The principal finding of this study was that serum UA levels among MDD subjects with suicide risk were significantly lower than those in patients without suicide risk, indicating decreased function of the purinergic system-in comparison with MDD patients without suicide risk. It could be inferred that serum UA levels in the CNS of those patients with suicide risk were also reduced, since there was a positive linear correlation between peripheral and central UA levels (Bowman et al. 2010). In this study, we also found that being unmarried was a risk factor for suicide, consistent with the results of previous studies in the general population (Xu et al. 2015).
To the best of our knowledge, this study is first to assess the association between the concentration of serum UA and suicide risk in drug-naïve patients with MDD. Of note, the sample of our comparative cross-sectional study consisted of only female subjects and included an appropriate group of depressive patients without suicide risk and healthy individuals. Moreover, several potential confounders, such as variables associated with metabolism and renal function, were taken into account. Our results were in general agreement with previous research that revealed an inverse relationship between UA levels and suicidal ideation severity in patients with major affective disorders (Bartoli et al. 2018c; Bartoli et al. 2018d). In addition, a decrease in the output of UA was also found in the urine of nonchemical suicide victims, although only 12 patients were included (Lis et al. 1975). Based on the available data, we speculate from our results that UA levels might act as a candidate biological marker to discriminate MDD patients with and without suicide risk.
Several hypotheses were proposed to explain the biological mechanism by which low UA levels may influence suicide risk, although the mechanism is far from clear. The first theory is related to the antioxidant properties of UA. Low UA levels lead to the overproduction of free radicals which in turn may cause oxidative damage to brain neuron integrity and function. In fact, oxidative stress is a notorious major underlying mechanism responsible for suicide independent of the effects of depression and classical risk factors, such as marital status (Vargas et al. 2013). Second, low UA levels imply that other purine metabolism may also be dysregulated, which might contribute to suicide risk. Adenosine, a purine cycle nucleoside, is an important endogenous inhibitory neuromodulator. The activation of adenosine A1 receptors inhibits neurotransmitter release such as glutamate release and suppresses the production of pro-inflammatory cytokines (Krugel 2016; Lorenzi et al. 2010). Therefore, UA may play an important role in neuroregeneration and neuroprotection (Krugel 2016), while neurodegeneration and neuroplasticity have been suggested as part of the neurobiology of suicide (Krugel 2016; Underwood and Arango 2011).
Over the past few years, decreased UA levels have been reported in individuals with current, but not remitted, MDD of both sexes and could be reversed after treatment with certain antidepressant drugs (Bartoli et al. 2017; Black et al. 2018; Chaudhari et al. 2010; Wen et al. 2012). Moreover, UA levels in patients presenting MDD were also significantly lower than those in patients presenting other mental disorders such as dementia, substance-related disorders, schizophrenia and bipolar disorder (Kesebir et al. 2014; Wen et al. 2012). In contrast, some similar research did not replicate these findings (Kotan et al. 2011; Sarandol et al. 2007; Wiener et al. 2014), even yielding opposite results (Tao and Li 2015). Notably, the present study showed that serum UA levels significantly decreased in only MDD patients with suicide risk, and not in those without suicide risk. More recent evidence indicates that UA levels have a strong negative association with the severity of depressive symptoms (Black et al. 2018; Gu et al. 2015), while depression severity is one of most important risk factors for suicide (Capuzzi et al. 2018; Wang et al. 2015).
Thus, we speculated that the inconsistency with previous research might be related to serum UA levels specifically decreasing due to severe MMD. Another possible explanation for the discrepancy is the high heterogeneity between studies, especially between the sample demographics and clinical characteristics, such as age and BMI, which can significantly influence UA levels.
Several limitations of the present study are worth mentioning. First, in this cross-sectional study with a relatively small number of female subjects, clinical subtypes of MDD (such as psychotic, atypical or melancholic features and seasonal onset) were not considered- all of which may limit the generalization of findings. Our results need replication in a larger sample study with additional confounding factors considered and both male and female patients included. Second, although unified dietary patterns were provided in inpatients and healthy individuals were advised to consume a light diet the whole day before blood samples were drawn, the amount and type of dietary were possibly different among the groups. Third, any altered metabolic activity of purinergic system may be linked with abnormal UA levels, and we did not evaluate the levels of more purine metabolites, such as adenosine inosine, xanthine, and hypoxanthine. Fourth, it has been shown that impulsivity, i.e., one of the main clinical correlates of suicide, may have a positive association with serum UA (Sutin et al. 2014). However, we did not consider impulsivity levels in our study. Last, menstrual and premenopausal hormones affect UA levels, for example, after menopause and at the time of onset of menstruation, the concentration of uric acid in the plasma increases (Bartoli et al. 2018a). In our study, the effects of female menstrual and premenopausal hormones on UA levels were not considered.
In conclusion, our study provides preliminary evidence of dysregulation of the purine cycle manifested as decreased levels of serum UA in MDD patients with suicide risk compared with those without suicide risk. Our results indicate that the purinergic imbalance might act as a characteristic biological marker of suicide risk in MDD patients, which might increase the better understanding of the physiological mechanisms of suicide and offer a potential target for effective therapeutic interventions and early preventions.