC groups, whether in AS or RS, which suggested that UA levels may be a potential biomarker to distinguish between BD and UD. Nevertheless, a recent study indicated that UA levels in UD were lower than HC; a possible reason was the heterogeneity of subjects in the UD group because the UA diagnosis is only based on clinical symptoms at present while some patients with BD often begin with depression. It was further confirmed by a recent study that the higher UA levels might be a predictor of BD [31]. The previous study showed that sex was an important factor that could affect UA levels [19], but the study analyzed separately by sex and got similar results. Beyond that, UA is also a selective antioxidant whose level is considered as a marker of oxidative stress, and results in this study indicated that patients with BD might have a higher oxidative stress level. Moreover, the study divided acute patients with BD into BD-M and BD-D subgroups, with results showing that differences of UA levels between BD-M subgroup and BD-D subgroup were not significant, and UA levels of both subgroups were higher than UD group. When analyzed stratified by sex, significant differences in UA levels between male patients of BD-M and BD-D subgroups were spotted, but the differences were not significant in female patients, which suggested that male patients might be more susceptible to different stages of illness.
In order to detect the effects of treatment on UA levels, the study divided the acute patients into drug-use and drug-naïve/free subgroups. It was observed that UA levels of the drug-use subgroup were higher than drug-naïve/free subgroup only in the UD group, and the differences were not significant when analyzing stratified by sex, which suggested that UA might be a steady biomarker to distinguish BD and UD. Moreover, UA levels in male patients of the BD-M subgroup were higher than the BD-D subgroup, whether in drug-use or drug-naïve/free subgroup, and the differences in female patients were not significant, which confirmed that male patients might be more susceptible to different stages of illness.
There are a few limitations to this study. Firstly, the study did not collect full demographic and clinical data, such as attack times, previous medication use, and so on. More else, diet is also an affecting factor to UA levels, but this study did not strictly control the diet. Secondly, biochemical indicators, like hepatorenal function and indexes of glycometabolism and lipometabolism, were not collected. Mediation analysis indicated that metabolic syndrome, triglyceride, and abdominal perimeter could affect UA levels, although it could not fully explain the correlation between UA and BD [8]. Thirdly, we did not evaluate the severity of the disease. A previous study showed that UA levels were positively correlated with the severity of mania [9], but recent studies indicated that there was no significant correlation between UA and severity of mania [18, 32], which is calling for more strictly designed prospective studies to explore the relation between UA and severity of the disease. Finally, although the study divided acute patients into drug-use and drug-naïve/free subgroup, the effect of different kinds of mood stabilizers on UA levels are diverse, such as lithium [33] and carbamazepine may decrease UA levels of BD patients, while valproates seemly have the opposite effect [34], and the effect of antidepressants, physiotherapeutic and psychotherapy on UA levels were not yet discussed due to restriction of the retrospective study.